ROMANIAN JOURNAL OF INTERNAL MEDICINE

Transcription

ROMANIAN JOURNAL
OF
INTERNAL MEDICINE
Volume 48
No. 4, 2010
CONTENTS
REVIEWS
CARMEN GINGHINĂ, RALUCA MIHALACHE, B.A. POPESCU, RUXANDRA JURCUŢ, Restrictive cardiomyopathy –
an outdated concept? ........................................................................................................................................................
GIANINA MICU, FLORICA STĂNICEANU, SABINA ZURAC, ALEXANDRA BASTIAN, ELIZA GRĂMADĂ, LUCIANA
NICHITA, CRISTIANA POPP, LIANA STICLARU, R. ANDREI, C. SOCOLIUC, Carcinogenesis and infection
with Helicobacter pylori ..................................................................................................................................................
MIHAELA BÎCU, MARIA MOŢA, N.M. PANDURU, CORINA GRĂUNŢEANU, E. MOŢA, Oxidative stress in diabetic
kidney disease ..................................................................................................................................................................
CORINA GRĂUNŢEANU, E. MOŢA, MARIA MOŢA, N.M. PANDURU, MIHAELA BÎCU, IULIA VLADU, Cardiovascular
risk in patients with diabetic kidney disease......................................................................................................................
293
299
307
313
ORIGINAL ARTICLES
LAURA POANTĂ, ANCA CERGHIZAN, DANA POP, Blood pressure pattern and heart rate variability in normotensive
patients with type 2 diabetes mellitus................................................................................................................................
VIOLETA ŞAPIRA, INIMIOARA MIHAELA COJOCARU, GABRIELA LILIOS, M. GRIGORIAN, M. COJOCARU,
Study of endothelin-1 in acute ischemic stroke .................................................................................................................
ALEXANDRINA LIZICA DUMITRESCU, CARMEN TOMA, VIORICA LASCU, Relationship of humour with oral health
status and behaviours ........................................................................................................................................................
M. POROJAN, SIMONA COSTIN, LAURA POANTĂ, ANCA CERGHIZAN, DANA POP, D.L. DUMITRAŞCU, Autonomic
neuropathy and plasma catecholamine in patients with diabetes mellitus .........................................................................
321
329
333
341
CASE REPORTS
DENISE CARMEN MIHAELA ZAHIU, M.RIMBAŞ, ADRIANA NICOLAU, SABINA ZURAC, M.R. VOIOSU,
Ankylosing spondylitis or Crohn’s disease? Case report and review of the literature......................................................
LUCIA AGOŞTON-COLDEA, L.C. MOCAN, TEODORA MOCAN, SILVIA LUPU, Right renal artery occlusion as a
complication of fibromuscular dysplasia...........................................................................................................................
347
355
POINTS OF VIEW
H. BĂLAN, At the dawn of a new era in treating angina pectoris, or just another antianginal drug? Some considerations
about ranolazine ................................................................................................................................................................
I.B. IAMNADESCU, LILIANA DIACONESCU, Stress vulnerability in patients with drug allergy. Psychological aspects
revealed from some personal studies.................................................................................................................................
ALEXANDRA BASTIAN, H.H. GOEBEL, Protein aggregation in inclusion body myositis, a sporadic form among protein
aggregate myopathies, and in myofibrillar myopathies. A comparative study ..................................................................
ROM. J. INTERN. MED., 2010, 48, 4, 291–385
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Carmen Ginghină et al.
REVIEWS
Restrictive Cardiomyopathy – an Outdated Concept?
CARMEN GINGHINĂ1,2, RALUCA MIHALACHE2, B.A. POPESCU1,2, RUXANDRA JURCUŢ1,2
1
Department of Cardiology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Department of Cardiology, “Prof. Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases, Bucharest, Romania
2
Restrictive cardiomyopathy is probably the least common of all cardiomyopathies, with a
nonspecific clinical presentation and a frequently unknown cause. The concept of RCM has changed
tremendously over time. Today it includes a large panel of disorders characterized by a nonhypertrophied, non-dilated cardiac phenotype and a restrictive ventricular filling pattern. Several
unsuccessful attempts to define and classify cardiomyopathies have been made, but they all proved
problematic due to the contradiction in terms and the overlap between classical patterns. Advances in
disease pathology, genomics and molecular biology are emerging as the framework of a new
revolutionary classification system, focused on the dynamic interaction between genotype and
phenotype. In this context, RCM is evolving as a self-contained hemodynamic and pathophysiological
concept, although questionable due to its uncertain practical utility.
Key words: restrictive cardiomyopathy, restrictive ventricular filling pattern.
DEFINITION AND CLASSIFICATION
Owing to the increasing number of pathologies
that are associated with a restrictive ventricular
filling pattern, the definition of restrictive cardiomyopathy (RCM) has always been a challenging
matter. Often, RCM is defined as an abnormal
diastolic ventricular function in which increased
stiffness of the myocardium causes precipitous rises
in ventricular pressure with only small increases in
volume. Restrictive ventricular physiology occurs
in the presence of normal or reduced diastolic
volumes (with single or biventricular involvement),
normal or reduced systolic volumes and normal or
increased ventricular wall thickness. Systolic function
is characteristically preserved, but not entirely
normal [1].
Finding the official place of RCM in the
spectrum of cardiovascular pathology proves to be
a difficult task, especially because of the spectacular
transformations undergone by the concept and the
classification system of cardiomyopathies in general
and of RCM in particular.
In the 1980 report of the WHO/ISFC task
force, RCM was acknowledged as one of the three
major cardiomyopathies (defined as “heart muscle
diseases of unknown cause” in order to differentiate
them from specific heart muscle diseases, of known
cause). Back then, RCM was divided into two
separate forms: with or without obliteration, including
endomyocardial fibrosis and Löffler cardiomyopathy.
Many of the entities that today are recognized as
ROM. J. INTERN. MED., 2010, 48, 4, 293–298
part of the RCM pattern (e.g. metabolic disorders,
infiltrative and familial storage diseases, muscular
dystrophies, etc.) [2] were known as specific heart
muscle diseases.
Fifteen years later, cardiomyopathies were
redefined as diseases of the myocardium associated
with cardiac dysfunction, five types of cardiomyopathies being described, according to the dominant
pathophysiology or to the etiological and pathogenetic factors. Still, the classification introduced
the term specific cardiomyopathies in order to
designate heart muscle diseases associated with
specific cardiac or systemic disorders, previously
known as specific heart muscle diseases [3].
Over the years, in accordance with the rapid
evolution of molecular genetics in cardiology and
dramatic advances in diagnosis and knowledge of
causation, many disease definitions have become
outdated and several other classification frameworks
emerged. Thus, in 2006 the American Heart
Association expert consensus panel introduced a
new genomic and molecular oriented classification
system intended to facilitate the interactions among
the clinical and research communities. According
to the broad definition, cardiomyopathies are
associated with failure of myocardial performance,
which may be mechanical (diastolic or systolic
dysfunction) or a primary electrical disease prone
to life-threatening arrhythmias. For the first time,
recently described ion channelopathies were de-
294
signated as primary cardiomyopathies, despite the
fact that there are no macroscopic abnormalities
identifiable by either conventional imaging or
myocardial biopsy. The panel recommends that
cardiomyopathies can be most effectively classified
as primary (solely or predominantly confined to heart
muscle): genetic, mixed (genetic and non-genetic),
acquired; and secondary (myocardial involvement
as part of a large number and variety of generalized
systemic disorders). The classification distinguishes
between the primary restrictive non-hypertrophied
cardiomyopathy as a primary mixed cardiomyopathy
and secondary cardiomyopathies that may share a
restrictive phenotype (infiltrative, storage, endomyocardial, inflammatory, craniofacial, neuromuscular,
toxic disorders, etc.) [4].
More recently, the 2008 European Society of
Cardiology position statement regarding the classifycation of cardiomyopathies supported the use of a
clinically oriented classification system according
to ventricular morphology and function. Each of
the five phenotypes of cardiomyopathies are subclassified into familial and non-familial forms in
order to raise awareness of the genetic causes of
heart muscle dysfunction and to offer a pertinent
framework for further investigations. According to
the new classification system, RCM may be either
familial (predominantly associated with autosomal
dominant inheritance, e.g. troponin I or desmin
mutations, or rarely with autosomal recessive or Xlinked inheritance) or non-familial (e.g. amyloidosis,
scleroderma, endomyocardial fibrosis, carcinoid
heart disease, etc.) [1].
However, an inevitable limitation of any
classification is the considerable overlap encountered
between categories into which diseases have been
segregated. The traditional classification of “hypertrophic-dilated-restrictive cardiomyopathies” has
major limitations, leading to confusion by mixing
anatomic designations (ie hypertrophic and dilated)
with a functional one (i.e. restrictive) [4]. While
distinct types of cardiomyopathies may share the
same anatomy and type of ventricular filling pattern,
other entities may segregate as distinct phenotypes.
For example, hypertrophic cardiomyopathy (HCM)
and infiltrative and storage cardiomyopathies are
both characterized by often substantially increased
left ventricular wall thickness, in the absence of
ventricular dilatation, and by restriction to diastolic
filling [4]. At the same time, there are several case
reports that emphasize the overlap between the
restrictive and the hypertrophic pattern in patients
with Noonan syndrome [5]. Up to 20% of patients
with Noonan syndrome have a cardiomyopathy
2
with clinical, echocardiographic, hemodynamic and
histopathological features indistinguishable from
the cardiac phenotype of HCM, while others display
a restrictive pattern [6]. Although myocyte hypertrophy is found in both conditions, RCM is not
associated with macroscopic hypertrophy or histological myocyte disarray [7]. Similarly, Watson or
Leopard syndrome, certain troponin I mutations,
Fabry disease, etc. may share either of the two
patterns. It is expected that genetic insights into
these disorders will soon offer a plausible explanation
of the genotype–phenotype interaction. Furthermore,
some diseases have a dynamic expression, progressing, through continuous remodeling, from one
pattern to another during their natural clinical
course. HCM, amyloidosis and other infiltrative
conditions may evolve from a nondilated (often
hyperdynamic) state with ventricular stiffness to a
dilated form with systolic dysfunction and failure.
As new cardiomyopathies are being defined by
means of genomics and proteomics and understanding of pathophysiology is evolving, the dilatedhypertrophic-restrictive classification pattern appears
unable to satisfy the new requirements [4].
A thorough review of the medical literature of
the last decades highlights important transformations
undergone by the concept of RCM. At first, primary
RCM raised as an independent hemodynamic entity
resembling constrictive pericarditis. Most of the
efforts, focused on the discrimination between the
two conditions, often require exploratory thoracotomy
and surgical biopsy. Histological findings revealed
a “non-tropical” form of endomyocardial fibrosis,
suggesting that eosinophilia may play a leading
role in the genesis of RCM [8]. Later research
introduced the term idiopathic RCM as a rare and
poorly characterized entity, carrying a variable
prognosis and showing a poor response to treatment,
that should not be confused or equated with other
diseases resulting in restrictive hemodynamics [9]
[10]. Extensive reports were dedicated to various
systemic disorders that share a restrictive ventricular
filling pattern, often known as secondary RCM.
Advances in cardiovascular imaging [11] and histopathology led to the characterization of a growing
number of disorders that may manifest as RCM
during their clinical course: infiltrative disorders
(familial or non-familial amyloidosis [12], sarcoidois),
storage disorders (hemochromatosis, Fabry disease
[13], glycogen storage diseases), pseudoxanthoma
elasticum [14], carcinoid syndrome, etc. Drugs like
anthracyclines, methysergide, busulfan proved to
be cardiotoxic causing endomyocardial fibrosis and
a restrictive ventricular filling pattern [15]. More
recently, genetic molecular testing in patients with
3
Restrictive cardiomyopathy
apparent idiopathic RCM discovered several mutations
in the genes encoding sarcomere proteins (e.g.
troponin, actin)[16].
DIAGNOSTIC APPROACHES
Beyond controversies over definition and
nomenclature, there are several definable pathophysiological, hemodynamic and echocardiographic
features that outline the concept of RCM.
Biatrial enlargement and normal sized
ventricles with normal or increased ventricular wall
thickness are the characteristic morphological features
of RCM. Microscopic examination may reveal
myocardial fibrosis, infiltration, endomyocardial
scarring and myocyte hypertrophy (especially in
the idiopathic form), as well as specific findings,
particular to secondary RCM [17].
Diastolic dysfunction is a definable feature of
all forms of RCM. Small sized (<100ml/m2) rigid
ventricles, high ventricular filling pressures (with
LV filling pressure at least 5mmHg greater than RV
diastolic pressure), elevated right and left-sided
295
atrial filling pressures (with associated secondary
pulmonary and systemic venous congestion and
diminished cardiac output) and preserved systolic
function (although contractility is not completely
normal) are the major pathophysiological characteristics of RCM [18].
The restrictive pattern of ventricular filling
often causes dyspnea, weakness, exercise intolerance
and exertional chest pain. Physical exam is
dominated by signs and symptoms of heart failure
(in the absence of cardiomegaly): elevated jugular
pulse with prominent x and y waves, Kussmaul
sign and rising jugular pressure during inspiration,
S3 and S4 gallops, a palpable apical impulse,
murmurs of mitral and/ or tricuspid regurgitation,
peripheral edema, hepatomegaly, ascites and anasarca,
with advancing disease [17].
Three clinical types of RCM can be identified
according to the site of myocardial restriction,
obtained from anatomic and hemodynamic data.
Type A is a symmetric pattern, affecting both
ventricles, while the other two are asymmetric,
involving selectively either the left (type B) or the
right ventricle (type C) [19] (Table I).
Table I
RCM anatomofunctional classification (modified after Guadalahara [19]
Type A
symmetric biventricular
involvement
Type B
asymmetric left ventricle
involvement
Type C
asymmetric right ventricle
involvement
Specific laboratory tests may contribute to
the diagnosis of secondary RCM. BNP has been
recently introduced as a reliable marker for the
discrimination between RCM and idiopathic constrictive pericarditis, with levels five times greater
in the restrictive disease. Normal BNP levels in the
context of right-sided heart failure should raise the
suspicion of constrictive pericarditis [17] [20]. ECG
displays non-specific ST-T changes, low voltage
(despite increased ventricular wall thickness), atrial
– large atria, normal/ small ventricles
– signs of pulmonary and venous congestion
– small left ventricle, large left atrium and right heart
chambers
– signs of pulmonary congestion
– small right ventricle, large right atrium
– signs of venous congestion
– decreased pulmonary and systemic pressures
abnormalities, atrial and ventricular arrhythmias
(atrial fibrillation being the most common) or conduction delays (particularly in infiltrative diseases).
Chest radiography shows an abnormal cardiac
silhouette caused by left atrial or biatrial dilatation,
evidence of pulmonary venous congestion or
pericardial effusion. CT and MRI discriminate
between RCM and constrictive pericarditis and
emphasize aspects particular to specific disorders
associated with RCM.
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Echocardiography is the method of choice for
assessing the morphological and functional characteristics of RCM. Typically, RCM is characterized
by normal ventricular size with variable degrees of
ventricular hypertrophy (with single or biventricular
involvement), biatrial enlargement, dilated inferior
vena cava, reduced mitral and tricuspid annular
motion, moderate pulmonary hypertension. Although
systolic function is classically preserved with a
normal ejection fraction, tissue Doppler echocardiography often reveals reduced systolic and
protodiastolic myocardial velocities in both septum
and lateral wall and a globally reduced strain and
strain-rate (Fig. 1)
2D mode echocardiography may emphasize
clues suggestive of secondary RCM: concentric left
ventricular thickening or right ventricular thickening,
prominent valves, infiltration of the atrial septum,
“granular sparkling” myocardial texture in
amyloidosis; concentric or asymmetric ventricular
hypertrophy and a hyperechogenic endocardium in
Fabry disease; pericardial effusion in sarcoidosis;
apical obliterative thrombosis, posterior mitral valve
adhesion to a densely echogenic posterobasal
ventricular wall and secondary mitral regurgitation
in the hypereosinophilic syndrome. Diastolic left
ventricle dysfunction progresses along with increases
in ventricular filling pressures, from impaired
relaxation to a pseudonormalized and finally a
restrictive pattern [21] [22]. Echocardiography is
also essential for the exclusion of constrictive
pericarditis.
Right and left heart catheterization helps to
establish the type and severity of ventricular
involvement and to characterize specific pathologies by endomyocardial biopsy. It is as well a key
step in the differential diagnosis with constrictive
pericarditis. Hemodynamically, both conditions have
a rapid early diastolic pressure decline followed by
a rapid rise and plateau in early diastole, the socalled square root sign. Though diastolic pressure
gradient between left and right ventricle is often
greater than 5 mmHg in RCM (the difference being
accentuated during Valsalva maneuver, exercise or
by fluid challenge), there is equalization of diastolic
pressures in constrictive pericarditis. In constrictive
pericarditis, the plateau of right ventricular diastolic
pressure is usually at least one third of peak systolic
pressure, while in RCM it is lower. Pulmonary hypertension is more severe in RCM than in pericardial
disorders, with systolic pulmonary pressures often
exceeding 50 mmHg. Right and left-sided atrial
filling pressures are elevated. Atrial pressure tracing
shows a classic square root pattern or a M or W
4
waveform, with a rapid x wave descent and prominent equal a and v waves. Left ventriculography
reveals normal EF and the lack of motion
abnormalities [17].
Radionuclide ventriculography offers an
accurate, complementary assessment of patients
with RCM, showing an excellent correlation index
(0.95) with cardiac catheterization measurements.
Normal or reduced ejection fraction, reduced filling
fraction, prolonged time to peak filling velocity
(> 200 msec), reduced filling fraction in the first
third of the diastole, increased (>30%) atrial contribution to ventricular filling are often encountered
in patients with RCM [23] (Fig. 2).
Endomyocardial biopsy is extremely valuable
in the identification of secondary RCM (infiltrative
heart disease, hypereosinophilic syndrome) and in
the differential diagnosis with pericardial disease.
Surgical exploration is rarely needed today [17].
PROGNOSIS
RCM carries a variable prognosis dependent
on etiology. Most often, especially in the case of
amyloidosis, it responds poorly to medical or
surgical treatment, invariably progressing to death.
Apart from the etiological treatment (e.g. iron
removal in hemochromatosis, enzyme replacement
therapy in Fabry disease), the management of
idiopathic RCM is directed at reducing pulmonary
and systemic congestion by carefully decreasing
filling pressure with diuretics, controlling heart rate
to allow adequate filling time, maintaining atrial
contraction, correcting atrioventricular conduction
disturbances with permanent pacing, if needed, and
avoiding anemia, nutritional deficiency, calcium
overload and electrolyte imbalance. In addition,
patients with atrial fibrillation should be considered
for chronic anticoagulation, to decrease the risk of
thromboembolism. Experience with cardiac transplantation in RCM is limited [9] [10]. Unlike
adults, idiopathic RCM in children evolves with an
accelerated progression to heart failure and severe
pulmonary hypertension. Medical treatment of
these patients has not shown any significant long
term benefit and transplantation appears the only
realistic treatment option [24].
CONCLUSION
Despite its shortcomings (mainly regarding
its questionable practical utility and polymorphic
5
Restrictive cardiomyopathy
297
presentation), RCM remains a self-contained hemoimportance of applying Bayesian principles at all
dynamic pattern. The presence of dilated atria and
phases of diagnostic evaluation and the consideration
non-hypertrophied, non-dilated ventricles in patients
of the clinical context are critical steps when
with congestive heart failure should be more
interpreting results of diagnostic testing. Given the
commonly recognized as a separate disease entity
difficulties encountered in its assesment, RCM was
and should raise the suspicion of RCM, although
and continues to be an issue of clinical debate and
this is only just the beginning of a long and comscientific research and above all a tough challenge
plicated etiologically oriented algorithm. Still, the
to any cardiologist.
__________________________________________________________________
Cardiomiopatia restrictivǎ este probabil cea mai rarǎ cardiomiopatie, având
o prezentare clinicǎ nespecificǎ şi adeseori cauzǎ necunoscutǎ. Conceptul de
cardiomiopatie restrictivǎ s-a schimbat fundamental de-a lungul timpului. Astǎzi
include o gamǎ largǎ de boli caracterizate printr-un fenotip cardiac non-hipertrofic,
non-dilatativ şi un profil restrictiv al umplerii ventriculare. Deşi au existat
numeroase tentative de clasificare şi definire a cardiomiopatiilor, toate s-au
dovedit problematice din cauza contradicţiei în termeni şi a suprapunerii tipurilor
clasice de cardiomiopatie. Progresele în întelegerea patologiei, genomicii şi biologiei
moleculare vin sǎ punǎ bazele unui sistem nou, revoluţionar de clasificare, bazat
pe interacţiunea dinamicǎ dintre genotip şi fenotip. În acest context, cardiomiopatia restrictivǎ evolueazǎ ca un concept hemodinamic şi fiziopatologic de sine
stǎtǎtor, a cǎrei utilitate clinicǎ rǎmâne însǎ incertǎ.
__________________________________________________________________
Corresponding author: Carmen Ginghină, MD, Professor
“Prof.C.C.Iliescu” Institute of Cardiovascular Disease
285,Sos.Fundeni, Bucharest, Romania
E-mail: carmenginghina2010@gmail.com
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Received October 29, 2010
Carcinogenesis and Infection with Helicobacter pylori
GIANINA MICU1, FLORICA STĂNICEANU1,2, SABINA ZURAC1,2, ALEXANDRA BASTIAN1, ELIZA GRAMADĂ1,
LUCIANA NICHITA1,2, CRISTIANA POPP1, LIANA STICLARU1, R. ANDREI1, C. SOCOLIUC1
1
“Colentina” Clinical Hospital, Department of Pathology, Bucharest, Romania
2
“Carol Davila” University of Medicine, Bucharest, Romania
It was accepted several years ago that, in the carcinogenesis process of human cancers,
biologic agents, especially the viruses, are playing an etiologic role. This is the case of lymphomas
(retroviruses), hepatocarcinoma (hepatic viruses) and cervical carcinoma (papilloma viruses). Helicobacter
pylori is the first bacteria recognized as a first class carcinogen for gastric cancer. Nevertheless,
comparing with the most validated human carcinogens, the activity of H. pylori is very little studied.
As a consequence, at this moment, in its case, explanation of carcinogenesis mechanism is more or
less hypothetical.
Key words: Helicobacter pylori, CagA, VacA, carcinogenesis, epithelial premalignant lesions,
lymphoid malignities.
THE EPIDEMIOLOGICAL PERSPECTIVE
In the last fifty years we witnessed a significant
decrease of gastric cancer incidence in the developed
countries population. An important contribution to
this decrease was brought by the Japanese school of
gastroenterology [1] [3] by healing of early gastric
cancers in over 90% cases. Even so, at a world
level, this terrible disease continues to be a frontrunner among cancer-caused deaths (2nd place) and it
is considered the world’s 14th cause of mortality [1].
Until H. pylori (Fig. 1) to become known as a
direct carcinogen [2], the association of the H. pylori
gastric infection with different gastric lesions was
considered a facilitating (and not inductive) factor
for carcinogenesis through the induction of intestinal
metaplasia, glandular atrophy and hypochlorhydria
followed by the accumulation of N-nitrous carcinogenic components, through the free radicals-generating inflammatory reaction and excessive cellular
proliferation.
Afterwards it was demonstrated that bacteria
not only favour, but also produce malign modifycations at the level of the gastric mucosa: both
histological variants of antral gastric adenocarcinoma
(the intestinal type and the diffuse type, according
to the Lauren classification) and the gastric lymphoma, without being implicated in eso-cardial
junction cancers. Cardial lesions appear in patients
with a significant gastro-oesophageal reflux, and in
this case H. pylori infection can have a protective
role [4].
ROM. J. INTERN. MED., 2010, 48, 4, 299–306
Recently, sero-epidemiological studies approximate that at least 70% of diagnosed gastric
carcinomas have Helicobacter pylori as a determining
cause [3] [4], and the serologic presence of HP
antibodies was demonstrated at least ten years before
the disease was diagnosed.
The arguments belong to descriptive epidemiology that presents a geographical distribution [3][5]
of the gastric cancer overlapped by that of
Helicobacter pylori infection. In countries with a
high presence of gastric cancer, the incidence of
Helicobacter pylori infection is also high. These
observations are also sustained by the conclusions
of the epidemiological studies that show a high
frequency of the gastric cancer in patients that
belong to economically disadvantaged classes,
subjects that also proved to have a significantly
high incidence of the infection [1] [6].
Epidemiological paradoxes
From the researchers in epidemiology point
of view there are still several unsolved paradoxes:
– Why, even if H. Pylori infection affects about
half of the planet’s population, only very
few subjects develop a gastric cancer? [7]
Explanations for this situation are probably
in the role of genetic and diet factors.
– On the other hand, even if H. pylori infection has a relatively even distribution in
both sexes, why does the gastric cancer affect
mainly men? [4] [7]
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– How come there are areas where the
infection’s prevalence is very high (around
100%), but the gastric cancer’s prevalence
is almost null? [1] [5] [7].
But, with or without clarifying the epidemiological paradoxes that, one fact remains certain: the
risk of developing gastric cancer by a person with
H. pylori infection is under 1% and seems to
depend on the interaction between the virulence
factors of the infecting bacteria strain and the host’s
genetically-determined immune response [8].
The implications of H. pylori in carcinogenesis are sustained by epidemiological studies as
well as by animal models and researches made for
clarifying the molecular mechanisms involved in
gastric carcinogenesis. Most gastric cancers are
preceded by premalignant lesions that evolve for
decades. Atrophic gastritis perturbs the secretion of
gastric acid by increasing the pH, allowing gastric
colonization with anaerobe bacteria. These bacteria
produce reductase, implicated in the formation of
N-nitroso carcinogenic components [8] [9].
PATHOGENIC MECHANISMS OF INDUCTION IN
GASTRIC CARCINOGENESIS
H. pylori induces carcinogenesis both directly
through his virulence factors, as well as indirectly
through the induction of the inflammatory response
from the host [7–9].
A. DIRECT FACTORS – VIRULENCE FACTORS OF
HELICOBACTER PYLORI
The direct carcinogenetic action of Helicobacter pylori: Helicobacter pylori’s virulence factors
are produced due to its endowment with a series of
structural factors or the bacteria’s secretion products,
among which the most significant are urease,
phospholipase A, proteolytic enzymes, adhesins –
common to all Helicobacter pylori strains–, as well
as the cag cytotoxin, present in 60–70% of the
strains and the vacuolisant protein vacA, present in
60–65% of Helicobacter pylori strains [10] [11].
Helicobacter pylori genome is heterogenic,
with some strains playing a more significant role in
developing malignity. This gene group bears the
name of pathogen islet CagA (PAI) and is made of
31 genes. While the positive CagA types are
proved to imply a high risk of gastric cancer in the
Western population, in Asian population this
correlation is poorly supported. The vacuolisant
cytotoxin vacA is responsible for the lesion of
epithelial cells associated with carcinogenesis –
2
genotypes vacA s1 and vacA m1 have a high
malignnant potential. The carcinogenetic action of
both CagA and vacA was expressed experimentally
through their inoculation in Mongolian gorillas,
which determined intestinal metaplasia and gastric
cancer. On the other hand, the development of B cells
gastric lymphoma was recently associated with
virulent forms of H. pylori, such as HopZ [11–13].
Oxidative stress. Gastritis is associated with
the increase in production of nitric acid (NO). The
nitroso components are recognized as gastric carcinogens in experimental milieus.
Among the host’s response factors to Helicobacter pylori infection, interleukin 1 and the necrotic
tumoral factor (TNF–A–308) present a high risk
for gastric cancer.
B. INDIRECT FACTORS – CHRONIC INFECTION AND
ITS CONSEQUENCES ON GASTRIC MUCOSA CELLS
The inflammation of the gastric mucosa
infected with H. pylori implicates cytokines, gamma
interferon, TN-α, IL-1b, IL-6, IL-8, IL-12 and IL-17.
The expression of cytokines is secondary to the
activation of the transcriptional factor NF-kB,
activation induced in epithelial cells through the
translocation of the cagA gene. The intensity of the
gastric inflammation depends on the host’s hereditary
factors [12] [13]. Some H. pylori strains induce a
severe inflammatory reaction while others are not
at all accompanied by inflammation. This difference
of the inflammation degree is parallel to the
balance of pro- and anti-inflammatory cytokines.
H. pylori is capable of modulating the cytokines’
response. The bacteria’s genomic recombination
seems to play a very important role in perpetuating
the bacteria in spite of the inflammatory response.
The bacteria can survive about 24 h the macrophages’ phagosomes, the bacteria’s lipopolysaccharides inhibiting the macrophages’ apoptosis. On
the other hand, the vacuolisant toxin vacA permits
the survival in an acid milieu through the formation
of intercellular vacuoles containing ammonia which
is freed when the bacteria come into contact with
the cell’s apical pole. Thus, the bacteria’s virulence
factors allow it to survive in spite of host’s immune
response [14].
I. CARCINOGENESIS ON THE EPITHELIAL LINE
THE CARCINOGENIC CASCADE
The carcinogenic cascade triggered by H. pylori
infection, as it was proposed by Correa et al in
3
Carcinogenesis and infection with H. pylori
1975, goes through several important stages [1]
[11] [17]:
fundic and corporeal infection with Helicobacter
pylori → chronic gastritis → glandular atrophy →
intestinal metaplasia → dysplasia → adenocarcinoma
PREMALIGNANT LESIONS ON
THE EPITHELIAL LINE
The initial lesion is constituted by chronic
gastritis together with the decrease of peptic acid
secretion and of the intragastric ascorbic acid concentration, a substance recognised as having protective
role against cancer (Fig. 2). The absence of H. pylori
in the areas of intestinal metaplasia, areas where
the neoplastic transformation originates, suggests a
distant carcinogenic influence through the bacteria’s
products, as well as through the inflammatory
response generated by the infection [9] [10] [19].
Intestinal metaplasia associated to cancer is
the incomplete type, either 2 or 3, and it is distributed
diffusely, antro-fundic, or along the lesser curvature,
from the cardia to the pylorus [18] – Fig. 3.
As far as the atrophy associated with cancer
is concerned, recent studies confirm that it can be
continuous or multifocal, located most often antral
and fundic. German researchers have put forward
the hypothesis that the gastric cancer risk is higher
in subjects with fundic-located gastritis if the level
of activity is equal to the antral one. Japanese
studies confirm the fact that the predominance of
gastritis at the gastric fundus, as well as severe
atrophy and intestinal metaplasia are risk factors
for gastric cancer [17] [19]. Atrophy is defined by
a glandular depletion, probably a consequence of a
fault in the replacement of cells through apoptosis
(Fig. 3). The histopathologic examination highlights
the abundance of inflammatory cells and apoptotic
epithelial cells at the level of the neck glands,
which is precisely where there are epithelial strain
cells. The multi factorial analysis done on patients
with adenocarcinoma, duodenal ulcer or gastritis
indicates the association between genotype s1 and
m1 cag and the density of the inflammatory infiltrate,
the mucosa’s degree of atrophy and the type of
intestinal metaplasia. A role in the appearance of
the gastric mucosa atrophy seems to be also played
by the auto-antibodies through the activation of the
local immune system and the induction of a cellular
mediated reaction followed by the destruction of
parietal cells by cytotoxic lymphocytes [18–20].
301
Apoptosis. Among the carcinogenesis
mechanisms there is also the maladjustment of the
apoptotic ways. Apoptosis is a form of geneticallyprogrammed cellular death in view of regulating
the number of epithelial cells of the digestive tract.
Both the presence of inflammatory mediators and
the secretion product of H. pylori can intervene
directly in the enzyme cascade that forms the base
of the molecular mechanisms of the apoptosis [19].
As a consequence, modifications of the cellular turnover appear. The ways through which H. pylori can
induce the acceleration of the apoptosis’ rhythm in
the gastric epithelial cells belong to two main
categories:
a) Direct pathway, through the bacteria’s
virulence factors, especially cagA, cagE
and the vacuolisant cytotoxin vacA, which
is confirmed by the absence of an accelerated
apoptosis in infections with H. pylori strains
with the above-mentioned virulence factors.
b) Indirect pathway, via the inflammation’s
mediators: the gamma interferon (IFN-γ)
and TNF-α amplify the apoptosis induced
by H. pylori through a mechanism that
implies the over-expression of the Fas
receptor at the level of gastric epithelial cells.
This increases the susceptibility of gastric
epithelial cells towards T-cells. Apoptosis is accelerated by a series of bacterial elements: ammonia,
urease, ceramide [7] [18].
In cell cultures the over expression of Bak
(correspondent of the Bcl-2 protein, inductor of the
apoptosis) was also noticed. At the present moment
there are two theories regarding the significance of
apoptosis in H. pylori infection. According to the
first one, the induction of apoptosis stimulates the
cellular proliferation, explaining the hyper prolixferative response of the host epithelium associated
to the infection. The second theory affirms that, on
the contrary, apoptosis could be the answer to
epithelial hyper proliferation in view of preventing
tissue hypertrophy [23].
In vivo the apoptosis’ mechanisms depend
significantly on the level of pro inflammatory
cytokines (IL-8, IL-6, gamma interferon and TN-α).
These induce apoptosis through the induction of
synthetase nitrogen monoxide. NO has a degrading
effect on the DNA, the increase in the production
of NO can determine irreversible lesions of the
genome and the appearance of pro carcinogenic
mutations. The free radicals and NO induce the
expression of the P53 protein, that repairs DNA’s
lesions or produces cells’ apoptosis [20] [22].
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Epithelial proliferation – Fig. 4. In the
gastric mucosa infected with H. pylori there is a
concomitance between the accelerated apoptotic
process and the cellular proliferation. When the
balance between these two opposed effects processes
is broken in favour of the proliferative factors, the
evolution leads to cancer. Cellular proliferation is
secondary to the inflammation induced by the
H. pylori bacteria. The central role in its production
seems to be played by cyclooxygenase Cox-2 and
nitrogen monoxide (NO), both expressed at an
increased level in gastric adenocarcinoma. Excessive
cellular proliferation decreases significantly after
the eradication of H. pylori infection [20]. On the
other hand, one must note its increase in the
absence of a parallel increase of the apoptosis, of
genetic (genetic mutations) or epigenetic (modifycations of the gene’s expression) alterations. Genetic
modifications seem to be more precocious in the
diffuse-type cancer than in the intestinal type, even
if in the latter’s case precancerous lesions such as
intestinal metaplasia can be described. Somatic
mutations of gene E-cadherine or a hypermethylation of one of these gene’s promoters are
characteristic to the diffuse type of adenocarcinoma,
while for the intestinal type the mutations frequently
affect gene p53. Mutations of the APC and betacatenina genes are much rarer. All these genetic
modifications can be induced by the oxidative
stress produced by H. pylori [20] [22] [24].
H. pylori interferes in angiogenesis through
the induction of a vascular factor for endothelial
growth – A (VEGF – A). Other growth factors
induced through H. pylori’s virulence include the
epidermal growth factor (EGF), the heparin growth
factor (EGF-like) and amphiregulin. Through the
CagA protein it also activates the c-Met growth
factor.
There are numerous studies that describe
cellular and genetic modifications in malignant
gastric cells: the affection of the intercellular adhesion
owing to the mutations E-cadherin, alpha and betacatenins, as well as to the increase in the activity of
telomerase and the instability of microsatellites.
The most common genetic abnormalities are
connected to p53, as well as to the activation of the
oncogenes c-Med and Her2/Neu, while the K-raz
mutations occur less and less frequently. It was
demonstrated that some of these genetic modifycations can appear even before intestinal metaplasia is
installed [20] [25].
Intraepithelial neoplasia (“dysplasia”) represents a renewal and tissue-development process;
it is frequently associated to chronic gastritis and
can recede under treatment. It appears at the level
4
of the normal gastric mucosa and is signalled by a
foveolar hyper-proliferation and/or intestinal metaplasia. Cytoarchitectural alterations start at the level
of the glands’ neck, where glands appear grouped
in small “packages”. It can be plane/polypoid/
depressed from a macroscopic point of view, with a
microscopic tubular/tubulo-villous/ villous or
papillary pattern [20–22] [25] – Fig. 5.
Microscopic criteria of considering the gastric
intraepithelial neoplasia are:
– structural disorganisation: deformation of
the crypts, the appearance of epithelial
intraluminal buds, the relation between the
epithelial tissue and the conjunctive one,
modified in favour of the former.
– the presence of cellular atypia, predominantly
nuclear: polymorphism, hyperchromasia,
loss of nuclear polarity, stratification, presence of an increased number of mitoses.
– anomalies of differentiation: modification
of the secretion, increase of the number of
non-differentiated cells.
According to these criteria two types of intraepithelial neoplasia can be described, comprising
the three degrees of epithelial dysplasia formerly
described: low degree intraepithelial neoplasia
(light and medium epithelial dysplasia) and high
degree intraepithelial neoplasia (severe epithelial
dysplasia); the cases which lack of criteria for a
certain definition are classified in the indefinite
intraepithelial neoplasia category (OMS) [1] [25].
In the low degree intraepithelial neoplasia,
the mucosa’s architecture is slightly modified, and
it presents tubular ramified/ budded structures, with
elongated crypts, cystic dilatations, glands covered
by large-size, low-Muncie columnar cells; pseudo
stratified vesiculous round-ovoid nuclei.
In the case of high degree intraepithelial
neoplasia visible architectural distortions appear;
the tubes gain an irregular, ramified shape; the
glandules become crowded and one can identify
visible cellular atypical situations; there is no
stromal invasion; the mucus secretion is either
minimal or absent; the nuclei become pseudo
stratified, pleomorphic, hyperchromatic, cigar-shaped
with prominent, amphophilous nucleoli.
THE PROGRESSION OF INTRAEPITHELIAL
NEOPLASIA TOWARDS CARCINOMA
Over 80% of intraepithelial neoplasia cases
progress towards invasion. The carcinoma diagnosis
is imposed when the tumour invades lamina
propria (intramucous carcinoma) or the muscularis
mucosae [24] [27].
5
N.B.: the association of extensive lesions of
intestinal metaplasia with lesions of intraepithelial
neoplasia in the presence of the sulphomucinesecreting phenotype has a high risk of evolving
towards carcinoma – Figs. 6, 7.
PHYSIOPATHOLOGICAL AND CLINIC
MODIFICATIONS: GASTRITIS,
HYPOCHLORHYDRIA AND THE RISK OF
ADENOCARCINOMA
The chronic infection with H. pylori can lead
in time to the appearance of pan gastritis when
inflammatory lesions at the level of the fundic
mucosa lead to the decrease of the acid secretion.
From a physiopathological point of view, hypochlorhydria is partly caused by the decrease in the
secretion of histamines by the ECL cells; on the
other hand, the parietal cells’ acid secretion is
inhibited by TN-α and IL1β [26].
H. pylori infection induces an immune reaction
from the organism, whose first stage is the alteration
of gastric epithelium through the presence of the
bacteria in the mucosa that covers cells’ apical pole.
The consequence is secretion of numerous chemotactic factors, of cytokines and the stimulation of
lymphocytes. Even if sometimes it is spontaneously
eliminated by local defence mechanisms, in most
cases the infection continues to persist. In time, it
appears a local inflammatory reaction that provokes
the acceleration of the cellular turn-over and,
sometimes, genomic lesions that can lead to cancer
if lesions of the DNA-repair mechanisms appear.
Chronic inflammation can also induce hypochlorhydria in patients with a pre inflammatory genotype
of interleukins. Convergence of bacterial virulence
factors with the host’s immune response can generate
varied diseases, from ulcer to the atrophy of the
mucosa and afterwards the development of cancer
[26] [27].
ERADICATION OF H. PYLORI AND PREVENTION
OF GASTRIC CANCER
The major problem with gastric cancer prevention strategies derives at this moment from the
fact that we do not know exactly at which stage
gastritis, atrophy, intestinal metaplasia or intraepithelial neoplasia become irreversible. Random,
prospective studies and placebo (like the one
303
applied by Wong and his team) suggest the fact
that the eradication of H. pylori reduces the
incidence of gastric cancer only in patients that did
not present gastric atrophy and/or intestinal metaplasia. But even in the case where these lesions’
point of no return has been surpassed, eradication
of H. pylori seems to stop their evolution. The
regression of precancerous lesions is thought 66%
possible for patients that become H. pylori negative
after treatment and only 14% possible for patients
that stay positive after treatment [1] [26].
According to some studies, non-atrophic
gastritis is completely reversible after the eradication of the H. pylori infection. Others, in contrast
[19] [28], have demonstrated that both atrophic
gastritis and intestinal metaplasia could be reversible,
even if these studies have noticed a decrease in the
incidence of gastric cancer; this was though related
to the decrease of cellular proliferation after
eradication of active infection [27].
Some researchers [20] [26] mentioned the
existence of a stage of pre-atrophic gastritis in
which the parietal epithelial cells have disappeared,
but the glandular architecture was conserved and
the strain cells were also not affected. At least
theoretically, at this stage the lesions are reversible.
To conclude, the real amplitude of the role
played by H. pylori’s eradication in the prevention
of gastric cancer remains still a subject for study.
As long as after the eradication of H. pylori
precancerous lesions stop evolving and, sometimes,
they even regress, the practical decision imposes
itself: the infection’s treatment must be applied
even without the evidence of pre neoplasia modifications.
Another important, but theoretical idea, is
that of the existence of the point of no-return, beyond
which bacteria-induced genetic modifications make
atrophy and intestinal metaplasia irreversible, in
spite of the elimination of the carcinogen agent
(H. pylori) [25–27].
REVERSIBILITY OF PRECANCEROUS LESIONS
At the present moment there are still few
studies concerning the role that the infection’s
eradication can have in the prevention of the gastric
cancer through the reversibility of pre neoplasia
modifications: atrophic gastritis, intestinal metaplasia and the intraepithelial neoplasia of different
degrees [16] [25] [26].
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Gianina Micu et al.
II. PATHOGENESIS OF H. PYLORI-INDUCED
LYMPHOID MALIGNITIES
As far as the malign transformation on a
lymphoid line is concerned, the pathogenic sequence
described above at this moment is the following:
Gastric infection with Helicobacter pylori→
lymphoid hyperplasia → clone abnormalities at
the level of B lymphoid population → low degree
MALT lymphoma dependent on the Helicobacter pylori infection’s level→ (possibly via the
t translocation (1;14) → low degree MALT lymphoma independent of the level of Helicobacter
pylori infection→ (possibly via the p53 mutation)
→ high degree MALT lymphoma.
EPIDEMIOLOGY
Epidemiological studies, as well as the
detection of the H. pylori infection in most gastric
lymphomas have proved the tight connection
between these and the bacteria. The regression and
even healing of some lymphomas following the
antibiotic treatment aimed at H. pylori infection
also come in support of this idea [1] [21].
The carcinogenetic steps in this case begin
with the activation of T cells in the presence of the
chronic H. pylori infection, starting towards cells
that further on activate the population of polyclonal
B lymphocytes. In time, a proliferation of monoclonal B cells with the possible accumulation of
genetic mutations takes place. Because the lymphoma
appears in the lymphoid tissue associated to the
mucosa (MALT), they are called MALT-oms. B-cells
that proliferate come from the lymphoid follicle’s
peripheral area, which explains this tumour’s other
name, that of marginal area lymphoma [1] [21] [24].
Even if the first studies concerning the low
degree MALT lymphoma launched the idea of the
presence of Helicobacter pylori infection among
the etiologic factors up to 98%, more recent studies
keep the bacteria in the fore-group, but decrease its
incidence at 62–77%. It was proven that lymphoma
is preceded by a H. pylori infection, but there are
still controversies concerning this theme, especially
because a series of serious studies have published
partially contradicting results. For example, some
studies mention the association between high degree
lesions and positive cagA strains and the nonassociation of this strain with low degree lymphoma [21].
6
THE MALT LYMPHOMA CONCEPT
The term MALT was proposed by Isaacson et
al. for the immune system’s components developed
at the level of the gastrointestinal tract’s mucosa;
these contain lymph ganglions (which in ileum form
the Payer paches), the lymphocyte and plasmocytes
in lamina propria and the intraepithelial lymphocytes. These immune components of the MALT
system have distinct morph functional traits, as well
as the lymphoma developed from them (MALT). It is
considered that, in order to develop a tumour from
this tissue, an important role is played by H. pylori,
the latter’s eradication leading to the lymphoma’s
remission [1] [28].
Between the lymphoid follicles there are
variable sized lymphoid cells, without mitosis,
frequent immunoblasts, post-capillary venules and
sometimes plasmocytes – Fig. 8.
The specific immunohistochemical markers
are: CD19, CD20, CD21, CD35, bcl-2, sometimes
CD43.
LYMPHOID HYPERPLASIA
Lymphoid hyperplasia, named until recently
“pseudo-lymphoma”, represents a reactive condition
that appears frequently in association with ulcerations/
gastric erosions and who is accompanied by an
extensive fibrosis and a vascular proliferation. At a
microscopic level, one can describe the presence of
reactive germinal centres in a polymorph inflammatory population (including mature lymphocytes and
plasmocytes).
Initially, the pseudo-lymphoma was considered
a benign reactive inflammatory process. Later on, it
was recognised as a pre-malignant lesion. At the
present moment, thanks to data provided by immunohistochemical studies and molecular biology, that
can make the difference between monoclonal (neoplasia) and polyclonal (reactive) lymph proliferations,
the term of pseudo-lymphoma is not longer used
[1] [23].
MAIN CHARACTERISTICS OF MALT
GASTRIC LYMPHOMA
Over 95% of gastric lymphoma is non-Hodgkin
type. Most of them are B cells lymphoma, T cells
being reported fewer than 8%.
7
Lesions appear at the level of the mucosa’s
junction with the submucosa, making difficult at
this stage a diagnosis through endoscopic biopsy.
Also difficult is the differentiation of the low-degree
malignity lymphoma from benign inflammatory
infiltrates at the level of endoscopic biopsies. In
early or borderline cases there can be significant
confusions with follicular gastritis. In these cases it
is necessary to have a immunohistochemical and
molecular confirmation of the monoclonality of
B cells [1] [21] [23].
THE TUMORIGENIC ROLE OF H. PYLORI
IN MALT-TYPE GASTRIC LYMPHOMA
305
TUMOUR CELLS E RESPONSE OF
TO H. PYLORI INFECTION
Tumour B cells are not directly stimulated by
the bacteria. H. pylori stimulate the intratumoral
T cells that, in their turn, favour the proliferation of
tumour cells. It was demonstrated that the same
patient’s spleen T cells do not respond to H. pylori,
which implies that the population of T cells
responsive to the bacteria is a local one. This is one
of the explanations for the fact that the MALT
gastric lymphoma at least initially remains localized,
the lymphoma being dependent on the activated
T cells present in great number in H. pylori produced
gastritis [24].
It is necessary for the progenitors of the
malign B cells clone to have certain properties, a
possible genetic alteration or the ability to recognise
antigens that allow their uncontrolled proliferation
in the presence of T cells. The MALT lymphomatous cells present a genetic instability, genetic
anomalies and respond to a variety of auto antigens.
In 2000, De Jong proposed a model of oncogenesis for the MALT-type gastric lymphoma.
H. pylori → chronic gastritis → gastric lymphoma
Non H type MALT, low malignity → gastric
lymphoma Non H type MALT, high malignity. If
the passage from chronic gastritis to the low degree
MALT lymphoma is regulated through immunological processes, the passage to the high degree
lymphoma is achieved through an autonomous
proliferation [23] [26].
It was demonstrated (Isaacson et al. 1984,
Wyatt et al. 1988, Worth Erspool, 1991) that chronic
H. pylori infection determines the stimulation of
the lymphoid tissue in the gastric mucosa. The
presence of lymphoid follicles at this level is
pathognomonic to the long-term infection with H.
pylori; the appearances of lymphoepithelial lesions
definitely mark the development of a MALT
lymphoma. The chronic infection with Helicobacter
pylori determines the recruitment of B and T cells
in gastric mucosa as an immune response. The
proliferation of B cells is secondary to the specific
activation of T cells by the bacteria and cytokines.
Because gene alterations of the malign clone are
not sufficient for insuring autonomy in relation to
cellular death, the MALT lymphoma can regress
the anti-Helicobacter pylori treatment. In time, the
malignant clone can accumulate varied gene
alterations (t (1; 14)), inactivation of the p53 gene
REGRESSION OF THE MALT GASTRIC LYMPHOMA
or the p16 gene) that determine acquiring of an
AFTER ERADICATION OF H. PYLORI
autonomous proliferation capacity and/or apoptosis
inhibition. As a consequence, the low degree MALT
Antibiotic therapy for the MALT gastric
lymphoma that would have responded to the
lymphoma is efficient only in low degree lymphoma
antibiotic treatment become high degree lymphoma
and the extension is limited to the mucosa and/or
that do not respond to the antibiotic treatment
the submucosa [23] [25] [28].
anymore and tend to lead to metastasis.
__________________________________________________________________
În procesul carcinogenezei cancerelor umane au fost acceptaţi de mulţi ani
agenţi biologici cu rol etiologic, în special virusurile. Acesta este cazul limfoamelor
(retrovirusurile), hepatocarcinomului (virusurile hepatitice) şi cancerului de col
uterin (papiloma virusurile). Helicobacter pylori este prima bacterie recunoscută
ca şi carcinogen de clasa I, fiind demonstrat epidemiologic ca agent cauzal pentru
cancerul gastric. Totuşi, prin comparaţie cu cei mai mulţi carcinogeni umani
validaţi, acţiunea carcinogenetică a H. pylori este încă puţin experimentată. În
consecinţă, la momentul prezent, în cazul său, explicarea mecanismelor carcinogenezei este încă mai mult sau mai puţin una ipotetică.
__________________________________________________________________
306
Gianina Micu et al.
8
Correponding author: Gianina Micu
Colentina Clinical Hospital, Department of Pathology
19–21 Şos. Ştefan cel Mare, Bucharest
E-mail: dr_geanina@yahoo.com
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Received July 24, 2010
Oxidative Stress in Diabetic Kidney Disease
MIHAELA BÎCU1, MARIA MOŢA2, N. M. PANDURU5, CORINA GRĂUNŢEANU4 , E. MOŢA3
1
County Clinical Emergency Hospital of Craiova, Clinic of Diabetes, Nutrition and Metabolic Diseases, Craiova, Romania
2
University of Medicine and Pharmacy Craiova, Department of Diabetes, Nutrition and Metabolic Diseases
3
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Department of Physiopathology
4
County Clinical Emergency Hospital of Craiova, Clinic of Nephrology
5
University of Medicine and Pharmacy Craiova, Department of Nephrology
Diabetic Kidney Disease (DKD) represents a worldwide public health problem, due to its ever
growing incidence and high costs connected to the imposed therapies regarding substitution of kidney
functions.
DKD includes all the anatomical, clinical and functional alterations that occur at kidney level
in a patient with Diabetes Mellitus (DM), as a result of numerous metabolic and haemodynamic
factors at the level of kidney microcirculation, based on a polygenous genetical polymorphism that
generates an individual susceptibility for this complication. DKD is found in 20–40% of DM patients
and it represents the main cause of chronic kidney disease. In DKD pathogeny, an important part is
played by the oxidative stress determined by hyperglycemia. Among the mechanisms by which
hyperglycemia may affect the kidney we may enumerate polyol pathway activation, C protein-kinase
activation (PKC), non-enzymatic protein glycosylation. Out of the highly reactive molecules involved
in the oxidative stress of DKD, an important role is attributed to •O2–, •NO and ONOO.– The role of
oxidative stress played in DKD pathogeny is also supported by the promising results of some
antioxidant therapies in DKD: AGE inhibitors (pyridorin, 2,3 diamino-phenazine, bromo-phenylacetic
thiazolium, aminoguanidine/pimagedine), diacylglycerol pathway inhibitors (vitamin E, thiamine,
benfotiamine, aminoguanidine), PKC inhibitors (ruboxistaurin), transketolase activators (thiamine
and benfotiamine).
Key words: oxidative stress, diabetic kidney disease, hyperglycaemia.
Diabetic kidney disease (DKD) includes all
the anatomical, clinical and functional alterations
that occur at kidney level in a patient with Diabetes
Mellitus (DM), as a result of numerous metabolic
and haemodynamic factors at the level of kidney
microcirculation, having as basis a polygenous
genetical polymorphism that generates an individual
susceptibility for this complication [1–7].
DKD is found in 20–40% of DM patients and
represents the main cause of chronic kidney disease
(CKD) [6] [7]. In USA, approximately 50% of
patients included in therapies regarding the substitution of kidney functions (TSKF) have DM and
CKD in terminal stage [7]. In Europe, 13.1% of
CKD cases in the 5th stage that have been treated
through haemodialysis are due to DKD, and 4% in
Romania [7] [8].
In type 1 DM, DKD incidence increases
alongside DM duration, reaching 2–3%/year after
13–20 years of evolution, and after 20 years, the
incidence decreases to 0.5%/year [7] [9]. The DKD
prevalence in type 2 DM is approximately 40%,
with high variability of literature data, data concerned
with genetical inheritance, lifestyle, ethnicity, etc. [7].
ROM. J. INTERN. MED., 2010, 48, 4, 307–312
Afro-American, Mexican-American, Indian-American
and Polynesian patients present the highest risk in
developing DKD and also a rapid progression of
DKD to a terminal stage [7] [10].
In DKD pathogeny, an important role is played
by the oxidative stress determined by hyperglycemia [11–14].
Oxidative stress may be defined as the
imbalance between the production of antioxidants
and free-radicals, as a result either of antioxidants
decrease or of free-radicals increase, or of both
mechanisms, with potential consequences over the
emergence of oxidative lesions [14].
Oxidative stress represents the excessive formation of highly reactive molecules as reactive
oxygen species (ROS) and reactive nytrogen species
(RNS) [11] [15][16]. ROS include free-radicals:
•
O2– (superoxide), •OH (hydroxyl), •RO2 (peroxyl),
•
HRO2– (hydroperoxyl) and nonradicals: H2O2
(hydrogen peroxide), HClO (hydrochlorous acid).
RNS include free-radicals: •NO (nitric oxide), •NO2–
(nitrogen dioxide) and nonradicals: ONOO– (peroxynitrite), HNO2 (nitrous oxide), RONOO (alkyl
peroxynitrates) [11] [15] [17]. Relatively recent
308
Mihaela Bîcu et al.
researches study the implication of sulphur reactive
species in oxidative stress [14].
Among the mechanisms by which hyperglycemia may affect the kidney we may enumerate
polyol pathway activation, C protein-kinase activation
(PKC), protein non-enzymatic glycosylation.
Polyol (sorbitol) pathway. Through the polyol
pathway, glucose excess may be metabolized into
sorbitol and fructose by aldose reductase (AR) and
sorbitol dehydrogenase (SDH). Polyol pathway
seems to intervene in DKD pathogenesis, especially
through the interference with the formation of
advanced glycosylation end-products (AGE) out of
fructose. At kidney level, AR is found in
glomerular podocytes, in distal contort tubes and in
Henle loop. In rat induced diabetes, there appears
the increase of polyol pathway agents, decrease of
myoinositol tissular levels and increase of intracellular osmolarity, some phenomena that precede
proteinuria [7] [12–14] [18–20].
Polyol pathway determines an endothelial
dysfunction (ED) by 3 mechanisms:
– high sorbitol accumulation increases osmotic
stress [18];
– increase of NADH/NAD+ cytosolic ratio, as
a result of a redox imbalance similar to that
of tissular hypoxia, also called hyperglycemic
pseudohypoxia [22];
– accumulation of triose-phosphates stimulates
the formation of methylglyoxal (MG), the
most active AGE predecessor, thus increasing the oxidative stress [7] [18].
PKC pathway. PKC activation is accomplished by de novo synthesis of diacylglycerol
(DAG), through acylation of glycerol-3-phosphate
(GP) into phosphatidic acid (PA). In the cells with
low AR activity (like the endothelial cells), DAG is
de novo synthesized from glycolysis intermediates,
dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA-3-P) [23]. PKC is stimulated
in DM by polyol pathway, angiotensin II (Ang II),
activation of NAD(P)H oxidase [24] [25] [26–32].
PKC activity is high in the glomerules of DM
patients, having the following effects:
– direct or indirect alterations of vascular
permeability (through the vascular endothelial
growth factor – VEGF) [33];
– alterations of blood flow by decreasing
endothelial nitric oxide synthesis (eNOS)
activity and/or by increasing endothelin-1
(ET-1) synthesis [34];
– thickening of glomerular basement membrane
(GBM) through TGF-β (transforming growth
2
factor-β), which mediates the growth of
type IV collagen and fibronectin synthesis
[18];
– fibrinolysis modifications through the plasmatic growth of PAI-1 (plasminogen activator
inhibitor-1) [18];
– increase of oxidative stress by activating
NADPH oxidase [18];
– alterations of the receptors of some hormones
and growth factors (pathway of activating
TGF-β synthesis);
– alterations of ionic channels activity;
– alterations of intracellular pH levels [14].
In diabetic animals, oral administration of
LY333531 – a selective inhibitor of isoform βII of
PKC – ameliorates the growth of glomerular filtration
rate and the accelerated expansion of glomerular
mesangium, thus partially correcting albumin urinary
excretion (AUE) [12] [14] [18].
AGE pathway (Non-enzymatic glycosylation)
consists in the non-enzymatic reaction of glucose
and dicarbonyl compounds (MG, glyoxal and
3-deoxyglucosone) with basic aminoacids (lysine
and arginine) [7] [13] [14] [18] [19] [21] [35].
AGE may grow through glucose self-oxidation
to glyoxal, Amadori products formation and their
decomposition into 3-deoxyglucosone and also
GA-3P glycolise formation, decomposing into MG.
AGE are accumulated into glomerules and kidney
tubes only in DM patients.
In diabetic animals, the AGE accumulation in
the kidneys determines protenuria, proliferation of
mesangial cells and GBM thickening [7] [36].
AGE acts through AGE-R1, AGE-R2, AGER3 receptors (RAGE), and also by receptor-independent pathways [7] [14] [37]. As a result of AGE –
RAGE interaction there are activated the serine/
threonine kinases family, PKC and other important
transcription pathways: nuclear factor – kappa B
(NF-kB) and mitogen activated protein-kinases
(MAPK) [7] [36]. At a cellular level, the AGE –
RAGE interaction induces the synthesis and release
of cytokines: TGF-1, platelets-derived growth
factor (PDGF), insulin-like growth factor (IGF),
increasing the production of collagen IV, laminin
and fibronectin, [7] [14] [36]. Synthesizing, the
AGEs role in DKD is the following: ↑AGE in
GBM, ↑vascular permeability, GBM thickening,
↑production of mesangial matrix with glomerular
hypertrophy and glomerulosclerosis [14].
Hyperglycaemia may increase ROS by activating NAPDH oxidase or by inactivating antioxidant
enzymes, like SOD (superoxide dismutase), catalase,
or eNOS (Fig. 1) [18] [19].
3
Oxidative stress in kidney disease
309
Fig. 1. – Mechanisms of oxidative stress in DKD (modified after C.G. Schalkwijk, R.B. Jadidi). AGE advanced glycosylation
end-products; NADP+ nicotinamide adenine dinucleotide phosphate; NADPH reduced form of NADP+; SOD superoxide dismutase;
eNOS endothelial nitric oxide synthase; AR aldoreductase; SDH sorbitol dehydrogenase; G-6-P glucose-6-phosphate;
F-6-P fructose-6-phosphate; F-1,6 bi-P fructose 1,6 biphosphate; NAD+ nicotinamide adenine dinucleotide; NADH
reduced form of NAD+; DHAP dihydroxyacetone phosphate; GA-3-P glyceraldehyde-3-phosphate; GADPH
glyceraldehyde-3-phosphate dehydrogenase; PARP Poly (ADP-ribose) polymerase; ROS reactive oxygen species;
•
O2– superoxide; Acyl CoA – Acyl Coenzyme A; GP glycerol-3-phosphate; PA phosphatidic acid; DAG dyacyl glycerol;
PKC – C protein kinase; MG metylglioxal.
AN IMPORTANT ROLE IN OXIDATIVE STRESS OF
DKD IS PLAYED BY •O2–, •NO AND ONOO–
O2– is generated through the reduction of
oxygen, by various means: NAD(P)H oxidase,
xantin-oxidase, cyclooxygenase, eNOS, mitochondrial transport chain [11] [38–41]. Under normal
conditions, •O2– is rapidly eliminated through antioxidant defense mechanisms: •O2– is transformed
into H2O2 by manganese superoxide dismutase
(Mn-SOD) at mitochondrial level and by copper
superoxide dismutase (Cu-SOD) at cytosolic level
[11] [38]; H2O2 may be transformed into H2O and
O2 by glutathione peroxidase (GSH-Px) at mitochondrial level or by catalase at lysosomal level;
also, H2O2 may be converted into •OH, in the
presence of Fe or Cu [18]. •O2– may activate the
AGE pathway, the polyol pathway and PKC,
involved in DKD pathogeny. •O2– and H2O2 activate
stress signaling mechanisms, like NF-kB, p38-MAPK
and STAT-JAK (Signal Transducer and Activator
of Transcription – Janus kinase), thus determining
•
the migration and proliferation of vascular smooth
muscular cells [11].
•
NO is produced normally from L-arginine by
eNOS; it has a vasodilatation, antiplatelet, antiproliferative and antiinflammatory effect [11] [41],
inhibits platelets and leukocytes adhesion to vascular
endothelium, regulates cytokines expression VCAM-1
(vascular cell adhesion molecule-1) and MCP-1
(monocyte chemotactic protein-1) [42]. The main
beneficial effects of NO in DKD are: antagonizing
Ang II effects; increasing capillary flow; inhibiting
mesangial proliferation; decreasing endothelial permeability for albumin; reducing oxidative stress in
endothelial cells [7].
In the first stages of experimental DM, the
NO synthesis increases and its vasodilatation effect
seems to be modulated by VEGF; in advanced
stages of DM, the NO production decreases, thus
determining the alteration of vasodilatation response
[7].
ONOO– results in the reaction of •NO with
•
O2–; cytotoxic ONOO– favours lipid peroxidation
310
4
– AGE inhibitors: pyridorin, 2,3 diamino[15], alters the functions of biological membranes
phenazine, bromo-phenacetylthiasonium,
[11] [16] [39–42], determines DNA alteration, de•
aminoguanidine (pimagedine – prevents
creases NO bioavailability, oxidizes tetrahydroincrease of genic expression of TGF β1)
biopterin (BH4) – an important cofactor for NOS,
[14] [46]
thus resulting in uncoupled eNOS, and producing
•
– diacylglycerol pathway inhibitors – vitamin
O2– instead of •NO [16].
E, thiamine, benfotiamine, aminoguanidine
Oxidative stress represents a cause for ED
[46]
in DKD [14]. In DKD, ROS directly determines
–
PKC
inhibitors – ruboxistaurin, vitamin E
ED (through peroxidation of lipidic membranes,
[14]
[46]
[47]
NF-kB activation and interference with NO avail– Aldosereductase inhibitors – sorbinil –
ability) and indirectly (through growth factors and
clinical studies in progress
cytokines): TGF-β, TNF-α (tumor necrosis factor– Inhibitors of matrix accumulation by transα), IGF-1, EGF (epidermal growth factor) [18] [43]
formation factors, modified heparingluco[44]. Micro- and macroalbuminuria are associated
samine, sulodexide (reducing micro- and
with ED both in type 1 DM and in type 2 DM as
macroalbuminuria in type 1 and type 2 DM)
well [11] [45].
[46]
The role of oxidative stress played in DKD
– Transketolase activators (thiamine, benfotiamine) in high doses prevent DKD
pathogeny is also supported by the promising
development [47] [48].
results of some antioxidant therapies in DKD:
__________________________________________________________________
Boala renală diabetică (BRD) reprezintă o problemă de sănătate publică la
nivel mondial, prin incidenţa sa în continuă creştere şi prin costurile ridicate ale
terapiilor de substituţie a funcţiilor renale pe care le impune. BRD include toate
modificările anatomo-clinice şi funcţionale ce apar la nivel renal la un pacient cu
diabet zaharat (DZ), fiind rezultatul interacţiunii a numeroşi factori metabolici şi
hemodinamici la nivelul microcirculaţiei renale, având ca substrat un polimorfism
genetic de tip poligenic, ce generează o susceptibilitate individuală pentru această
complicaţie. BRD apare la 20–40% dintre pacienţii cu DZ şi este principala cauză
a bolii cronice de rinichi. În patogenia BRD un rol important îl are stresul
oxidativ determinat de hiperglicemie. Printre mecanismele prin care hiperglicemia
poate afecta rinichiul se numără activarea căii poliol, activarea protein kinazei C
(PKC), glicozilarea non-enzimatică a proteinelor. Dintre moleculele înalt reactive
implicate în stresul oxidativ din BRD, un rol important este atribuit •O2–, •NO şi
ONOO.– Rolul stresului oxidativ în patogenia BRD este susţinut şi de rezultatele
promiţătoare ale unor terapii antioxidante în BRD: inhibitorii AGE (pyridorin,
2,3 diaminofenazina, bromura de fenacetilthiazonium, aminoguanidina/pimagedine),
inhibitorii căii diacilglicerol (vitamina E, tiamina, benfotiamina, aminoguanidina),
inhibitorii PKC (ruboxistaurina), activatorii transketolazei (tiamina şi benfotiamina).
__________________________________________________________________
Corresponding author: Professor Maria Moţa, MD, PhD
Clinical Centre of Diabetes, Nutrition & Metabolic Diseases
1, Tabaci Str., Craiova, Romania
E-mail: mmota53@yahoo.com
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Received September 2, 2010
Cardiovascular Risk in Patients with Diabetic Kidney Disease
CORINA GRĂUNŢANU1, E. MOŢA1, MARIA MOŢA1, M.N. PANDURU2, MIHAELA BÎCU1, IULIA VLADU1
2
1
University of Medicine and Pharmacy, Craiova, Romania
“N.C.Paulescu” National Institute for Diabetes, Nutrition, and Metabolic Diseases, Bucharest, Romania
In the past decades, chronic kidney disease has become a public health problem all over the
world. Both the incidence and the prevalence are continually increasing. Diabetic nephropathy is, by
far, the most frequent cause of CKD, with a prevalence of 40% in patients with end-stage renal
disease (ESRD). Present studies have shown the fact that microalbuminuria and chronic kidney
disease are independently associated to a high risk of cardiovascular events, as well as to a high
mortality rate of all causes and also of cardiovascular cause, both in the general population and also in
patients with high risk or an already present cardiovascular disease. There is a permanent association
between the level of urinary albumin excretion and the risk for cardiovascular disease, macroalbuminuria and clinical nephropathy being associated to a higher risk for cardiovascular events than
microalbuminuria.
Due to the importance of clinical data and low cost, microalbuminuria and glomerular
filtration rate should be introduced in the clinical practice for the evaluation of cardiovascular risk,
especially in the patients with previously known heart disease. An early identification of the factors
that determine the emergence and progression of diabetes complications is essential, in order to
reduce the cardiovascular mortality and morbidity.
Key words: diabetic kidney disease, cardiovascular disease, microalbuminuria, chronic kidney
disease.
Present studies have shown the fact that
microalbuminuria and chronic kidney disease are
independently associated to a high risk of cardiovascular events, as well as to a high mortality rate
of all causes and also of cardiovascular cause, both
in the general population and also in patients with
high risk or an already present cardiovascular disease.
DEFINITIONS OF MICROALBUMINURIA AND
CHRONIC KIDNEY DISEASE (CKD)
Microalbuminuria as a predicting factor for
diabetic nephropathy in patients with type 1 diabetes
was first described in 1982 by Viberti et al. [1], and
since then, the definition of albuminuria has been
permanently readjusted in order to include all the
possible determination methods for urinary albumin
excretion. Currently, microlbuminuria is defined as
the urinary albumin excretion between 30 and 300 mg/
day if measured in a 24 hrs urine collection, 20–
200 µg/min if measured in a timed urine collection
or 30–300 mg/g if there is measured the urinary
albumin/ creatinine ratio in a spot urine collection.
Values under these limits are considered to be
ROM. J. INTERN. MED., 2010, 48, 4, 313–319
normal and those above reflect the presence of
macroalbuminuria or clinical proteinuria [2].
Chronic kidney disease is defined as the kidney
damage confirmed by kidney biopsy or by markers
of damage, or as the decline of glomerular filtration
rate (eGFR) under 60 ml/min/1.73 m2, for a period
longer than 3 months. Decreased kidney function
starts at GFR < 89 mL/min and it is considered to
be pronounced if the eGFR is < 60mL/min, which
corresponds to 1.5 mg/dL of creatinine in men and
1.3 mg/dL in women [3–5].
25–30 years ago, diabetic nephropathy was
identified with Kimmelstiel-Willson nodular glomerulosclerosis. In time, there was proven that all
types of kidney lesions overlap in each patient and,
depending on the genetic susceptibility, they may
lead to the progression towards chronic kidney
disease.
Because various authors associate the notion
of diabetic nephropathy with the old concept, there
should be more and more suggested the adoption of
a new terminology, like diabetic kidney disease
(DKD), which includes all the lesions that appear at
kidney level in a patient with diabetes mellitus.
314
Corina Grăunţeanu et al.
PREVALENCE OF CHRONIC KIDNEY DISEASE AND
DIABETIC NEPHROPATHY (DN)
In the past decades, chronic kidney disease
has become a public health problem all over the
world. In the National Health and Nutrition Examination Survey (NHANES) III (1988–1994), the
prevalence of CKD in adult population was of 11%
in the USA, approximately 20 million of American
adults suffering from CKD, out of which 8 million
having GFR < 60 mL/min/1.73 m2.
Both the incidence and the prevalence are
continually increasing. Diabetic nephropathy is, by
far, the most frequent cause of CKD, with a prevalence of 40% in patients with end-stage renal
disease (ESRD).
The microalbuminuria incidence in patients
with type 1 diabetes was of 12.6% over a period of
7.3 years in the European Diabetes (EURODIAB)
Prospective Complications Study Group [6] and of
33% in a study performed over a period of 18 months
in Denmark [7]. In patients with type 2 diabetes,
the microalbuminuria incidence was of 2.0% per
year, with a prevalence of 25% after 10 years after
diagnosis in the U.K. Prospective Diabetes Study
(UKPDS). The proteinuria prevalence is between
15 and 40% in patients with type 1 diabetes, with a
high incidence 15–20 years after diagnosing diabetes,
while in patients with type 2 diabetes, the proteinuria prevalence varies more, between 5 and
20% [7–9].
NATURAL PROGRESSION OF DIABETIC KIDNEY
DISEASE (DKD)
Primary studies highlighted a high prevalence
of microalbuminuria in patients suffering from
diabetes, but recent studies did not confirm these
outcomes. These prevalence variations may be
attributed to differences regarding age, race, blood
pressure (BP), or DKD stages in the studied population, as well as to the determination methods of
microalbuminuria.
The incidence of microalbuminuria is of 2.0%
per year since the diagnosis, the progression of
microalbuminuria to macroalbuminuria is of 2.8%
per year and from macroalbuminuria to high values
of seric creatinine is of 2.3% per year. In the
UKPDS Study, after 10 years since the diagnosis,
microalbuminuria was present in 24.9% of the
patients, macroalbuminuria or clinical proteinuria
in 5.3% of the patients and seric creatinine was
high in 0.8% of the patients [8].
2
The progression rate of diabetic nephropathy
as well as the cardiovascular risk seem to be lower
in patients with a good glycaemic and blood pressure
control [10].
The Diabetes Control and Complication Trial
(DCCT) performed on 1.441 volunteers with type 1
diabetes compared the effects of a standard control
versus the intensive glycemic control and it showed
that a well-balanced metabolism slows down the
emergence and progression of kidney and eye
damage. The Epidemiology of Diabetes Intervention
and Complications Study (EDIC) has shown that
an intensive glycemic control reduced the risk for
cardiovascular events with 42% and death from
cardiovascular causes with 57% [11] [12].
A poor glycemic control is a major risk factor
for microalbuminuria, while the progression to
advanced stages of diabetic kidney disease is
influenced by high blood pressure, dyslipidaemia
and genetic factors [13].
Recently, there has been brought into discussion the HbA1C variability and the risk for
diabetes complications. Theoretically, a variable
glycemic profile may determine a high risk for
diabetes complications by the increase of oxidative
stress. In the FinnDiane Study, performed on 2107
patients with type 1 diabetes, the HbA1C variability was associated to the progression of chronic
kidney disease (HR 1.92) and to the presence of
cardiovascular events (HR 1.98) [14].
The impact of lipids in the progression of
diabetic kidney disease was studied within the same
prospective study (FinnDiane). High values of triacylglycerol, apolipoprotein (Apo) B, ApoA-II and
HDL3-cholesterol predict microalbuminuria. The
progression to macroalbuminuria was associated to
triacylglycerol and apolipoprotein (Apo) B [15].
Also, there has recently been noticed that
high seric levels of uric acid in patients recently
diagnosed with type 1 diabetes are associated to an
increased risk for later development of diabetic
nephropathy [16].
MICROALBUMINURIA AND THE
CARDIOVASCULAR RISK
The first in reporting an association between
microalbuminuria and cardiovascular disease was
Yudkin et al. [17]. Since then, various studies
performed either on the general population or on
high risk patients have reported an association
between microalbuminuria and traditional cardiovascular risk factors (age, high blood pressure,
3
Cardiovascular risk and diabetic kidney disease
obesity, smoking, cholesterol, LDL-cholesterol, high
triglycerides, low HDL-cholesterol), as well as
other new risk factors (insulin-resistance, endothelial dysfunction, oxidative stress) [18–27].
Lipoprotein subclasses, measured by NMR
spectroscopy increase the prediction for coronary
heart disease in patients with type 1 diabetes [28].
That is why the risk factors for atherosclerosis may
also be risk factors for diabetic kidney disease:
oxidative stress, circulant immune complexes containing LDL oxidation, adhesion molecules play an
important part in the progression of diabetic
nephropathy [29].
Systemic inflammation markers and cellular
adhesion molecules are high since the early stages
of diabetic kidney disease, before the onset of the
end-stage renal disease. High levels of C-reactive
protein (CRP) may favour lipid aterogenity and
may induce the expression of cellular adhesion
molecules (ICAM-1) [30].
Moreover, there has been suggested that microalbuminuria is an independent risk factor for
morbidity and mortality of cardiovascular cause,
both in patients with and without diabetes. Further
on, there were performed prospective studies that
confirmed the independent association between
microalbuminuria and cardiovascular or total cause
mortality [31–34]. Also, the post-hoc analysis of
long-term clinical trials points out the association
between albuminuria and cardiovascular risk.
In the Heart Outcomes Prevention Evaluation
(HOPE) Study, performed on patients with a history
of cardiovascular disease or diabetes mellitus, microalbuminuria was correlated to major cardiovascular
events (relative risk – RR 1.83), to all-cause mortality
((RR 2.09) and to hospitalization for congestive
heart ((RR 3.23), the relative risk being similar in
patients with or without diabetes. The risk for developing cardiovascular events started at the level
of urinary albumin excretion under the cut-off value
for microalbuminuria and has gradually increased.
For each growth of urinary albumin excretion of
0.4 mg/mmol, the risk for cardiovascular events
increased by 5.9% [35].
In a subpopulation of the NHANES II study,
examined between 1976 and 1980 and monitored
on a period of 16 years, the hazard rate for
cardiovascular and all-cause mortality was of 1.57
and 1.64 for patients with proteinuria between 30–
299 mg/dL, and 1.77, 2.00 respectively, in patients
with urinary protein excretion of 300 mg/dL in
comparison to the patients with levels below 30 mg/
dL [36].
315
The results of the European Prospective
Investigation into Cancer and Nutrition Study,
Norfolk, UK (the EPIC-Norfolk Study) support the
information above – after a monitoring period of
6.2–7.2 years the presence of albuminuria was
independently associated with a significant greater
risk of 36% for incident CHD, 49% for stroke,
103% for CV mortality and 48% for all-cause
mortality. The important fact is that the risk for
cardiovascular events was higher in the presence of
macroalbuminuria [37].
In a recent analysis of the New ONTARGET
Study, the doubling of albuminuria after 2 years,
observed in 28% of the participants, was associated
to a dramatic mortality growth (50%) (HR 1.47;
p<0.0001) [38].
It is still unknown if the decrease of urinary
albumin excretion is correlated to the reduction of
cardiovascular events. Many factors intervention in
early stages of diabetic nephropathy may reduce the
risk for clinical nephropathy [39]. The reduction of
albuminuria in the first 6 months seems to provide
a cardiovascular protection according to the results
obtained in the RENAAL Study [40]. Also, the
ADVANCE Study, including 12877 patients with
type 2 diabetes, resulted in the reduction of albuminuria progression by 22%, the reduction of
major kidney objective, the doubling of creatinine
by 21% as well as the reduction by 14% of
coronary events and by 18% of cardiovascular
mortality [41].
Surprisingly, in a recent study performed by
Mauer, inhibiting the RAA system did not reduce
the microalbuminuria incidence, the decline in
kidney function or the development of morphological kidney lesions. The incidence of microalbuminuria after 5 years was of 6% in the placebo
group and significantly higher, 17%, in the Losartan
group (P=0.02), but not in that with Enalapril 4%
(P=0.96) [42].
The screening for microalbuminuria may be
an important method for identifying the patients
with high cardiovascular risk. Patients with diabetes,
high blood pressure, dyslipidaemia and other risk
factors for cardiovascular disease progress to major
cardiovascular events, passing through an asymptomatic stage, characterized by a subclinical damage
of target organs (left ventricular hypertrophy (LVH),
peripheral atherosclerosis).
Microalbuminuria was associated to LVH
and to a high left ventricle mass in various studies,
that is why microalbuminuria is considered to be a
subclinical factor for cardiovascular damage [43].
316
In the Left Ventricular Function and Hemodynamic Features of Inappropriate LVH in Patients
With Systemic Hypertension (LIFE) Study, urinary
albumin excretion was correlated to LVH, initially
and after one year of treatment, independently of
age, blood pressure and glucose level [44].
Recently, McQuarrie has also shown that the
level of urinary albumin excretion is associated
with the left ventricle mass independently of BP.
The left ventricle mass was measured by magnetic
resonance imaging, a method that is not dependent
on the volume, like echocardiography [45].
The level of urinary albumin excretion is
associated to the severity of ischaemia and reperfusion, albuminuria early increases in patients with
acute myocardial infarction (heart attack), and its
level is proportional to the severity of the infarction
[46].
CHRONIC KIDNEY DISEASE AS A
CARDIOVASCULAR RISK FACTOR
When the therapy for substituting kidney
functions is initiated, the cardiac function is severely
affected in the majority of patients with CKD,
which suggests the fact that risk factors act even
from the early stages of chronic kidney disease [47].
There is a permanent association between the
level of urinary albumin excretion and the risk for
cardiovascular disease, macroalbuminuria and clinical
proteinuria being associated to a higher risk for
cardiovascular events than microalbuminuria [48–
50].
Due to the fact that macroalbuminuria is a
symptom of clinical nephropathy and is associated
to a more rapid damaging of the kidney function, it
is likely that the mechanisms involved in the
increase of the cardiovascular risk in patients with
macroalbuminuria to be different from the patients
with microalbuminuria. The cardiovascular risk for
patients with macroalbuminuria may be attributed
both to the generalized vascular damage, as microalbuminuria, and to the presence of some specific
factors of uremia.
Alongside the traditional risk factors (diabetes,
high blood pressure, dyslipidaemia, obesity) or the
non-traditional risk factors (hyperhomocysteinemia,
high fibrinogenous), while the eGFR decreases
under 60 ml/min/1.73 m2 and the physiological
kidney functions are damaged, there appear other
risk factors correlated to the decrease of kidney
function, factors that contribute to the increase of
cardiovascular risk. These factors become clinically
obvious when eGFR drops under 45 ml/min/1.73 m2.
4
Anemia secondary to the reduction of erythropoietine by the damaged kidneys and alteration
of the phosphorus-calcium metabolism are the most
important specific factors of uremia.
Anemia is a major risk factor, associated to
adverse cardiovascular effects by favouring the
development of LVH [51].
Alterations of the parathormone metabolism,
of calcemia and seric phosphorus are associated to
cardiovascular calcifications, to arteriosclerosis and
to a high cardiovascular risk [52–54]. Recent studies
have shown that hyperphosphatemia induces the
proliferation and differentiation of vascular endothelial cells into cells with a similar activity to that
of osteoblasts and, thus, promoting vascular calcification [55].
Also, there has recently been shown that low
seric values of Vitamin D contribute to the increase
of cardiovascular cause mortality in patients with
chronic kidney disease. Correction of Vitamin D
deficit and anemia, as well, may decrease the risk
for cardiovascular risk in these patients [56].
The fact that patients with chronic kidney
disease have a high risk for cardiovascular cause
mortality was noticed 30 years ago. Since then,
various studies have investigated the association
between renal function and cardiovascular or allcause mortality in patients with CKD, with or without any cardiovascular disease [57] [58].
Several studies have shown that a slight or
moderate increase of the creatinine level is associated
to a high risk for cardiovascular events and
cardiovascular mortality [59–62]. The limitations
of these studies are due to various factors, like: the
use of creatinine for evaluating kidney function, a
small number of subjects, the selection of cardiovascular disease or aged population.
Also, a recent analysis has examined the
association between kidney function in patients
with cardiovascular disease and chronic heart failure
in a population within the Candesartan in Heart
Failure Program: Assessment of Reduction in Mortality and Morbidity (CHARM). After a monitoring
period of 34.4 months, the hazard rate for primary
events, cardiovascular cause mortality or hospitalization for the exacerbation of chronic heart failure
was of 1.54 in the patients with eGFR between 45–
60 ml/min/1.73 m2, and 1.86 in those with eGFR<
45 mL/min/1.73 m2, comparatively to those with
eGFR > 60 mL/min/1.73m2. This fact did not
correlate with the ejection fraction of the left
ventricle, which is an independent predictor for
cardiovascular risk [63].
Due to the importance of clinical data and
low cost, microalbuminuria and the rate of glomerular
5
filtration should be introduced in the clinical
practice for the evaluation of cardiovascular risk,
especially in the patients with previously known
heart disease. An early identification of the factors
that determine the emergence and progression of
diabetes complications is essential, in order to
reduce the cardiovascular mortality and morbidity.
317
For a better understanding regarding diabetes
mellitus and its complications, further clinical
studies are necessary. At present, there are current
clinical trials that study therapies preventing the
adverse effects of hyperglycaemia: advanced
glycation end products inhibitors, protein kinase C
inhibitors and aldose reductase inhibitors.
Fig. 1. – Cardiovascular mortality rate associated to eRFG, Am J Epidemiol., 2008, 167:1226–1234.
___________________________________________________________________
În ultimele decenii boala cronică de rinichi (BCR) a devenit o problemă de
sănătate publică în toată lumea. Incidenţa şi prevalenţa este în continuă creştere.
Nefropatia diabetică este, de departe, cea mai frecventă cauză a BCR cu o
prevalenţă de aproximativ 40% la pacienţii cu BCR în stadiul final. Studiile
efectuate până în prezent au evidenţiat faptul că microalbuminuria şi boala
cronică de rinichi sunt independent asociate cu un risc crescut de evenimente
cardiovasculare, precum şi cu o mortalitate crescută de toate cauzele şi de cauză
cardiovasculară, atât în populaţia generală, cât şi la pacienţii cu factori de risc
sau cu boală cardiovasculară deja prezentă. Există o asociere permanentă între
nivelul excreţiei urinare de albumină şi riscul de boală cardiovasculară,
macroalbuminuria şi proteinuria clinic manifestă sunt asociate cu un risc mai
mare de evenimente cardiovasculare decât microalbuminuria. Datorită importanţei
lor clinice şi costului scăzut, microalbuminuria şi rata filtrării glomerulare ar
trebui introduse în practica clinică pentru evaluarea riscului cardiovascular, în
special la pacienţii cu boală cardiacă cunoscută. Este esenţială identificarea
precoce a factorilor care determină apariţia şi progresia complicaţiilor diabetului
pentru a reduce mortalitatea şi morbiditatea cardiovasculară.
___________________________________________________________________
Corresponding author: Dr. Grăunţanu Corina, MD
Clinical Emergeny Hospital Craiova, Romania,
Nephrology Clinic
1, Tabaci Str., Craiova, Romania
E-mail: grcorina07@yahoo.com
318
6
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ORIGINAL ARTICLES
Blood Pressure Pattern and Heart Rate Variability in Normotensive Patients
with Type 2 Diabetes Mellitus
LAURA POANTĂ1, ANCA CERGHIZAN2, DANA POP3
1
“Iuliu Haţieganu” University of Medicine and Pharmacy, Second Department of Internal Medicine, Cluj-Napoca, Romania
2
County Hospital Cluj, Diabetes Center, Cluj-Napoca
3
“Iuliu Haţieganu” University of Medicine and Pharmacy, Hospital of Cardiac Reabilitation, Cluj-Napoca, Romania
Ambulatory blood pressure monitoring (ABPM) has shown that almost one third of presumed
normotensive patients with type 2 diabetes mellitus have instead masked hypertension. There is also a
relationship between cardiovascular autonomic neuropathy and blood pressure patterns even in
normotensive patients with diabetes mellitus. The aim of the present study was to analyze the blood
pressure patterns in type 2 diabetic patients without any history of hypertension and to establish the
connection between heart rate variability parameters, ultrasound parameters and ABPM parameters.
Material and methods. Fifty-two subjects with type 2 diabetes, aged 59 (±6), were
consecutively recruited at the Internal Medicine Department of the County Hospital in Cluj. Informed
consent was obtained from all participants. A control group of 47 subjects, age and sex matched, was
also analyzed.
Results. More than half of the patients had a non-dipping pattern, despite the fact that they are
considered normotensive patients. Heart rate variability parameters are lower in the non-dipping
group, but the difference is significant only for vagal activity. Left ventricle is thicker in non-dipping
group. The mean age of the non-dipping group (61.23 ±2.02 years) was significantly higher than the
age of the dipping group (55.11 ±3.88 years) (p<0.01).
Discussions and conclusion. We found a great number of patients with diabetes mellitus and
with altered patterns of blood pressure, even if they were previously considered as normotensive. The
non-dipping pattern is associated with abnormal values of heart rate variability parameters and with
thicker left ventricle walls, but the differences are not always statistically significant. It is important to
closely monitorize the patients with diabetes mellitus even if they have normal office blood pressure
determinations, mainly those with a history of more than 5 years of the disease.
Key words: ambulatory blood pressure monitoring, blood pressure.
Ambulatory blood pressure monitoring (ABPM)
has shown that almost one third of presumed
normotensive patients with type 2 diabetes mellitus
have instead masked hypertension [1]. The thickness
of inter-ventricular septum and posterior wall were
significantly increased in these patients, as compared
with confirmed normotensive patients. ABPM is
important for identifying these high-risk patient
groups and ensuring early interventions. Also, left
ventricle hypertrophy parameters are greater among
hypertensive patients with diabetes mellitus, as they
had a higher rate of non-dipping pattern. Another
study showed that only night-time systolic blood
pressure (BP) is associated with cardiovascular and
cerebro-vascular morbidity and mortality, in hypertensive patients with type 2 diabetes mellitus [2].
Pulse pressure is another parameter which proved
itself very useful in mortality prediction, but also
when measured by ABPM [3].
ROM. J. INTERN. MED., 2010, 48, 4, 321–327
ABPM allows the evaluation of some important
BP parameters such as the 24 h general mean,
daytime and nighttime systolic and diastolic BP
means, BP loads and the absence of nocturnal drop
of BP (dipping), as well as the identification of
white-coat and masked hypertension [4].
On the other hand, there is a relationship
between cardiovascular autonomic neuropathy and
blood pressure patterns even in normotensive patients
with diabetes mellitus, autonomic imbalance being
associated with abnormal patterns of 24 hours
blood pressure measurements (non-dipping pattern,
higher values of nocturnal blood pressure) [5–8].
The aim of the present study was to analyze
the blood pressure patterns in type 2 diabetic patients
without any history of hypertension and to establish
the connection between heart rate variability parameters (as the expression of autonomic balance),
ultrasound parameters (accounting for left ventricle
dimensions) and ABPM parameters.
322
Laura Poantă et al.
MATERIAL AND METHODS
Fifty-two subjects with type 2 diabetes, aged
59 (±6), were consecutively recruited at the Internal
Medicine Department of the County Hospital in
Cluj. Informed consent was obtained from all participants. A control group of 47 subjects, age and sex
matched, was also analyzed.
Inclusion criteria were: age under 65 years
and values of casual BP within normal range
(<140/90 mm Hg) without antihypertensive treatment.
Exclusion criteria were: impaired renal
function, clinically significant abnormality of hepatic,
haemopoietic, respiratory or endocrine function, history and/or evidence of cerebro-vascular or coronary
heart disease, arrhythmias, antihyper-tensive treatment and use of any other medication affecting
cardiovascular or autonomic nervous function.
BP monitoring
Non-invasive 24 h ambulatory BP monitoring
(ABPM) was performed using an oscillometric
recorder. The device was programmed to measure
BP every 20 minutes on daytime and every 30 minutes on nighttime, for 24 h. Patients were hospitalized and were following the hospital routines,
which allowed a better standardization of recording
conditions. Only the 24 h recordings that contained
a percentage of measurement errors under 30%
were accepted as valid. Systolic (SBP) and diastolic
BP (DBP) measurements were averaged for the day
and the night periods, according to reported time of
waking up and going to bed (6 a.m. and 10 p.m.,
respectively). The percentage change from day to
night in BP was calculated as: (day BP–night BP)
100/day BP. Non-dipper pattern is defined as a
reduction with less than 10% from the daytime
mean, or a day/night ratio over 0.9.
Blood pressure was also measured with a
classical sphyngomanometer at two different moments,
in the morning (awake BP, at 6 a.m.) and in the
evening (asleep BP, at 10 p.m.), at the same hour
for all the patients. We created two sub groups (dippers
and non-dippers) and we compared the results.
Heart rate variability
HRV was measured using a 24 hour ECG
monitoring system (Holter Digital recorder ASPEKT
2
812) in all subjects during normal daily activity.
Time domain parameters used are: SDNN expressed
in milliseconds (ms) accounts for standard deviation of all NN intervals. SDANN expressed in ms
accounts for standard deviation of the averages of
NN intervals in all 5 min segments of the entire
recording. pNN50% is the number of pairs of
adjacent NN intervals divided by the total number
of all NN intervals. Frequency domain parameters
used are: low frequency and high frequency
components of spectral analysis expressed in
squared milliseconds (ms2 or normalized units).
Echocardiography
Standard two dimensional and Doppler echocardiography was performed in all the subjects.
The standard views and the measurements of heart
chambers were performed according to American
Society of Echocardiography recommendations [9]
and the same clinician performed all the examinations. The following parameters were obtained
for the study: left ventricular diastolic diameter, left
ventricular systolic diameter, inter-ventricular septum
thickness (IVST) and posterior wall thickness
(PWT), expressed in millimeters.
Statistical analysis
Continuous variables were expressed as mean
(SD). Differences were tested for significance by
unpaired Student’s t test. Upper and lower 95%
confidence limits for each variable were calculated
from the two tails of the Student’s t test distribution. We compared the results among the study
group and with control group. A p value <0.05 was
considered significant. Pearson correlation coefficients
were used to explore linear relationships between
the study variables. Statistics were performed with
SPSS for Windows, version 10.0.
RESULTS
General characteristics of the DM patients are
shown in Table I.
Characteristics of the DM patients between
the two subgroups, dippers and non-dippers, are
shown in Table II.
Heart rate variability parameters in dippers
and non-dippers are shown in Table III.
3
Blood pressure and heart rate variability in diabetes mellitus
323
Table I
Demographic characteristics of diabetic patients and control group
Parameter
Diabetes mellitus
Control group
52
47
B: 30 (%)
B: 27 (%)
F: 22 (%)
F: 20 (%)
59 (±6)
58 (±5)
Disease duration (years)
7.21 (±7.95)
NA
Total-cholesterol (mg%)
244.88 (±76.93) §
176 (±18.22)
Tryglicerides (mg%)
201.45 (±89.07) §
154.45 (±85.07)
Fasting glucose (mg%)
131.35 (±61.13) §
81.22 (±14.03)
7.02 (±2.66) §
4.6 (±1.65)
Morning: 129 (± 8)
Morning: 130 (± 7)
Evening:
Evening:
Morning: 81 (± 6)
Morning: 79 (± 5)
Evening:
Evening:
Systolic: 120 (± 11)
Systolic: 114 (± 7.5)
Diastolic: 72 ± 6.1
Systolic: 122 (± 9.2)
Systolic: 119 (± 9.5)
Number
Gender
Age
HbA1 (%)
Systolic blood pressure (office)
Diastolic blood pressure (office)
24-h (mm Hg)
Day (mm Hg)
Night (mm Hg)
∆ day – night (%)
Systolic: 6.7 ± 6.3
Systolic: 9.1 ± 5
Diastolic: 14.5 ± 4.2
More than half of the patients had a nondipping pattern, despite the fact that they are
considered normotensive patients. The mean values
obtained with ABPM are higher in non-dipping
group, but the differences are not statistically
significant; ∆ day – night (%) parameter is significantly affected in non-dippers, but regarding only
systolic blood pressure. The awake systolic BP was
not significantly different between the dipping and
the non-dipping groups (p>0.05, Table II), but the
awake diastolic BP in the non-dipping group was
lower (p=0.03). The asleep systolic BP and diastolic
BP were, as expected, both significantly higher in
the non-dipping group (p<0.05). The mean age of
the non-dipping group (61.23 ±2.02 years) was significantly higher than the age of the dipping group
(55.11 ±3.88 years) (p<0.01) (Table II). Weight,
body mass index (BMI) and duration of diabetes
were also significantly higher in non-dippers
(Table II). Glycemic control and diabetes treatment
did not differ significantly between the two groups.
The total cholesterol concentration was signifycantly lower in the non-dipping group concentrations.
Heart rate variability parameters
There are differences between the two groups
regarding HRV parameters, but only for HF and
HF n.u. (as the expression of parasympathetic
activity) the differences are statistically significant
(Table III). There are strong positive correlations
between HF values and ∆ day – night (%)
parameter (only regarding systolic blood pressure)
(r = 0.54) and also between HF and HF n.u. and
office diastolic blood pressure measured in the
evening (r = 0.60 and 0.58, respectively).
324
4
Table II
Characteristics of diabetes patients according to blood pressure pattern over 24 hours
Non-dippers
Dippers
Value (mean ±SD) or N, %
Value (mean ±SD) or N, %
31
21
B: 17 (54.8%)
B: 11 (52.4%)
F: 14 (45.2%)
F: 10 (47.6%)
Age
61.23 (±2.02)
55.11 (±3.88)*
10.14 (±9.67)
6.88 (±10.55)*
Insulin treatment
12 (38.7%)
8 (38%)
Oral treatment (sulfoniluree)
7 (22.5%)
5 (23.8%)
Oral treatment (biguanids)
8 (25.8%)
5 (23.8%)
Cholesterol
206.58 (±76.63)
269.18 (±67.36)*
Tryglicerides
191.45 (±100.05)
184.68 (±99.11)
30.9 (±8.2)
24.8(±11.3)*
159.72 (±23.13)
139.72 (±43.76)
7.80 (±1.15)
7.40 (±1.66)
Morning: 128.9 (± 8)
Morning: 130 (± 7)
Evening: 131 (±6)
Evening: 116 (±8)*
Morning: 70.8 (± 6)
Morning: 79 (± 5)*
Evening: 70 (±5.5)
Evening: 63 (± 6.4)*
Systolic: 121 (± 9.5)
Systolic: 117 (± 9.5)
Systolic: 124 (± 8.9)
Systolic: 122.8 (± 9.5)
Systolic: 4.4 ± 7.4
Systolic: 12.7 ± 3*
Parameter
Number
Gender
BMI
Fasting plasma glucose
HbA1
Systolic blood pressure (office)
Diastolic blood pressure (office)
24 h (mm Hg) (ABPM)
Day (mm Hg) (ABPM)
Night (mm Hg) (ABPM)
∆ day – night (%)
Ultrasound parameters
Left ventricular diameters, inter-ventricular
septum thickness and end-diastolic posterior wall
thickness are greater among patients with type 2
diabetes and non-dipper patterns of blood pressure,
but the differences are not statistically significant
(Table II).
DISCUSSION
Only few data are available on the factors
involved in 24 h BP pattern in type 2 diabetic
patients, [10–13] and generally include both normotensive and hypertensive patients. A conclusive
link between abnormal circadian rhythm of BP and
5
autonomic neuropathy has not been established yet.
Lower HRV parameters were found to be related to
mean 24 h SBP and our study supports this connection. Recent data tend to indicate a significant
relationship between hypertension and autonomic
neuropathy in diabetes both in the sense of a
correlation of SBP to autonomic test impairment
[14] [15] and in the suggestion of hypertension as a
risk factor for peripheral neuropathy [16] [17].
HF and HF n.u. (which account for vagal
activity) were in fact the only parameters of
325
HRV which significantly correlate with nondipping pattern in our study, although all the
HRV parameters were lower in non-dipping group,
suggesting impaired cardiovascular autonomic functioning.
Our study has considered only normotensive
type 2 diabetic patients, most of them (over 50%)
showing a non-dipping nocturnal pattern of BP,
especially in those with abnormal HRV. The
differences between groups involved both SBP and
DBP, but in slightly different manners.
Table III
Heart rate variability parameters according to dipper or non-dipper profile of the patients
Dippers
Non-dippers
(mean ±SD)
(mean ±SD)
SDNN
116.17 (± 41.24)
111.37 (± 39.42)
SDANN
89.64 (± 44.18)
84.94 (± 59.28)
p50NN %
24.72 (±12.98)
22.53 (±16.85)
LF
637.19 (± 285.35)
564.11 (± 280.75)
HF
531.78 (± 367.28)
436.68 (± 337.13)*
LFnu
39.47 (± 12.09)
32.17 (± 17.05)
HFnu
23.13 (± 8.13)
15.94 (± 6.11)*
LF/HF
1.74 (± 0.53)
1.70 (± 0.61)
Parametru
The decision to exclude type 2 diabetic patients
with hypertension or other cardiovascular disease
was based on the need to avoid factors potentially
interfering with autonomic function assessment
such as hypertensive drugs or diseases affecting
cardiovascular system [18]. Thus, we cannot exclude
that with the occurrence of cardiovascular disease,
further factors beyond autonomic function could
affect BP circadian pattern in type 2 diabetic patients,
as stated in other studies [19].
Qualitative and quantitative differences in
daily activities or nocturnal sleep can affect BP
monitoring. In this study day and night periods
were fixed intervals. ABPM was performed when
patients were hospitalized, thus allowing a better
standardization of recording conditions in particular
with regard to physical activity [19].
The present study has demonstrated that nondipping of nocturnal blood pressure in people with
type 2 diabetes was strongly associated with increasing age and with a longer disease duration.
Other studies (by Nakano et al. [20] and Sturrock
et al. [21]) have shown an association between
increasing age and non-dipping status in people
with diabetes. Of course, determination of the true
duration of diabetes is difficult, as type 2 diabetes
often remains subclinical for many years before the
diagnosis.
In a previous study, glycemic control
correlated with non-dipping, with higher levels of
glycemic control observed in non-dippers [22]. In
our study, also the glycemic control was associated
with non-dipping pattern, but the difference was
not statistically significant.
326
The total cholesterol level was significantly
lower in the non-dipping cohort, but triglyceride
and high-density lipoprotein levels were not
significantly different between the two groups. This
may reflect the higher incidence of the use of
statins in the non-dippers. It was also apparent that
non-dipping status was associated with increased
body weight and BMI.
Non-dipping of nocturnal blood pressure is of
prognostic importance. Evidence suggests that a
blunted reduction in the normal nocturnal blood
pressure fall may play a pivotal role in the
development of target organ damage [23–25] such
as left ventricular hypertrophy, which is a powerful
predictor of cardiovascular mortality [26] [27].
Also in our study, non-dipping pattern was associated
6
with higher values of left ventricle diameters and
wall thickness, but the differences between those
and dipping pattern were not statistically significant.
CONCLUSIONS
Blood pressure determination by ABPM is
capable of identifying more adequately stratifying
patients at risk for developing chronic complications
of DM, and has become an indispensable
instrument for BP measurement in these patients. It
is of a great importance the fact that blood pressure
patterns are modified even in normotensive patients
especially associated with heart rate variability
changes.
___________________________________________________________________
Scopul lucrării. Măsurarea ambulatorie a tensiunii arteriale a arătat că
aproape o treime dintre pacienţii presupuşi normotensivi cu diabet zaharat tip 2
aveau, de fapt, hipertensiune arterială (HTA) mascată. Există, de asemenea, o
relaţie între neuropatia autonomă cardiovasculară şi patternurile presionale chiar
şi la pacienţii normotensivi cu diabet zaharat (DZ). Scopul prezentei lucrări este
de a analiza patternurile tensiunii arteriale la pacienţii cu DZ tip 2 fără istoric de
HTAşi de a stabili conexiunea dintre parametrii variabilităţii frecvenţei cardiace,
cei ai tensiunii arteriale şi cei ecocardiografici.
Material şi metode. Cincizeci şi doi pacienţi cu DZ tip 2, cu vârsta medie
59 (±6), au fost recrutaţi consecutiv prin ambulatorul de medicina interna al
Spitalului Clinic Cluj. Consimţămânul informat a fost semnat de toţi participanţii.
A fost folosit un grup martor alcătuit din 47 de indivizi.
Rezultate. Mai mult de jumătate dintre pacienţi au avut un pattern tensional
de tip non-dipping, în ciuda faptului că erau consideraţi normotensivi. Parametrii
variabilităţii frecvenţei cardiace au fost mai scăzuţi la cei cu acest pattern
tensional, dar diferenţele au fost semnificative statistic doar pentru activitatea
vagală. Ventriculul stâng este mai gros la pacienţii non-dipping. Vârsta medie a
celor cu pattern non-dipping (61.23 ± 2.02 ani) a fost semnificativ mai mare decât
a celor cu pattern tensional normal (55.11 ± 3.88 years) (p < 0.01).
Discuţii şi concluzii. Un număr mare de pacienţi cu diabet zaharat au avut
patternuri anormale ale tensiunii arteriale, chiar dacă erau consideraţi
normotensive. Paternul de tip non-dipping este asociat cu anomalii ale variabilităţii
frecvenţei cardiace şi cu grosime mai mare a pereţilor ventriculului stâng, dar
diferenţele nu sunt întot deauna semnificative statistic. Este importantă monitorizarea atentă a pacienţilor cu DZ, chiar dacă tensiunea lor arterială la cabinet
este normală, în special dacă durata bolii depăşeşte 5 ani.
___________________________________________________________________
Acknowledgement. Research supported by the CNCSIS project number 1277 of the Romanian Ministry of Education and Research.
Corresponding author: Laura Poanta, MD
2–4, Clinicilor, 400013, Cluj-Napoca, Romania
E-mail: laurapoanta@yahoo.com
7
327
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Study of Endothelin-1 in Acute Ischemic Stroke
VIOLETA SAPIRA1-2, INIMIOARA MIHAELA COJOCARU2-3, GABRIELA LILIOS1, M. GRIGORIAN1, M COJOCARU4
1
“Ovidius” University, Faculty of Dental Medicine, Constanţa
Department of Neurology, Colentina Clinical Hospital, Bucharest
3
“Carol Davila” University of Medicine and Pharmacy, Bucharest
4
“Titu Maiorescu” University, Faculty of Medicine, Bucharest
2
Endothelins (ETs) are potent vasoconstrictor and may play a role in the pathophysiology of
several cardiovascular diseases. Endothelin-mediated vasoconstriction may enhance ischemic neuronal
damage. The study aimed to find out whether the plasma ET-1 levels may serve as marker of early
ischemic stroke. Plasma ET-1 levels were tested in 20 patients with acute ischemic stroke, mean age
63.7 ± 5.03 years, 12 men and 8 women, within 24 hours of stroke onset as compared to 10 sex- and
age-matched control subjects; only the patients with normal CT-scan at admission were included in
the study. Plasma ET-1 was measured by ELISA. The results were statistically analyzed by Student
test and a p < 0.05 (95% CI) was considered statistically significant. ET-1 levels in patients with
hemiplegia and normal CT-scan at admission were significantly higher as compared to control group
(0.0910 ± 0.0256 pg/mL vs. 0.0490 ± 0.0185 pg/mL, p < 0.0001) (95% CI). Ischemic stroke is
associated with acute and marked increased levels of ET-1 in plasma. This may reflect enhanced
production by damaged endothelial cells within the infarcted lesion. ET-1 may be used as additional
marker of cerebral ischemia in selected cases to distinguish between the onset of an ischemic stroke
and other non-vascular diseases presenting similar symptoms.
Key words: endothelin-1 (ET-1), early ischemic stroke.
The endothelial cells synthetize many active
substances in order to maintain the potency of the
blood vessels and the fluidity of blood, including
endothelin-1 (ET-1).
In healthy humans, levels of ET-1 measured
by radioimmunoassay of plasma have been estimated
to range from 0.26 to 5 ng/L. However, the concentrations of ET-1 are likely to be much higher at the
interface of the endothelin and smooth muscle
(because of the small volume of distribution) than
in the blood stream [1].
ET-1 is the most active pressor substance yet
discovered [2–4].
Cerebral arterial endothelial cells may produce
ET-1 [5].
Current interventions for ischemic stroke being
time dependent, the stroke diagnosis must be quick.
The research of new biomarkers may help in
the evaluation of patients with potential ischemic
stroke [6] [7].
The study aimed to find out whether the plasma
ET-1 levels may serve as marker of early ischemic
stroke.
ROM. J. INTERN. MED., 2010, 48, 4, 329–332
Plasma ET-1 levels were tested in 20 patients
with acute ischemic stroke, mean age 63.7 ± 5.03
years, 12 men and 8 women, within 24 hours of stroke
onset as compared to 19 sex- and age-matched
control subjects.
At each sampling, the patients underwent a
complete neurological evaluation. All stroke risk
factors were recorded, an array of laboratory tests
were performed, and computer tomography (CT)
was performed and subsequently, only the patients
with normal CT-scan at admission were included in
the study.
Exclusion criteria were: intracerebral hemorrhage, hemorrhagic infarction, brain tumor, demyelinating disease, vascular headache, acute or chronic
infection, inflammatory disease of the central nervous
system (CNS), systemic metabolic disease, or systemic vasculitis.
Plasma ET-1 was measured by ELISA [8].
The results were statistically analyzed by
Student t test and a p<0.05 (95% CI) was considered
statistically significant.
330
Violeta Şapira et al.
For all eligible patients the informed consent
was given for the use of their blood in this study.
The research received approval by the ethical
committee of the institution.
RESULTS
ET-1 levels in patients with hemiplegia and
normal CT-scan at admission were significantly
higher as compared to control group (0.0910 ±
0.0256 pg/mL vs. 0.0490 ± 0.0185 pg/mL, p <
0.0001) (95% CI).
DISCUSSION
ET-1 induces a vasoconstrictor effect on
blood vessels of the brain, regional blood flow and
cerebral microvasculature, fact demonstrated in the
choroid plexus of the rabbit [9] and in the large
cerebral arteries of cats [10]. This vasoconstriction
effect on cerebral microvessels is dose-dependent
in response to ET-1 but not ET-3 [11] and last for
24 to 2 hours [12] [13].
Some authors have observed that ET-mediated
vasoconstriction aggravated the ischemic effect of
an existing cerebral lesion and was associated with
an increased ET-1 concentration in brain tissue and
plasma [14–16].
The ET-1-mediated ischemic effect and the
neurodestructive mechanism could be revealed by
specific ET-receptor blocking [17–19] as well as
by N-methyl-D-aspartate antagonists [20].
It was found a factor that decreases ET-1 levels
in the endothelial cell microvessels, and is released
from cultured astrocytes. Astrocytes may be also
involved in a regulatory loop of ET-1 production.
At the level of the blood-brain-barrier (BBB) [21].
ET-1 and ET-3 were both detected in astrocytes
after focal or global ischemia, specially in damaged
hippocampal tissue [22].
In animal models studies it was shown that
administration of ET-1 into the CSF is followed by
severe vasospasm lasting for up to 72 hours [12]
[13].
Intraventricular administration of ET-1 reduced
cerebral blood flow and led to the development of
brain infarction [23]. Injection of ET-1 into the
lateral ventricles of rats induced hypometabolism
of various brain structures [24]; this effect could be
completely reversed by intraventricular ET-1 receptor
antagonist [17].
In serum of patients with acute vascular
headache [25] and in patients with subarachnoid
2
hemorrhage [26–30] increased ET-1 concentrations
have been demonstrated.
In patients with ischemic stroke plasma ET-1
levels were examined at various stages after the
event and were found to be elevated [31–35].
We have observed significantly higher plasma
ET-1 levels in patients with hemiplegia at the onset
of acute ischemic stroke.
It was demonstrated the elevation of ET level
in neural tissue after focal ischemia and in the
extracellular fluid in global ischemia [36].
Some authors have observed that ET-1
concentration in the plasma is correlated with the
clinical status on admission and the final outcome,
but not with the size of infarction [32] [37].
It was found a discrepancy between the
normal ET level in patients with ischemic stroke
found by some researches and the high level of ET
observed by other studies, the explanation may be
the very early stage of measurement in the first
group [38] [39].
The ET-1 levels were significantly higher in
the CSF of patients with large cortical infarcts
compared with smaller subcortical lesions [38].
Patients with mitral stenosis and history of
cerebral thromboembolism did not present elevated
levels of plasma ET-1 [40].
In a group of patients after 1 year of followup after ischemic stroke plasma ET-1 levels were
higher in patients with cardioembolic disease when
compared with patients with small- and large vessel
disease [34].
ET-1 causes vasoconstriction if applied from
the adventiceal side [41], so explaining the mechanism of such reaction.
In patients with alteration of BBB, ET-1 may
have access also to the vascular smooth muscle
cells and thus induce an additional contraction
mechanism. New trends in stroke therapy are administration of combined ET-A and ET-B blockers
for protection against the development of stroke
[42–48].
CONCLUSIONS
Ischemic stroke is associated with acute and
marked increased levels of ET-1 in the plasma.
This may reflect enhanced production by
damaged endothelial cells within the infarcted lesion.
ET-1 may be used as additional marker of
cerebral ischemia in selected cases to differentiate
between the onset of an ischemic stroke and other
non-vascular diseases presenting similar symptoms.
3
Endothelin-1 in acute ischemic stroke
331
Endotelinele sunt vasoconstrictoare puternice şi pot prezenta un rol în
fiziopatologia unor boli cardiovasculare. Vasoconstricţia mediată de endotelină
poate agrava leziunea neuronală ischemică. Studiul a urmărit dacă nivelurile
plasmatice ale ET-1 pot fi utilizate ca marker ale stroke-ului ischemic la debut. Au
fost testate nivelurile plasmatice ale ET-1 la 20 pacienţi cu stroke ischemic acut,
vârsta medie 63,7 ± 5,03 ani, 12 bărbaţi şi 8 femei, în primele 24 ore de la debut
comparativ cu 10 martori cu vârstă şi sex asemănătoare; au fost incluşi în studiu
numai pacienţii cu CT scan normal la internare. Probele de sânge au fost analizate
cu ELISA. Rezultatele au fost prelucrate statistic prin testul t, un p < 0.05 (95% CI) a
fost considerat semnificativ statistic. Nivelurile ET-1 la pacienţii cu hemiplegie şi
CT scan normal la internare au fost semnificativ mai mari comparativ cu ale
martorilor (0,0910 ± 0,0256 pg/ml vs. 0,0490 ± 0,0185 pg/ml, p < 0.0001) (95% CI).
Stroke-ul ischemic este asociat cu creşterea marcată şi acută a nivelurilor
plasmatice ale ET-1. Aceasta poate reflecta creşterea producţiei de către celulele
endoteliale afectate în leziunea de infarct. ET-1 poate fi utilizată ca marker
suplimentar al ischemiei cerebrale la cazuri selectate pentru a deosebi debutul
unui stroke ischemic de alte afecţiuni nevasculare cu simptome similare.
__________________________________________________________________
Corresponding author: Senior lecturer Violeta Sapira MD, PhD
“Ovidius” University, Constanta, Faculty of Dental Medicine,
Romania
E-mail: violetasapira@yahoo.com
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Received August 22, 2010
Relationship of Humour with Oral Health Status and Behaviours
ALEXANDRINA LIZICA DUMITRESCU1, CARMEN TOMA2, VIORICA LASCU2
2
1
University of Tromsø, Norway
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
A sense of humor and an ability to laugh reduces stress, enhances hope, relieves tension, and
stimulates the immune system. This study explored the role of humour on oral health status and
behaviors. The factor structure and the construct validity of the Romanian version of the Multidimensional Sense of Humour Scale (MSHS) was also assessed.
Material and Methods. The present study sample consisted of 213 first year dental students.
The questionnaire included information about socio-demographic factors, behavioral variables and
self-reported oral health status. Sense of humour was assessed using the Multidimensional Sense of
Humour Scale (MSHS) (Thorson and Powell, 1993).
Results. There was no significant gender difference with regard to total MSHS scale of
humour; however, a detailed analysis of the factors and items reveals some differences in constructions of sense of humor between males and females. We have compared the highest and the
lowest 30% of individuals with respect to their MSHS humour scores, in order to test the hypothesis
that persons in high humour groups would report higher levels of good health than those in low
humour groups. It was revealed that four of the dependent variables, oral health status, gingival health
status, toothbrushing frequency and dental visit frequency differed significantly among the two
groups. It was also shown that participants who flossed their teeth or used mouthwash once a month
presented significant lower values of humour thon those who used everyday dental floss or oral
mouthrinses. The independent variables (demographic variables [age, gender, tobacco usage] and
humour) were regressed on each of the dependent oral health status and behaviour scales. Although
the multiple regression analysis on gingival status was non-significant overall, humour contributed a
small, but significant 1.51% of the predictive variance, P < 0.05.
Conclusions. Further research is required in order to gain a better understanding of the
concept of humour and its uses in healthcare.
Key words: humour, oral health, toothbrushing, flossing, mouthrinse.
Humour has been a focus of much contention
and deliberation for centuries with over 100
humour theories [1] in evidence. Most texts, however,
tend to support the view that three theories dominate
the field. The Superiority Theory or Tendentious or
Disparagement Theory (Hobbes 1588–1679): “Considered an aggressive form of humour which takes
pleasure in others’ failings or discomfort. A ‘sudden
glory of some eminency in ourselves, compared
with infirmity of others’, incongruity theory (Kant
1724–1804): “Humour where the punchline or
resolution is inconsistent or in-congruous with the
set-up”, and Relief or Release Theory (Freud 1856–
1938): “Humour released by ‘excess’ nervous energy
which actually masks other motives and/or desires.”
The field of psychology across psychobiology, personality, developmental, cognitive, social
and health domains dominates humour research. In
particular, the humour-health hypothesis asserts
that there is a link between humour and health and
currently that link is perceived to be a positive one
ROM. J. INTERN. MED., 2010, 48, 4, 333–339
which may occur by four separate processes [2]
[3], giving rise to both direct and indirect relationships [1]. First, laughter might produce physiological
changes in various systems of the body, which may
have beneficial effects on health. Vigorous laughter
exercises and relaxes muscles, improves respiration,
stimulates circulation, increases the production of
pain-killing endorphins, decreases the production
of stress-related hormones, and enhances immunity.
According to this theoretical model, hearty laughter
is crucial in the humor-health connection, whereas
humorous perceptions and amusement without
laughter would not be expected to confer any
health benefits [3]. Second, humour and laughter
might affect health by inducing positive emotional
states, which may in turn have beneficial effects on
health, such as increasing pain tolerance, enhancing
immunity, and undoing the cardiovascular consequences of negative emotions. Third, humor
might benefit health indirectly by moderating the
adverse effects of stress on health. A sense of
334
Alexandrina Lizica Dumitrescu et al.
humor may enable individuals to cope more
effectively with stress by allowing them to gain
perspective and distance themselves from a stressful
situation, enhancing their feelings of mastery and
well-being in the face of adversity. Individuals with
a good sense of humor may cope more effectively
with stress than other people do, and therefore
might also experience fewer of the adverse effects
of stress on their physical health. Finally, humor
may indirectly benefit health by increasing one’s
level of social support. Individuals with a good sense
of humor may be more socially competent and
attractive than other people, and better able to
reduce tensions and conflicts in relationships, which
might result in greater intimacy and more numerous
and satisfying social relation-ships. In turn, the
greater levels of social support resulting from these
relationships may confer stress buffering and healthenhancing effects [3] [4].
Hypotheses of our study were:
1) that the assessment of the factor structure
of the Multidimensional Sense of Humour Scale
(MSHS) would support its construct validity in the
Romanian context.
2) that individuals with a greater sense of
humour would report significantly higher levels of
good oral health and oral health behaviour as
compared with those with less humour.
Sample
The subjects of the study were 213 first year
dental students at “Carol Davila” University of
Medicine and Pharmacy who were invited to this
survey using the two anonymous questionnaires, at
the beginning of the academic year. All students
selected for the survey answered the questionnaire.
A total score was calculated based on the response
on each statement. The subjects gave their informed
consent to participate in the study. The mean age
(S.D.) of medical students was 19.26 (1.37) years
old. The percentage of female students was high in
the sample (73.7%).
Instruments and measures
Data were collected through a Romanian selfadministered questionnaire and the MSRS scale. A
structured, anonymous questionnaire was specifically
developed for this study and addressed the following:
(1) socio-demographic factors (age, gender, smoking);
2
(2) perceived oral health status (dental health, nontreated caries, extracted teeth, satis-faction by
appearance of own teeth, dental pain, gingival
condition, gum bleeding); (3) oral health habits
(toothbrushing, flossing, mouthrinse frequency,
dental visiting) [5–7]. Subjects were classified as
smokers, past-smokers and non-smokers.
Sense of humour was assessed using the
Multidimensional Sense of Humour Scale (MSHS)
[8]. Eighteen statements are positively-phrased and
six are negatively-phrased to control for responseset bias. In addition to an overall Sense of Humor
score, factor analysis of the MSHS indicates four
principal factors: 1) humor creativity and uses of
humor for social purposes, 2) uses of coping humor,
3) appreciation of humorous people, and 4) appreciation of humor.
The items are scored on a Likert-type scale
ranging from 0 = strongly disagree to 4 = strongly
agree. Scores range from 0 to 96 (4 × 24), with
higher scores suggesting a greater sense of humour.
Descriptive statistics and statistical analyses
were performed with computerized statistical package
(SPSS 17.0, Inc., Chicago, USA) software. To assess
reliability, Cronbach’s alpha values were calculated.
The corrected item-to-total correlations were
computed to examine the extent to which each item
related to the scale as a whole. To assess construct
validity, a principal component factor analysis with
Varimax rotation was performed to identify possible
underlying factors of personal sense of humor.
Pearson correlations among the MHSH subscales
were also done.
The second hypothesis, concerning the differrence in oral health status and behaviour between
those high and low in humour, was answered using
Fisher’s exact test. Multiple linear regression
analyses were performed to delineate predictors of
self-reported oral health status and behavior,
entering age, gender, tobacco usage and humour
scores from MSHS.
RESULTS
Cronbach alpha coefficient obtained for the
MSHS instrument in the present study was 0.86.
Item to total MSHS score correlations ranged from
0.30 to 0.70. There was no significant gender
difference with regard to total MSHS scale of
humour; however, a detailed analysis of the factors
3
Relationship of humour and oral health status
and items reveals some differences in construction
of sense of humor between males and females.
Table I presents an item analysis from a student
sample that completed the MSHS. It can be seen in
this comparison that there were significant male/
female differences on four of the scale’s 24 items:
1. Sometimes I think up jokes or funny
stories – males scored significantly higher than
females (t = 2.87, P = 0.004).
2. I can often crack people up with the things
I say. – males scored significantly higher than
females (t = 2.05, P = 0.04).
3. Humour is a lousy coping mechanism.
– females scored significantly higher than males
(t = 2.80, P = 0.006).
4. Coping by using humour is an elegant way
of adapting. – females scored significantly higher
than males (t = –2.65, P = 0.009).
The principal components factor analysis
with Varimax rotation of the 24 items disclosed six
factors with Eigen values greater than 1 (Table II).
The six factors all together accounted for 60.63%
of the total variance. Also the scree test (Fig. 1)
indicated at least six factors. Table III presents the
intercorrelation matrix between the derived factors.
Correlations between demographic variables,
humour and dependent variables (oral health status
and behaviour scales) were calculated. Using twotailed test, significant positive correlation was
identified between humour and gingival status
(r = 0.15, P < 0.05).
We have compared the highest and lowest
30% of individuals with respect to their MSHS
humour scores, in order to test the hypothesis that
persons in high humour groups would report higher
levels of good health than those in low humour
groups. Fischer tests revealed that four of the dependent variables, oral health status, gingival health
status, toothbrushing frequency and dental visit
frequency differed significantly among the two
groups (Table IV). It was also revealed that participants who flossed their teeth or used mouth-wash
once a month presented significantly lower values
of humour as than who used everyday dental floss
or oral mouthrinses (67.45 ± 10.78 vs. 73.66 ±
8.42, P < 0.05, respectively 63.87 ± 8.62 versus
72.44 ± 9.46, P = 0.001).
The independent variables (demographic
variables [age, gender, tobacco usage] and humour)
were regressed on each of the dependent oral health
status and behaviour scales. Although the multiple
regression analysis on gingival status was nonsignificant overall, humour contributed a small, but
significant 1.51% of the predictive variance, P < 0.05.
335
CONCLUSIONS
To our knowledge, this is the first study to
examine the interrelationship between humour and
oral health status and behaviour.
Participants who scored their oral and gingival
health status as being good/excellent revealed higher
values of total humor values compared with those
who rated it as being normal. When oral health
behaviours were evaluated, it was revealed that
participants who brushed their teeth once a day or
less, who flossed their teeth or used mouthwash
once a month presented significant lower values of
humour than those who brushed their teeth twice a
day and used everyday dental floss or oral mouthrinses.
These results correlate with findings of the
research that has been done to date and it would
seem that sense of humor is related to a number of
elements of physical and psychological health [1]
[3] [9] [10]. Kuiper and Nicholl [11] undertook a
study of 132 undergraduates and did demonstrate a
relationship between increased sense of humour
and better perceptions of health. Similarly, Boyle
and Joss-Reid [12] investigated the effects of
humour on health, using a sample of 504 individuals
comprising three groups (community group, university students, and respondents with a medical
condition). The authors concluded that humour is
associated with health and suggested that individuals
who are basically healthy appear to use and view
humour differently from those who have a medical
condition. More recently, in a community-dwelling
older adults, Marziali et al. [13] showed that coping
humor and self efficacy are important factors for
explaining health status in older adults. Correlations
among coping humor, self efficacy and social
support suggested that a sense of humor may play
an important role in reinforcing self-efficacious
approaches to the management of health issues in
older adults. In contrast, Svebak et al. [14] concluded that there was no relationship between bodily
complaints and sense of humour. A large population
study (n = 65 333) in Norway also failed to explicate a concrete link between sense of humour
and health [15].
There is a growing body of evidence of
clinical studies regarding the impact of psychosocial stressors, anxiety and depression on the oral
health behaviours and their consequent impact on
oral health status [16–20]. There is also a considerable amount of research indicating that certain
personality variables and coping styles can serve to
336
moderate the degree to which potential stressors
lead to such adverse health outcomes. Thus, a
humorous outlook on life and ability to see the
funny side of one’s problems may enable individuals to cope more effectively with stress by
allowing them to gain perspective and distance
themselves from stressful situations, enhancing
their feelings of mastery and well-being in the face
of adversity. As a consequence, these individuals
may experience fewer of the adverse effects of
stress on their physical health [14] [21].
A limitation of the design was that the
detection of oral health status as well as the
assessment of humour levels had to be made on the
basis of self-reported evaluations, which may have
caused some bias. In addition, the results are based
4
on cross-sectional data. In future, longitudinal
design should be performed to study individual
developmental changes in time. It is not known to
what extent the first year students sample can be
considered a valid reflection of the general
population. A strong point in this study has been
the use of a large sample of young participants.
Another important aspect is that, as far as we
know, it is probably one of the first studies to focus
on the extent to which the use of humour may be
related to the severity of self-rated oral health.
Overall, this article provides an excellent
model for future research exploring the parameters
of effects of humor and laughter on oral healthrelated variables, such as aspects of the self-rated
oral health status and behaviour.
Table I
Item analysis: Mean MSHS scores of Males (n = 56) and Females (n = 127)
Item
Q1 Sometimes I think up jokes or funny stories.
Q2 Uses of wit or humour help me master difficult situations.
Q3 I’m confident that I can make other people laugh.
Q4 I dislike comics.
Q5 Other people tell me that I say funny things.
Q6 I can use wit to help adapt to many situations.
Q7 I can ease a tense situation by saying something funny.
Q8 People who tell jokes are a pain in the neck.
Q9 I can often crack people up with the things I say.
Q10 I like a good joke.
Q11 Calling somebody a `comedian’ is a real insult.
Q12 I can say things in such a way as to make people laugh.
Q13 Humour is a lousy coping mechanism.
Q14 I appreciate those who generate humour.
Q15 People look to me to say amusing things.
Q16 Humour helps me cope.
Q17 I’m uncomfortable when everyone is cracking jokes.
Q18 I’m regarded as something of a wit by my friends.
Q19 Coping by using humour is an elegant way of adapting.
Q20 Trying to master situations through uses of humour is really dumb.
Q21 I can actually have some control over a group by my uses of humour.
Q22 Uses of humour help to put me at ease.
Q23 I can use humour to entertain my friends.
Q24 My clever sayings amuse others.
*P < 0.05; **P < 0.01; ***P < 0.001
Males
M
SD
2.44** 1.27
3.21 0.82
3.27 0.79
3.53 0.84
2.97 0.77
2.82 1.01
2.92 0.87
3.51 0.87
3.05* 0.77
3.66 0.66
3.14 1.16
3.19 0.72
3.33** 1.08
3.21 0.80
2.85 0.84
2.92 0.96
3.14 1.08
2.06 1.01
2.67** 0.85
3.12 1.07
2.03 1.11
3.00 0.76
3.01 0.82
2.62 1.07
Females
M
SD
1.87 1.26
3.15 089
3.11 0.75
3.73 0.61
2.80 0.80
2.92 0.87
2.81 0.86
3.68 0.66
2.78 0.96
3.72 0.57
3.25 0.99
2.87 0.78
3.37 1.05
3.32 0.79
2.72 0.81
2.92 0.86
3.08 1.02
2.47 0.92
2.82 0.93
3.13 1.03
1.80 1.07
2.91 0.84
2.93 0.78
2.33 1.00
5
337
Fig. 1. – Eigenvalue Plot for Scree Test Criterion.
Table II
Varimax Rotated Factor Matrix, MSHS Items, for 213 participants
Item
Q1 Sometimes I think up jokes or funny stories.
Q2 Uses of wit or humour help me master difficult situations.
Q3 I’m confident that I can make other people laugh.
Q4 I dislike comics.
Q5 Other people tell me that I say funny things.
Q6 I can use wit to help adapt to many situations.
Q7 I can ease a tense situation by saying something funny.
Q8 People who tell jokes are a pain in the neck.
Q9 I can often crack people up with the things I say.
Q10 I like a good joke.
Q11 Calling somebody a `comedian’ is a real insult.
Q12 I can say things in such a way as to make people laugh.
Q13 Humour is a lousy coping mechanism.
Q14 I appreciate those who generate humour.
Q15 People look to me to say amusing things.
Q16 Humour helps me cope.
Q17 I’m uncomfortable when everyone is cracking jokes.
Q18 I’m regarded as something of a wit by my friends.
Q19 Coping by using humour is an elegant way of adapting.
Q20 Trying to master situations through uses of humour is
really dumb.
Q21 I can actually have some control over a group by my uses
of humour.
Q22 Uses of humour help to put me at ease.
Q23 I can use humour to entertain my friends.
Q24 My clever sayings amuse others.
Percentage of variance
Eigen value
1
2
3
4
0.61
5
6
0.45
0.75
0.67
0.81
0.62
0.63
0.63
0.77
0.61
0.56
0.67
0.70
0.75
0.65
0.38
0.62
0.82
0.57
0.59
0.75
0.47
0.63
26.89
6.45
11.92
2.86
7.11
1.71
5.52
1.32
4.69
1.12
0.53
4.50
1.08
338
6
Table III
Correlation matrix for MSHS factors
Factor
1
2
3
4
5
6
1
1
0.39***
0.42***
0.29***
0.40***
0.36***
2
3
4
5
6
1
0.39***
0.40**
0.07
0.16*
1
0.27***
0.17*
0.29***
1
0.08
0.16*
1
0.19**
1
*P < 0.05; **P < 0.01; ***P < 0.001
Table IV
Participants characteristics stratified by MSHS level
n (%)
Lower
30%
MSHS
group
(n = 70)
n (%)
Higher
30%
MSHS
group
(n = 77)
n (%)
69 (32.5)
135 (63.7)
39 (18.3)
81 (38.2)
61 (28.7)
101 (47.4)
129 (60.6)
17 (24.3)
30 (42.9)
11 (15.7)
25 (35.7)
23 (32.8)
27 (38.6)
46 (65.7)
35 (42.1)
30 (36.1)
13 (15.7)
31 (37.3)
23 (27.7)
50 (60.2)
49 (59.0)
0.008
NS
NS
NS
NS
0.001
NS
21 (10)
105 (49.5)
66 (31.1)
21 (9.9)
13 (18.6)
35 (50.7)
21 (30.4)
4 (5.7)
1 (1.2)
45 (54.2)
30 (36.1)
14 (16.9)
0.0004
NS
NS
0.02
96 (45.1)
35 (50)
36 (43.3)
NS
Total
sample
Self-rated oral health status
Very good/Excellent dental health
Current non-treated caries
Current extracted teeth
Insatisfaction by appearance of own teeth
Toothache during last 3 months
Very good/Excellent gingival condition
Self-reported gum bleeding
Oral health-related behaviours
Daily toothbrushing frequency: once a day or less
Flossing frequency: never
Mouthrinse frequency: never
Last dental visit: more than 2 years ago
Reason for the dental visit: when treatment is needed
or when pain
Scopul studiului: Umorul şi abilitatea de a râde permit reducerea stress-ului, a
tensiunilor nervoase şi stimuleaza sistemul imun. Scopul acestui studiu a constat în
explorarea implicaţiilor umorului asupra stării de sănătate orală.
Material şi Metodă. Grupul de studiu a fost format din 213 studenţi ai anului
întâi a Facultăţii de Medicină Dentară. Chestionarul a inclus informaţii referitoare la
factorii socio-demografici, variabilele comportamentale şi starea de sănătate orală.
Simţul umorului a fost evaluat cu ajutorul Scalei Multidimen-sionale a Sensului
Umorului (Thorson şi Powell, 1993).
Rezultate. S-a observat că patru dintre variabilele dependente, starea sănătăţii
orale, gingivale, frecvenţa periajului şi a vizitelor la medicul dentist diferă semnificativ între pacienţii cu nivele ridicate şi reduse ale umorului. Participanţii care
au utilizat aţa dentară şi apele de gură odată pe lună au prezentat nivele
semnificativ mai reduse ale umorului decât cei care foloseau zilnic aceste metode
P
7
339
ajutatoare de igienă dentară. Analiza de regresie multiplă a relevant că umorul a
contribuit în procent redus, dar semnificativ statistic (1.51%, P < 0.05), la starea de
afectare gingivală, alături de variabile independente (vârsta, sexul şi fumatul).
Concluzii. Rezultatele prezentului studiu recomandă o mai bună înţelegere a
conceptului de umor şi aprofundarea implicaţiilor sale în tratamentul stării de
sănătate a populaţiei.
Corresponding author: Alexandrina L. Dumitrescu DDS, PhD, BA Psychology, Associate Professor
Institute of Clinical Dentistry, Faculty of Medicine, University of Tromsø
Tromsø, Norway
E-mail: alexandrina.dumitrescu@uit.no
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Autonomic Neuropathy and Plasma Catecholamine in Patients with Diabetes Mellitus
M. POROJAN1, SIMONA COSTIN1, LAURA POANTĂ1, ANCA CERGHIZAN2, DANA POP3, D.L. DUMITRAŞCU1
1
“Iuliu Haţieganu”University of Medicine and Pharmacy, Cluj-Napoca, Romania, 2nd Department of Internal Medicine
2
County Hospital Cluj, Diabetes Center, Cluj-Napoca
3
“Iuliu Haţieganu”University of Medicine and Pharmacy, Cluj-Napoca, Romania,
Department of Cardiac Prevention and Rehabilitation
Background. Cardiovascular autonomic neuropathy (CAN) is a common form of autonomic
dysfunction in diabetes mellitus (DM) patients, but it can be asymptomatic for years. Low baseline
plasma noradrenaline levels have been found in diabetic patients, but this decrease seems to associate
clinically severe autonomic neuropathy.
Purpose. To evaluate the impact of DM on heart rate variability (HRV) parameters and to
determine the correlations with plasma adrenaline and noradrenaline, as a possible mechanism of
early disruption in HRV.
Methods. A group of 34 patients with type 2 diabetes mellitus, without clinical signs of CAN,
was enrolled. HRV (as a measure of autonomic balance) was measured using a 24 hour ECG monitoring
system in all subjects during normal daily activity. Plasma catecholamines and other laboratory markers
were measured.
Results. HRV parameters are lower in DM group as compared with control group. More than
half of the patients had HRV parameters below the normal range (54%). There are lower levels of
noradrenaline value in DM, as compared with controls, but the difference is not statistically
significant (p = 0.08). Adrenaline levels were similar in both groups.
Discussion and conclusion. CAN is best evaluated using heart rate variability (HRV) on 24 hours
recordings. There is a tendency for HRV parameters to decrease even in asymptomatic patients,
especially after years of evolution. We did not find significant correlations between HRV and plasma
catecholamine, even if noradrenaline was lower in DM patients. Holter monitoring remains a reliable
method for early diagnosis of CAN.
Key words: diabetes mellitus, heart rate variability, plasma catecholamine.
The autonomic nervous system is often imbalanced in patients with type 2 diabetes mellitus
(DM) and this may be clinically inapparent. Cardiovascular autonomic neuropathy (CAN) is a common
form of autonomic dysfunction in DM patients and
associates abnormalities in heart rate control, as
decreased heart rate variability (HRV) and in central
and peripheral vascular dynamics [1].
Plasma catecholamines generally provide an
index of sympathetic neural activity (noradrenaline),
or an index of sympatho-adrenal activity (adrenaline)
[2]. Under normal conditions, these hormones show a
circadian rhythm with higher levels during daytime
activity and lower levels during the night [3, 4].
Subnormal baseline plasma noradrenaline levels
have been found in diabetic patients [5], but this
decrease is only found in patients with a long
duration of diabetes, with clinically severe autonomic
neuropathy. On the other hand, is well known the
fact that cardiovascular system, including HRV, is
under sympatho-vagal control, so plasma catechoROM. J. INTERN. MED., 2010, 48, 4, 341–345
lamines level could be an indicator of altered HRV
in diabetics [5] [6].
At the time of diagnosis, a reduced HRV is
evident in type 2 DM which reflects the asymptomatic process over many years, before diagnosis
[6–8]. Autonomic nervous function can be assessed
according to the consensus statement of the American
Diabetes Association and the American Academy
of Neurology, using four tests, the description of
which is beyond the interest of this study; 24 hour
ECG recording is another method used more and
more in the last decade, as an alternative of above
mentioned tests, and seems more reliable and more
sensitive [9–11].
The objective of this study was to evaluate
the impact of diabetes mellitus on heart rate
variability parameters measured on 24 hour ECG
recording in a group of type 2 diabetes mellitus,
and to determine the correlations, if any, with
plasma adrenaline and noradrenaline, as a possible
mechanism of early disruption in heart rate variability.
342
M. Porojan et al.
Study population
The study group consisted of 34 patients,
males and females, diagnosed with type 2 diabetes
mellitus and followed up at an outpatient clinic. There
were excluded from the study patients with chronic
heart failure, chronic kidney failure, hypertension,
and body mass index over 25 kg/m2. The patients
included in the study had no clinical signs of
autonomic neuropathy. The control group consisted
of 29 healthy subjects who were matched for age
and sex.
Inform consent was obtained from all patients
and the study was conducted according to the
Declaration of Helsinki.
Heart rate variability
HRV was measured using a 24 hour ECG
monitoring system (Holter Digital recorder AsPEKT
812) in all subjects during normal daily activity.
Time domain parameters used are: SDNN expressed
in milliseconds (ms) accounts for standard deviation of all NN intervals. SDANN expressed in ms
accounts for standard deviation of the averages of
NN intervals in all 5 min segments of the entire
recording. pNN50% is the number of pairs of
adjacent NN intervals divided by the total number
of all NN intervals. Frequency domain parameters
used are: low frequency and high frequency components of spectral analysis expressed in squared
milliseconds (ms2 or normalized units [11].
Laboratory markers
Blood was collected into chilled tubes containing sodium ethylene-diamine tetra-acetic acid
for measurement of the plasma adrenaline and noradrenaline levels. Plasma was separated within 10 min
in a refrigerated centrifuge. Samples were then
immediately placed in a freeze and stored at –70°C
until assayed. Plasma adrenaline and noradrenaline
levels were measured by high performance liquid
chromatography [12]. Samples were collected at
6.00 , 18.00 , and 03.00 o’clock. There were also
measured: fasting plasma glucose, cholesterol, triglycerides and glycated hemoglobin (HbA1), from
the morning blood sample, collected in separate
tubes.
The data are presented as mean ± SD unless
otherwise specified. Comparison between groups
2
of subjects for various parameters was performed
by ANOVA using SPSS 8 for Windows. Student’s
paired t test and Pearson’s linear correlation
coefficients were also used to evaluate the data (for
statistical significance and for pairs of continuous
variables). A p value less than 0.05 was considered
statistically significant.
RESULTS
Characteristics of the DM patients are shown
in Table I.
Heart rate variability parameters are lower in
DM group as compared with control group, but
differences are significant only for SDNN (from
time domain parameters) and LF, HF, and normalized
units HF (for frequency domain parameters). More
than half of the patients had HRV parameters below
the normal range (54%) (Table II).
Laboratory measurements
A circadian variation with higher values in
the daytime was evident in both groups. There are
no differences between day/night values of adrenaline
or noradrenaline in the two groups. Also, adrenaline values were similar in both groups. Diabetic
patients exhibited a tendency for a lower noradrenaline value than did the controls, but the
difference is not statistically significant (p = 0.08).
Correlations
There was a mild positive correlation between
the mean 24 h plasma noradrenaline level and heart
rate (r = 0.35, p = 0.040). There were no significant
correlations between plasma noradrenaline and LF/HF
(which accounts for sympathovagal balance), LF
(which accounts for both sympathetic and parasympathetic activity) or HF (which accounts for vagal
activity).
DISCUSSION
CAN is best evaluated using heart rate
variability (HRV) on 24 hours recordings. A reduction
in time-domain parameters of heart rate variability
seems not only to carry negative prognostic value
but also to precede the clinical expression of
autonomic neuropathy [11] [13–15]. In diabetic
patients without evidence of autonomic neuropathy,
3
H. pylori and inflammatory infiltrate in gastric disease
reduction of the absolute power of low-frequency
(LF) and high-frequency (HF) during controlled
conditions was reported [11]. LF component accounts
for both sympathetic and vagal dysfunction, verylow frequency (VLF) component accounts for sympathetic dysfunction, and HF component accounts
for parasympathetic dysfunction. However, when
343
the LF/HF ratio is considered or when LF and HF
are analyzed in normalized units, no significant
difference in comparison to normal individuals is
present [11]. In advanced cardiac autonomic neuropathy all the components of HRV are reduced (both
for sympathetic and parasympathetic activity), along
with LF/HF ratio [11] [16].
Table I
Demographic characteristics of the study group
Parameter
Number
Gender
Age (years)
Insulin treatment
Per os treatment
Cholesterol (mg%)
Triglycerides (mg%)b
Fasting plasma glucose (mg%)
HbA1 (%)
Plasma catecholamines (24 h mean)
Adrenaline (nmol/l)
Noradrenaline (nmol/l)
Diabetes mellitus
34
B: 18 (52.9%)
F: 16 (47.1%)
58.34 (±6.71)
8.22 (±6.67)
7 (20.5%)
18 (52.9%)
236.88 (±66.93)*
183.45 (±93.07)*
159.42 (±53.63)*
7.20 (±1.59)
Control
31
B: 16 (51.6%)
F: 15 (48.4%)
54.55 (±5.71)
NA
NA
NA
165.21 (±38.91)
110.33 (±49.21)
81.02 (±11.33)
4.1 (±2.1)
0.23 (±0.21)
2.76 (±1.84)
0.21 (±0.19)
3.45 (±2.26)
*p<0.05
Data are reported as mean ± standard deviation.
Table II
Parameter
SDNN
SDANN
p50NN %
LF
HF
LFnu
HFnu
LF/HF
Resting HR
Diabetes Mellitus
(mean ±SD)
107.37 (± 37.42) *
83.94 (± 59.28)
22.53 (±16.85)
564.11 (± 280.75)*
445.68 (± 339.13)*
31.17 (± 19.05)
16.44 (± 6.13)*
1.70 (± 0.51)
88.71 (± 9.51)
In our study, we found a positive correlation
between disease duration and HRV parameters. The
strongest correlation was between HF and disease
duration (r = 0.75). The correlation between disease
duration and autonomic damage is still under debate
[10]. As we already said, at the time of diagnosis, a
reduced HRV is frequently discovered in type
2 DM patients, which reflects the manifestation of
the asymptomatic process during many years [10]
[11] [17]. The connection between autonomic neuropathy, disease duration of diabetes and patient’s age
Control
(mean ±SD)
116.17 (± 41.24)
89.64 (± 34.18)
24.72 (±12.98)
637.19 (± 285.35)
537.78 (± 357.28)
39.47 (± 12.09)
22.43 (± 8.11)
1.75 (± 0.54)
70.01 (± 12.41)*
are still unclear [6]. On the other hand, even the
symptoms and signs of autonomic dysautonomy
may be stable over time, both in type 1 and type 2
DM patients [6]. This suggests the need of reliable,
objective diagnostic tools, other than clinical ones,
to allow early risk stratification [10] [11] [16].
The present study showed that diabetic patients
have also lower, even if non-significant, levels of
plasma noradrenaline compared with controls.
Catecholamines are neurotransmitters whose circulating levels reflect sympathetic nervous system
344
M. Porojan et al.
activity. Noradrenaline is mainly released from the
sympathetic nerve endings in response to nerve
impulses, while adrenaline is secreted from the
adrenal medulla upon sympathetic activation [18].
There are still some controversies concerning the
plasma catecholamine levels in diabetic patients.
Some investigators have described normal or elevated
plasma catecholamines [19] [20], and others, like
us, have found a reduction in the circulating concentrations of noradrenaline, in different extents
[21–23]. There are studies showing a depletion of
noradrenaline stores in the cardiovascular system
[24] [25] and destruction of distal postganglionic
sympathetic nerves in diabetic patients [26] [27].
To summarize, in our study, plasma catecholamines,
even if noradrenaline showed lower values (p =
0.08), had no significant correlations with HRV
parameters; it seems that in early stages of CAN,
24 hours Holter ECG registration remains the most
valuable and reliable method, being also not
expensive and non invasive.
A limitation of this study may be the dimension of the study group; it is possible that in a much
larger group the results were different regarding
plasma noradrenaline levels and/or correlations
4
between catecholamines and HRV parameters.
Another limitation could be hormone measurement;
there are studies providing a 4 hour interval blood
prelevation [24] [27], which may be more accurate
for a 24 h evaluation of plasma catecholamines.
CONCLUSION
It is important to remember that autonomic
dysfunction can be detected at the time of diagnosis
of DM, and correlates with poor glycemic control;
there is a long period of time in which patients are
asymptomatic but the disease progress; this so
called subclinical autonomic neuropathy should be
checked using autonomic function tests, including
24 hour Holter monitoring. Waiting for symptoms
to appear is not recommended, as clinical signs and
symptoms are not reliable tools in early diagnosis
risk stratification. Also, early alterations in plasma
levels of noradrenaline may explain the sympathovagal imbalance in these patients.
_____________________________________________________________
Scopul lucrării. Neropatia autonomă cardiovasculară (NAC) este o formă
obişnuită de disfuncţie autonomă la pacienţii cu diabet zahart (DZ), dar poate fi
asimptomatică ani de zile. Nivele scăzute de noradrenalină plasmatică au fost
descrise la pacienţii cu DZ, dar acestea se asociază, se pare, cu neuropatia
autonomă severă, simptomatică. Lucrarea a avut scopul de a evalua impactul DZ
asupra variabilităţii frecvenţei cardiace (VFC) şi de a stabili corelaţia cu
adrenalina şi noradrenalina plasmatică, ca un posibil mecansim al alterării VFC.
Metode. A fost înrolat un grup de 34 de pacienţi cu DZ tip 2 fără semne
clinice de NAC. VFC, ca semn al echilibrului sistemului nervos autonom, a fost
înregistrată cu ajutorul unui sistem Holter pe 24 de ore la toţi subiecţii, în timpul
activităţii cotidiene normale. Au fost determinate catecolaminele plasmatice, precum
şi alţi parametri biochimici.
Rezultate. Parametrii VFC sunt reduşi la grupul de diabetici, comparativ cu
grupul martor. Mai mult de jumătate dintre ei au parametrii VFC sub limita
normală (54%). Nivelul noradrenalinei plasmatice este mai scăzut la pacienţii cu
DZ, dar diferenţa nu este semnificativă statistic (p = 0.08). Nivelul de adrenalină
este similar în ambele grupuri.
Discuţii şi concluzii. NAC este correct evaluată cu ajutorul VFC pe durata a
24 de ore. Este dovedită o tendinţă la scădere a parametrilor VFC chiar şi la
pacienţii asimptomatici, după mai mulţi ani de evoluţie. Nu am găsit corelaţii
semnifcative între parametrii VFC şi catecolaminele plasmatice, chiar dacă
noradrenalina este uşor mai scăzută la cei cu DZ. Monitorizarea Holter rămâne,
deci, o metodă viabilă de diagnostic precoce al NAC.
Acknowledgement: Research supported from CNCSIS project number 1277 of Ministry of Education.
Corresponding author: Laura Poantă
Cluj-Napoca, Pascaly Street 9/16 postal code 400431, Romania
laurapoanta@yahoo.com
5
H. pylori and inflammatory infiltrate in gastric disease
345
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Received November 9, 2010
CASE REPORTS
Ankylosing Spondylitis or Crohn’s Disease?
Case report and review of the literature
DENISE CARMEN MIHAELA ZAHIU1,2, M. RIMBAŞ1,3, ADRIANA NICOLAU4, SABINA ZURAC5, M. R.VOIOSU1,3
1
Gastroenterology Department, Colentina Clinical Hospital, Bucharest, Romania
Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
3
“Colentina” Clinic of Internal Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
4 st
1 Internal Medicine Department, “Colentina” Clinical Hospital, Bucharest, Romania
5
Histopathology Department, “Colentina” Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
2
A 27-year-old male with a 2 year history of ankylosing spondylitis (AS) was investigated for
intermittent episodes of diarrhea and found to have granulomatous ileitis. Differential diagnosis,
discussions regarding similarities in immune alterations in both AS and Crohn’s disease and therapeutic
options are presented in this paper.
Key words: ankylosing spondylitis, Crohn’s disease, granulomatous ileitis.
CASE REPORT
R.M.G., a 27-year-old Caucasian man with a
2 year history of ankylosing spondylitis (AS) was
referred to the Gastroenterology Department for the
investigation of intermittent diarrhea during the last
5 years consisting in episodes of 4–7 unformed
stools/day for 2–3 weeks, 2 or 3 times/year. There
was no relevant family history. His rheumatologic
diagnosis relied on the lumbar and thoracic vertebral
inflammatory pain, the reduction of the spine
mobility and radiographic changes of bilaterally
grade II sacroiliitis, without HLA-B27 antigen. Three
years ago, he underwent a colonoscopic examination, which revealed only a small area of
erythematous mucosa in the sigmoid colon, histologically described as non-specific inflammation of
the mucosal layer; the terminal ileum was then not
evaluated. He was administered sulfasalazine, but
the treatment was discontinued 1 week afterwards
due to abdominal discomfort, a possible side effect
of the drug being considered. The patient denied
taking any medication for the AS symptoms in the
last year.
Physical examination revealed the lumbar
inflammatory pain and the reduction of the spine
mobility. The BASDAI score was 2.8. All the blood
tests results (including inflammation markers –
erythrocyte sedimentation rate, fibrinogenemia and
serum C reactive protein) were in the normal range.
Further investigation detected a high fecal calprotectin level (qualitative assay 3+) suggestive for
intestinal inflammation.
ROM. J. INTERN. MED., 2010, 48, 4, 347–353
The patient was further investigated for
inflammatory lesions of the small bowel and/or of
the colon using capsule endoscopy and colonoscopy,
respectively. At capsule endoscopy, in both jejunum
and ileum several small aphtous ulcers were
identified and in the terminal ileum there was an
area of mucosal edema and erythema, comprising
also several petechiae and small aphtous ulcerations
(Fig. 1). This area was accessible during ileocolonoscopy and tissue biopsies were taken. No colonic
macroscopic lesions were found.
Histological evaluation of the ileal biopsies
revealed mixed acute and chronic inflammatory
cells that involved mucosa, muscularis mucosae
and submucosa, with a fissure extending from the
base of an aphtous ulcer to the submucosa, and a
granuloma in the submucosal layer (Fig. 2).
The patient was given 2 grams of mesalazine
orally per day, with remission of the diarrhea, but
evaluation 6 months later revealed the same high
fecal calprotectin level (qualitative assay 3+)
suggestive for persistence of the intestinal inflammation, despite no intestinal symptoms; mild
low-back inflammatory pain still persisted, and the
BASDAI score was 2.5.
DIFFERENTIAL DIAGNOSIS
On the basis of the clinical history, signs and
symptoms and laboratory findings there is little doubt
about the diagnosis of ankylosing spondylitis in
this case (modified New York criteria fulfilled),
348
Denise Carmen Zahiu et al.
with the BASDAI score proving there is a mild
form of the disease. Given the presence of an
associated granulomatous ileitis which has many
potential causes, however, there is a wide differrential diagnosis.
Intestinal infection
Infection with Y. enterocolitica and Y. pseudotuberculosis could be associated with granulomatous
ileitis and reactive arthritis with some of the
features of a spondyloarthropathy, mostly in HLAB27 positive individuals [1]. In this case, however,
the patient had not been to an area endemic for
Yersinia spp., is HLA-B27 negative, the clinical
picture is not dominated by fever or abdominal
pain, and the aphtous ulcers involve the entire small
bowel, not only the ileum. For these reasons,
infection with Yersinia spp. is unlikely to explain
this patient’s presentation.
Reactive arthritis may occur also after an
enteric infection due to Salmonella, Shigella, or
Campylobacter species, but is not associated with
intestinal granuloma formation.
The gastrointestinal tract can represent the
site of infection with both Mycobacterium tuberculosis and M. bovis. Intestinal tuberculosis usually
causes large ileocecal ulcers (not present in this
case), and the pathological features include caseating
granulomas [2]. The most important findings that
argue against a diagnosis of intestinal tuberculosis
in this patient were absence of acid-fasting bacteria
on histology and the presence of small, noncaseating
granulomas.
Measles can also cause a granulomatous
ileitis, but this ileitis occurs in the setting of disseminated disease [2].
Intestinal Sarcoidosis
Intestinal sarcoidosis is very rare and patients
usually present with respiratory, skin and also eye
symptoms [3]. Lymphatic obstruction, which this
patient did not have, is a characteristic intestinal
finding of this condition [3]. Absence of other
manifestations of the disease makes this diagnosis
very unlikely. Testing for the serum level of
angiotensin-converting enzyme is probably not
indicated in this case, but if performed, its normal
level rules out the disease.
NSAID enteropathy
Most patients with ankylosing spondylitis are
treated with non-steroidal anti-inflammatory drugs
(NSAIDs), which are a potential cause of ulcerations
and/or inflammatory changes of the small-bowel
2
(NSAID enteropathy). The typical patient is one
taking NSAIDs for a rheumatic condition, the
duration of NSAID use to time of diagnosis is
widely variable (days to years), and it seems that
there is no difference in development of bowel
lesions between those taking COX-2 selective or
non-selective NSAIDs [4]. This condition is usually
asymptomatic. We must emphasize that the patient
denied taking anti-inflammatory medication for his
lumbar pain.
Localization of the most important inflammatory lesion to the terminal ileum (rather than
mid small bowel) would be unusual even if the
patient had taken over-the-counter NSAIDs. Also
worth mentioning, there have been no reports of
granulomatous reactions in intestinal biopsies from
patients with NSAID enteropathy [5].
Ileitis of spondyloarthropathy
or Crohn’s disease?
Ileocolonoscopy reveals subclinical intestinal
inflammation in approximately 60% of patients with
ankylosing spondylitis, predominantly in the terminal
ileum [6]. The gut lesions found in patients with
ileitis associated with AS are divided histologically
into acute (neutrophil dominant) or chronic (lymphocyte dominant). The chronic type, which is the
most frequently encountered, closely resembles ileal
Crohn’s disease (CD), as the mucosal architecture
is clearly disturbed, the villi are irregular, blunted
and fused; the crypts are distorted and the lamina
propria is edematous and infiltrated by mononuclear cells. In some cases aphtous ulcers and sarcoidlike granulomas are present [7]. Worth mentioning,
the presence of chronic ileal lesions might be a
predictor of an aggressive evolution of the spondyloarthropathy (SpA)[7] .
Fecal calprotectin is the only biological
marker of intestinal inflammation that is present in
this patient. Calprotectin is a major protein found in
the cytosol of inflammatory cells [8]. A considerable
proportion of patients with a false positive test
result will, however, prove to have a gastrointestinal condition different from IBD, such as
intestinal infection, intestinal lymphoma, NSAIDinduced bowel lesions, and autoimmune enteropathy,
among others [8]. It is considered that increased
fecal calprotectin levels may indicate a need for
endoscopy, whereas normal calprotectin levels are
less likely to be associated with intestinal inflammation and further investigations could be tailored
appropriately [8].
Suspicion of Crohn’s disease (CD) is raised in
SA patients with diarrhea that is persistent (≥ 4 weeks)
or recurrent (≥ 2 episodes in six months). Patho-
3
Ankylosing spondylitis or Crohn’s disease
gnomonic signs or symptoms do not exist. Endoscopic
evaluation with histopathologic sampling is generally
considered indispensable in the investigation of
patients with suspected Crohn’s disease (such is
this case, with clinical context of associated AS,
suggestive symptoms and positive markers of
intestinal inflammation). Ileoscopy should always
be attempted in patients with suspected Crohn’s
disease, because it adds little or no risk to a
diagnostic colonoscopy and can be routinely
accomplished by an experienced endoscopist in
most patients [9] [10], and biopsies of the terminal
ileum should be taken [11].
Predominant involvement of the terminal
ileum, as in this case, is highly suggestive of
Crohn’s disease. The spondyloarthropathy associated
with Crohn’s disease can only be distinguished
from idiopathic ankylosing spondylitis by the
prevalence of HLA-B27, which, while still high, is
significantly lower in patients with Crohn’s disease
than in those with ankylosing spondylitis. Classic
IBD, however, precedes the development of
spondylitis in most cases. On the other hand, a
small proportion (<5%) of patients with established
spondyloarthropathy can develop classic IBD
within 10 years of the primary diagnosis: 80% of
patients develop Crohn’s disease and 20% ulcerative
colitis [12].
Curiously, the main risk factor for IBD in
patients with established ankylosing spondylitis is
the absence of HLA-B27 (80% of cases), as is the
case of the patient presented here [13].
Therefore, at this point we cannot classify the
granulomatous ileitis present in this patient as
ileitis of SpA or Crohn’s disease. The only thing
that we could say is that he is at high risk for
developing the latter, if not already having it.
DISCUSSION
From a researcher’s point of view, the
interaction between intestinal inflammation and
arthropathy is a fascinating one. Studies show that
half of all first-degree relatives of patients with
either CD or AS have subclinical intestinal inflammation that is inherited according to an additive
trait [14]. Both disorders have high heritability
scores and patients with both diseases are significantly more closely related than controls. These
findings suggest that ileitis and arthritis are causally
related [14].
349
Some of the discovered similarities in the
immune alterations in CD and SpA are: an increased
expression of αE/β7 in T-cells from patients with
SpA and in the intestinal lymphocytes of patients
with CD; an increased expression of epithelial
A-cadherin; an increased expression of CD 163
positive macrophages in CD and SpA; relative
contribution of T-helper 1 cells; and presence of IgA
antibodies to Saccharomyces cerevisiae [14] [15].
Up to two-thirds of patients with AS have
subclinical gut inflammations shown either by
endoscopy or histology [7] [16]. A fraction of the
AS patients go on to develop clinically overt CD
[13]. It could be speculated that SpAs and CD
probably should be considered as distinct phenoltypes of a common immune-mediated inflammatory
disease pathway rather than as separate disease
entities and that ileitis of SpA might actually
represent subclinical Crohn’s disease [14].
Therefore, at present, ileitis associated with
ankylosing spondylitis cannot easily be distinguished from Crohn’s disease, either macroscopically
or microscopically. In these patients, the experience
of regular episodes of diarrhea early in the disease
history, the persistence of raised inflammatory
serum parameters, and the presence of chronic
inflammatory gut lesions were found to be risk
factors for the development of IBD. HLA-B27
negativity in the presence of sacroiliitis has been
considered an important risk factor for inflammatory bowel disease (IBD) [13].
THERAPEUTIC OPTIONS
The ileum is the most common region of the
small bowel involved in Crohn’s disease. Some
authorities do not feel compelled to treat patients
with Crohn’s ileitis who are minimally symptomatic,
because whether any treatment alters the natural
history of the disease in such patients is unproven.
Nevertheless, the granulomatous chronic ileal inflammation detected on the biopsy in this case
predicts that this patient is prone to having an
aggressive form of spondyloarthropathy, which
might represent an indication for early aggressive
intervention.
NSAIDs
In AS patients there is a rapid remission of
the symptoms with NSAIDs administration, but
they do not stop the progression of the rheumatologic disease. 70 to 80 percent of AS patients
350
report substantial relief of their symptoms with
NSAIDs [17]. Unless contraindicated because of
comorbidity, NSAIDs should be the first line of
treatment for all symptomatic AS patients [18].
Knowing the fact that the NSAIDs can lead
to exacerbation of preexisting IBD [19], there are
some concerns regarding administration of NSAIDs
in cases like this. However, our work proves that
the distal small bowel of spondyloarthropathy patients
is not affected by NSAIDs consumption [20].
Therefore, for controlling the articular symptoms, we consider that NSAIDs can be used with
caution in this case.
5-ASA Drugs
Oral 5-ASA agents are largely used for the
treatment of IBD, being effective both for the
treatment of active CD, and especially for maintenance of remission [21]. They are not useful for
the lesions involving other parts of the small bowel
other than the distal ileum, because the drug needs
to be splitted by the bacterial azoreductases from
the gut in order to become active. The precise
mechanisms responsible for the clinical efficacy of
5-ASA compounds are not known. However, in
vitro investigations have identified many antiinflammatory and immunosuppressive properties of
5-ASA, suggesting a multifactorial basis of its
therapeutic action [22].
In CD patients with mild symptoms, as the
case presented here, the treatment is usually begun
with a slow release oral 5-ASA agent. However,
with 4 grams per day, there is only an overall
modest reduction in disease activity compared with
placebo (the mean reduction in the Crohn’s Disease
Activity Index was reported to be 67 points,
25 points better than with placebo) [21]. In contrast
to mesalazine, sulfasalazine is less useful for ileitis.
The diminished response probably reflects the need
for colonic bacteria to cleave the drug to release the
active 5-ASA moiety [23].
There were small studies in SpA patients with
terminal ileitis receiving 5-ASA drugs and the
reduction of the bowel inflammation was confirmed
[7]. However, with regard to the articular symptoms
in AS, mesalazine or sulfasalazine are not effective
for the axial involvement, present in the case
discussed [18] [24].
Therefore, in this case, as mesalazine in doses
of 2 grams per day were not effective in controlling
the intestinal inflammation, an option would be to
increase its dose up to 4 grams per day and
reevaluate the patient after another few weeks.
4
Antibiotics
For patients with Crohn’s disease who do not
respond to or do not tolerate 5-ASA drugs, it is a
common practice to initiate a trial of one of several
antibiotics as primary therapy before beginning
glucocorticoids. It is unclear if the efficacy of antimicrobial therapy is due to treatment of an undetected
pathogen or of bacterial overgrowth [25].
Whether this approach is useful in the subset
of AS patients with ileal granulomatous inflammation, it remains to be proven.
Corticosteroids
Chronic administration of systemic corticosteroids is generally not recommended in AS,
because they are rarely effective and serve to
promote decreased bone mineral density, although
injection of a long-acting corticosteroid into painful
sacroiliac joints may relieve pain in patients whose
symptoms are refractory to NSAIDs. The efficacy
of systemic glucocorticoids in AS has not been
assessed in clinical trials [18] [26].
On the other hand, however, in CD, prednisone
continues to be a mainstay of treatment for patients
with mild disease who are unresponsive to the
above mentioned measures [27]. Controlled ileal
release (CIR) budesonide, a glucocorticoid with a
high first-pass hepatic metabolism may be used as
an alternative to prednisone in patients with mild to
moderately active Crohn’s ileitis, with potential
fewer side effects. It is used at a dose of 9 mg/day
for 8 to 16 weeks and then discontinued over two
to four weeks by tapering in 3 mg increments.
We suggest using the above-mentioned
measures to achieve remission of the ileal inflammation in this patient, if not obtained with
4 grams/day of mesalazine, and then maintenance
therapy with a 5-ASA drug once control of active
ileitis has been achieved, at a dose of 2–3 grams/
day, should be considered as long-term therapy
with the hope of preventing disease relapse [28].
However, it must be acknowledged that there is
inconsistent evidence supporting this approach, and
the articular symptoms will probably not be
influenced.
DMARDs
There is a paucity of data regarding the use of
immunosuppressive and disease-modifying anti
rheumatic drugs (DMARDs) in the diseases included
in the concept of SpA. Despite this, they are
commonly used in the different SpAs. On the other
5
hand, there is evidence that they favorably influence
the bowel inflammation, when administered in
different forms of IBD.
A common and challenging problem is the
patient who remains symptomatic despite adequate
doses of steroids (not used in this case). An evolving
trend among some authorities in the field of IBD
has been to use the immunomodulatory agents early
in the course of disease before patients become
steroid-dependent or resistant [25].
For refractory patients with Crohn’s ileitis,
the major alternatives are azathioprine or its active
metabolite 6-mercaptopurine (6-MP). The response
rate to these medications is 60 to 70 percent and
will usually be seen within three to six months.
Patients receiving these drugs require regular monitoring for toxicity [25]. Methotrexate is an alternative
for the patient who does not tolerate or is unresponsive to azathioprine or 6-MP and may be used
in preference to azathioprine or 6-MP in patients
with troublesome Crohn’s disease-related arthropathy,
such this patient. However, a 2006 meta-analysis of
the efficacy of methotrexate for the articular
symptoms in AS found no evidence of a beneficial
effect in this disease [29]. Moreover, the use of the
combination of methotrexate and infliximab did not
increase efficacy or decrease the risk of adverse
effects compared with infliximab alone [30].
Biological agents
Part of the inflammation in both AS and
Crohn’s disease is believed to result from the
generation of cytokines by antigen-stimulated
T cells. Elevated concentrations of TNF mRNA are
found in the inflamed gut of patients with Crohn’s
disease [31], and in the inflamed sacroiliac joints of
patients with AS [18].
As the gut inflammation in Crohn’s disease is
mainly dependent upon Th1 cytokines [25], the
joint inflammation seems to be more dependent
upon Th2 cytokines [32] [33]. No in situ data are
available on cytokine expression in the gut in
SpAs. Biological compounds, such as cytokines,
anti-cytokines as well as compounds interfering
with recirculation have been applied in research
protocols for selected groups of patients. Since
some of these interventions interact specifically with
gut inflammation, it is tempting to speculate upon
their effect in patients with ileitis of SpA.
There are some differences seen with different
biologic agents between CD and AS. Three antiTNF therapies are approved for treatment of
Crohn’s disease in adults and all are effective in
treatment of luminal Crohn’s disease: infliximab,
351
adalimumab, and certolizumab pegol [34]. Clinical
trials and experience have demonstrated their
significant utility for induction of remission in
moderately active, steroid refractory Crohn’s disease,
improvement in quality of life, and maintenance of
remission in these patients. The efficacy of etanercept
in CD, however, has not been demonstrated [25].
On the other hand, a 2007 meta-analysis
indicated that all of the anti-TNF alpha agents then
available (adalimumab, etanercept, and infliximab)
were similar in efficacy in patients with AS [35],
with respect to the patient global and pain assessment, the functional assessment, and the degree of
inflammation as assessed by morning stiffness. The
responses are typically rapid and appear to be
durable. Patients who do not respond to or do not
tolerate one anti-TNF agent may respond to an
alternate anti-TNF agent [36].
Despite their efficacy, the indiscriminate use
of anti-TNF-alpha drugs is discouraged because of
cost concerns and a lack of long-term safety data
[37]. They should be used primarily in Crohn’s
disease patients refractory to standard therapy, in
order to help taper patients off steroids and
transition them to effective long-term maintenance
therapy using biological agents plus 6-MP or
azathioprine, or in AS patients with active disease,
as indicated by both the Bath ankylosing spondylitis disease activity Index (BASDAI) score and a
physician global assessment, and failure of previous
treatments. A BASDAI score of ≥ 4 is indicative of
active disease that warrants consideration of antiTNF therapy, but this criterion was not met in the
mentioned case [18] [38].
Although the theoretic concept regarding the
favorable influence of all these anti-inflammatory/
disease-modifying agents on the associated gut
inflammation exists, there is a striking paucity of
controlled trials regarding this issue. Moreover, in
spite of improvements in parameters of inflammation, the radiographic progression of AS
patients seems not significantly be influenced by
the biologic therapy [39].
Therefore, as biologic agents should be used
only in patients with active articular disease, or
when the intestinal inflammation is not responsive
to other treatment modalities, it seems that there is
no place at this moment for these drugs in the
treatment of our patient. The problem is that the
chronic ileal inflammation detected on his ileum
predicts that the patient will have an aggressive
form of SpA, and this might represent an indication
for early intervention with aggressive therapy. Our
opinion, however, is that we should wait for the
disease to become more active, and for the failure
352
6
of less aggressive therapeutic approaches in order
to initiate anti-TNF-alpha agents, and probably
etanercept is not a choice in this case.
pathway. There is emerging evidence that ileitis of
spondyloarthropathy might represent subclinical
Crohn’s disease.
There is rationale for carrying out ileocolonoscopy on patients with ankylosing spondylitis and
CONCLUSIONS
abdominal symptoms as the ileal inflammation
could give prognostic information and could guide
treatment. Fecal calprotectin level could be used to
This case report is important as a reminder
stratify the need for evaluation of the bowel in
that there is a wide differential diagnosis for
patients with seronegative SpAs.
granulomatous ileitis, even though the vast majority
NSAIDs should be used with caution in this
of such cases will be associated with Crohn’s
subset of patients, due to the inconsistent evidence
disease.
of exacerbation of intestinal inflammation.
The case also illustrates the strong association
It is not clear at this point if more aggressive
between SpAs and IBD. The relationship between
therapy should be initiated early in the course of
the two diseases is of particular interest to research
this patient in order to prevent progression to a full
workers, recent studies sustaining the hypothesis of
IBD phenotype, since there is a paucity of data in
a common immune-mediated inflammatory disease
the literature regarding this issue.
___________________________________________________________________
Un pacient de 27 ani având un istoric de 2 ani de spondilită anchilozantă se
prezintă pentru evaluarea unui sindrom diareic intermitent, descoperindu-se
afectare inflamatorie granulomatoasă la nivelul ileonului terminal. Diagnosticul
diferenţial, similarităţile în alterările imunologice din spondilita anchilozantă şi
boala Crohn, precum şi opţiunile de tratament sunt discutate în această lucrare.
___________________________________________________________________
Acknowledgement. This paper was supported through a research grant PN-II/IDEI, contract no. 320/01.10.2007, entitled
“The characterization of small bowel and colonic involvement in patients with seronegative spondyloarthritides”, financed by the
Romanian Ministry of Education and Research – Executive Unit For Financing Higher Education And Scientific University Research
(CNCSIS/UEFISCSU).
Corresponding author: M. Rimbaş, M.D.
Gastroenterology Department, “Colentina” Clinical Hospital
19, Sos.Stefan cel Mare 19, 020125, Bucharest, Romania
Email: mrimbas@yahoo.com
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Right Renal Artery Occlusion as a Complication of Fibromuscular Dysplasia
LUCIA AGOŞTON-COLDEA1, L.C. MOCAN2, TEODORA MOCAN3, SILVIA LUPU1
“Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca
1
Department of Medical Sciences, II nd Medical Clinic
2
Department of Surgery, II nd Medical Clinic
3
Department of Morphology and Normal Functions, Physiology Department
Renovascular hypertension is defined as elevated blood pressure levels due to the stenosis/
occlusion of the renal artery caused by fibromuscular dysplasia or atherosclerosis. We present the
case of a 59-year old female patient with recently diagnosed arterial hypertension due to renal artery
occlusion through intimal fibromuscular dysplasia. In this case, arterial blood pressure levels have not
been controlled by maximum doses of antihypertensive drugs, used in association; rapid deterioration
of the renal function, as well as important kidney damage, proven by imaging explorations, motivated
the laparoscopic nephrectomy.
Key words: fibromuscular dysplasia;renal artery stenosis; arterial hypertension.
Renovascular hypertension is defined as
elevated blood pressure determined by renal artery
stenosis. It represents less than 5% of all cases of
arterial hypertension [1] and can be caused by
atherosclerosis or dysplasia. Atherosclerosis causes
70–90% of all renal artery stenosis and usually
affects the ostium and the proximal area of the
renal artery [2], while fibromuscular dysplasia, a
non-atherosclerotic, non-inflammatory disease, is
responsible for 10–30% of the cases [3]. Fibromuscular dysplasia can affect carotid and visceral
arteries, involving all three vascular wall structures
(intima, media and adventitia). Media impairment
determines arterial stenosis, ischaemia and renal
infarction, whereas intima and adventitia impairment
is frequently associated with stenosis, dissection
and renal artery thrombosis. Genetic predisposition
plays an important role in this condition, as it is
frequent in first degree relatives of the patients with
fibromuscular dysplasia and among individuals
who possess ACE-1 allele for the angiotensin conversion enzyme [4]. Other rare causes of renal artery
stenosis include Takayasu arteritis, radio-induced
arteritis, spontaneous dissection of arterial aneurysms
and Von Recklinghausen’s disease. Selective kidney
angiography still represents the “golden standard”
for the diagnosis of renal artery stenosis. However,
non-invasive techniques such as Doppler ultrasonography, MRI-angiography or computer tomography
are more accurate in assessing renal artery stenosis
and offer a valuable diagnostic alternative when
ROM. J. INTERN. MED., 2010, 48, 4, 355–359
compared to angiography [5] [6]. We present the
case of a patient with renal artery occlusion caused
by fibromuscular intimal dysplasia, insisting on the
diagnostic and therapeutic approach.
CASE REPORT
A 59-year old female patient was admitted to
the hospital with severe occipital, pulsing headaches,
dizziness and blurry vision; firstly, the symptoms
occurred three weeks previously, being associated
with elevated blood pressure levels (up to 220/
130 mmHg). After the first episode, the general
physician recommended Nifedipin 2 × 20 mg/day
and Captopril 3 × 25 mg/day, but the prescribed
therapy proved to be insufficient under the circumstances. No other disease in the patient’s history
or in her family background could provide a
reasonnable explanation for the described symptoms.
Clinical examination at the admission indicated a
low body mass index of 18 kg/m2, regular heart
beats with a heart rate of 80/minute, without audible
cardiac or vascular murmurs and an arterial blood
pressure of 200/130 mmHg on both arms.
Standard laboratory explorations were consistent with kidney impairment: creatinine=1.35 mg/dL
(5.76 mg/dlL; urea = 51 mg/dL (215 mg/dL); Na =
140 mEq/L; K = 3.05 mEq/L (3.2 mEq/L); creatinine
clearance = 65 ml/min; albuminuria +++; isosthenuria; urinary sediment: granular and hyaline
356
Lucia Agoşton-Coldea et al.
cylinders; negative urine culture; proteinuria = 1.23g/
24h. Additional blood work, as well as the electrocardiogram, chest radiography and echocardiography,
were normal.
Abdominal ultrasound showed a small right
kidney of 8/3.2 cm, with a parenchymal index of
6–8 mm and small cysts in the tissue, while the left
kidney had a parenchymal index of over 2 cm and
measured 11.5/5.5 cm. Other abdominal organs
proved to be normal.
Considering the presence of arterial hypertension and the small, unilateral kidney, several
diagnostic alternatives have been taken into account:
1. Chronic pyelonephritis: usually occurs when
predisposing factors such as bladder-ureteral
reflux, urinary tract obstruction, neurologic
conditions with impaired evacuation, diabetes
mellitus, genito-urinary interventions are
present. The patient’s history indicates a progressive onset of the symptoms, sometimes
consistent with acute pyelonephritis, isolated
pollakiuria episodes, dysuria or flank pain.
These patients often present with leukocyturia, bacteriuria, proteinuria, isosthenuria,
diminished sodium reabsorption, metabolic
acidosis, hyperkaliemia, anaemia. Abdominal
ultrasound showed small, asymmetric kidneys,
polycyclic contour of the kidneys, reduced
tissue, kidney stones, dilations and cysts.
2. Unilateral congenital kidney hypoplasia:
clinical symptoms appear in infants; one of
the kidneys is small and has very few
calices and tubes.
3. Obstructive kidney atrophy: obstructive
kidney disease leads to a low glomerular
filtration rate, tubular atrophy and, finally,
renal ischaemia.
2
4. Renal artery stenosis: determines arterial
hypertension, uncontrolled by medication,
with sudden onset, before 30 years of age
or after 55.
Kidney function, evaluated using dynamic
renal scintigraphy with Tc 99m and DTPA radiopharmaceuticals, showed a small, non-functional
atrophic right kidney and a hypertrophic, hyperfunctional left kidney (Fig. 1). Renal artery Doppler
ultrasound indicated a rich vascularisation of the
left kidney, with a maximum systolic flow speed of
1.42 m/s in the left renal artery and a small, nonvascularised right kidney with randomly elevated
impedance of the sinus (capsular collateral branches),
without proper identification of the right renal
artery trunk. The Doppler and 2D ultrasound aspect
of the kidneys pleaded for right renal artery
occlusion with ischemic hypotrophy of the right
kidney.
Selective renal arteriography indicated the
occlusion of the right renal artery at its origin, with
an urographically “mute” kidney, but with normal
left renal artery and aorta.
By gathering all data, renal artery stenosis
was considered and differential diagnosis between
the two most common causes – atherosclerosis and
fibromuscular dysplasia – became essential; occlusion
by superimposed thrombosis or embolism was
taken into account (Table I).
The patient has been initially treated with
anti-hypertensive drugs and potassium supplements
(Leridip 5 mg/day; Nebilet 10 mg/day; Tertensif
SR 1.5 mg/day; Spironolactone 50 mg/day), which
did not provide enough control over blood pressure
values. Because the right kidney was considered
unviable, we resorted to nephrectomy in this case.
Table I
Elements of differential diagnosis between atherosclerotic and dysplasic renal artery stenosis
1. Average age
2. Lesion localisation
3. Renal impairment
4. Arterial occlusion
5. Ischemic atrophy
6. Frequency
Fibromuscular dysplasia
– <40 years
– medium/distal portion
– unilateral 40%
– bilateral 60%
– rarely (with the exception of intima and
adventitia FMD with dissection and
thrombosis)
– rarely
– 10%
The surgical procedure included several
essential steps, first of which consisted in Sevofluran induction, right ureter catheterisation and
Atherosclerotic stenosis
– > 55 years
– ostial and proximal portion
– unilateral 25%
– bilateral 75%
– often
– often
– 90%
urinary bladder Foley catheter insertion. Veres
needle umbilical insertion provided the necessary
pneumoperitoneum and trocars were positioned in
3
Right renal artery occlusion and fibromuscular dysplasia
the following manner: an 11 mm umbilical trocar;
an 11 mm subcostal trocar, on the right medium
clavicular line; a 5 mm trocar on the right medium
clavicular line, 2–3 cm under the umbilicus; a
5 mm trocar on the right anterior axillary line, at
the umbilical level; 5 mm trocar on the right anterior
axillary line, on the XIIth ribb level. The patient was
placed in left lateral decubitus and Toldt’s fascia
was removed in order to allow colo-parietal
removal, ascending colon mobilisation and free
access to the right kidney area. The ureter was
identified and imobilised and then the inferior and
superior renal poles, as well as the lateral side of
the kidney, were exposed, with anterior prehension
of the kidney and hilar outlining, followed by the
stapling and sectioning of the renal artery and vein.
The ureter was then stapled and cut, allowing the
safe removal of the kidney and its placement in a
collecting pouch, which was later extracted from
the abdomen, fragmented and aspired. The intervention was completed by surgical hemostasis,
renal area draining and trocar orifice suture.
Histopathological examination showed fibrous
thickening of the intimal layer, as well as an
irregular lumen of the renal artery (Fig. 2); cortical
kidney hemorrhage, with atrophic tubuli and glomeruli (Fig. 3); glomeruli with chronic alterations
(Fig. 4); “pseudo-thyroid” tubes.
Blood pressure values became normal after
nephrectomy and renal function of the controlateral
kidney also normalized.
DISCUSSION
The discovery of fibromuscular renal artery
dysplasia with intima impairment in a 59-year old
357
woman is somewhat atypical and quite rare. Renal
artery stenosis prevalence can vary with the studied
population and it has been estimated at around 4%
[4]. Almost 90% of all renal artery stenosis cases
are determined by atherosclerosis, while only 10%
are due to fibromuscular dysplasia – a vascular
disease affecting women 15 to 50 years of age [2].
In 90% of the cases, the arterial media is afflicted,
whilst the intima and adventitia are only affected in
10% of the cases, with very frequent impairment of
the distal two thirds of the renal artery and small
aneurysms formation. Intimal and periarterial fibromuscular dysplasia is often associated with progressive dissection and thrombosis, but it rarely leads
to renal artery occlusion if compared to atherosclerosis.
The cause of fibromuscular dysplasia is unknown, although several theories have been
elaborated, which focus on risk factors such as
genetic predisposition, hormonal factors, smoking
related factors and vasa vasorum anomalies [2].
The most important mechanisms involved in the
development of renovascular hypertension are low
renal perfusion pressure and renine-angiotensinaldosterone system activation. Although a differential
diagnosis between renovascular and essential arterial
hypertension can be difficult in some cases, there
are several clinical features which can point to
renal artery stenosis (Table II). Early revascularisation by angioplasty or surgery can often lead to
hypertension and renal function correction and
even reversal of the kidney damage; however, if
left untreated, renal artery stenosis will lead to
important renal degradation and severe, uncontrolled arterial hypertension.
Table II
Clinical features suggesting renal artery stenosis
Arterial hypertension
• Accelerated or malignant arterial hypertension
• Medication resistant hypertension (three or more associated drugs)
• Sudden onset of arterial hypertension in children, young adults or after the age of 50
Renal anomalies
• Azotemia or sudden deterioration of kidney function in hypertensive patient
• Small unilateral kidney
• Angiotensin conversion enzyme inhibitors therapy induced azotemia
Other anomalies
• Audible arterial murmurs (carotid, epigastric, abdominal)
• History of carotid artery atherosclerosis (e.g., cerebrovascular event), coronary events (e.g., angina pectoris,
myocardial infarction) and peripheral vascular disease (e.g., claudication, ulcer)
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Lucia Agoşton-Coldea et al.
Proper renovascular hypertension evaluation
should include a complete study of the renal
function, physiological studies on the renin-angiotensin system, perfusion studies for differential
renal blood flow evaluation and imaging techniques
for renal artery stenosis identification. For assessing
renin-angiotensin system functioning, some crucial
elements are required, such as: renin and sodium
profile, plasmatic renin activity before and after
captopril administration, the evaluation of angiotensin
conversion enzyme inhibitors on blood pressure
and kidney function, renal captopril scintigraphy
for assessing renal differential perfusion. These
tests are not recommended in elderly patients with
atherosclerotic renal artery stenosis because hypertension in these patients is not renin-dependant and
the results are inconclusive if used to predict
hypertension evolution after revascularisation. On
the contrary, such studies are very useful in identifying patients with fibromuscular dysplasia, which
is often renin-dependant [1] [8].
Evaluating renal artery stenosis is still an
intriguing topic for debate in many medical establishments that resort to different clinical algorithms.
Most begin by employing non-invasive imaging
techniques. Renal scintigraphy has, undoubtedly,
the lowest sensitivity (68%) and a specificity of
87% [5], the first significantly lower when compared
to that of the renal Doppler ultrasound (81%),
which also has a 87% specificity, but provides the
additional advantages of low costs and reasonable
diagnostic accuracy. [6]. Almost 20% of all renal
artery stenosis cases remain undiagnosed after ultrasound evaluations due to obesity and/or intestinal
4
gas overload which can lead to poor echographic
images [6]. Although renal angiography has a high
diagnostic accuracy [3], CT and 3D gadolinium
angio-MRI proved to be superior, with a sensitivity
and specificity of 90–100% [7].
Renal artery stenosis patient evaluation should
be individualised after basic clinic factors such as
age, pre-existant clinical conditions, the possibility
of an efficient blood pressure control and renal
function improvement after the surgical correction,
as well as the general risk of this invasive
procedure. The primary objective is to preserve the
kidney function and is firstly based on clinical
characteristics, risk factors evaluation, basic kidney
function and renal flow asymmetry (Table III).
If non-invasive study results suggest the
presence of unilateral renal artery stenosis, other
imaging exploration are recommended to determine
the total glomerular filtering rate, as well the
individual glomerular filtering rate, for each kidney.
If the patient has unilateral renal artery stenosis,
normal kidney function and symmetrical blood
flow in both renal arteries, the follow-up will include
non-invasive vascular imaging and the annual
measurement of the glomerular filtering rate [8].
Indications for renal artery revascularisation
have often led to controversy. If unilateral renal
artery stenosis is present and it is associated with
asymmetric arterial blood flow, or in the case of
bilateral arterial stenosis, angiography and revascularisation are indicated, provided that the kidney
function is normal. Conventional angioplasty is also a
valid option for hypertensive patients with renal
artery stenosis by renovascular dysplasia [1] [8].
Table III
Main recommendations for treating renal artery stenosis
Technique
1. Percutaneous transluminal renal angioplasty
2. Endoprosthesis (stent) implant
3. Surgical procedures:
– revascularisation
- endarterectomy
- removal of the obstruction
– aorto-renal bypass
– total/partial nephrectomy (classic/laparoscopic)
The revascularisation technique is chosen in
accordance with the presence or absence of an
associated aorto-iliac disease. If no aortic disease is
present, endoprosthesis implantation is a reasonable
Indication
– young fibromuscular dysplasia patients
– elderly atherosclerotic stenosis patients
– in ostial stenosis
– angioplasty failure
– eccentric stenosis
– uni – or bilateral arterial occlusion
– unilateral arterial stenosis >75%
– bilateral arterial stenosis >75%
– atrophic kidney
option; however, if there is an aortic aneurysm or
an occlusive aortic disease, surgical revascularisation or renal by-pass are indicated. Some
surgeons prefer to replace the aorta by a dacron
5
Right renal artery occlusion and fibromuscular dysplasia
prosthesis, followed by percutaneous transluminal
angioplasty of the renal artery. The follow-up includes
an annual glomerular filtration rate assessment, as
well as an angio-MRI or Doppler ultrasonography evaluation of renal perfusion and vascular patency [8].
For patients with advanced kidney function
impairment, the revascularisation of both renal
arteries or of a single renal artery when only one
functional kidney is present can be considered, but
the decision should be supported by the absence of
other co-morbidities [8]. Angioplasty or surgical revascularization yielded moderate benefits in patients
with fibromuscular dysplasia renal artery stenosis,
with substantial variation across studies [9].
359
Several indications for laparoscopic nephrectomy have been provided: unilateral renal artery
stenosis, with small, unviable kidney – the kidney
is smaller than 9 cm (long axis), when evaluated by
ultrasound or computer-tomography; resistance
index < 0.8; renal function degradation after angiotensin conversion enzyme inhibitors and sartans
therapy; perfusion by collateral branches when the
renal artery trunk is partially or totally obstructed –
assessment by angiography; kidney biopsy showing
minimal interstitial scars and preserved glomeruli
[10]. These indications motivated our therapeutic
conduct in the presented case.
Hipertensiunea renovasculară este definită prin valori crescute ale tensiunii
arteriale datorate stenozei de arteră renală prin displazie fibromusculară sau
ateroscleroză. Prezentăm cazul unei paciente de 59 de ani cu istoric recent de
hipertensiune arterială datorată unei ocluzii de arteră renală având ca substrat
displazia fibromusculară de intimă a arterei renale. Valorile ridicate ale tensiunii
arteriale necorectate sub terapia de antihipertensivă asociată, degradarea rapidă
a funcţiei renale şi neviabilitatea rinichiului dovedită prin explorările imagistice
au impus nefrectomia laparoscopică.
___________________________________________________________________
Corresponding author: Lucia Agoşton-Coldea
The University of Medicine and Pharmacy “Iuliu Haţieganu”
2–4, Clinicilor Street, 400006 Cluj-Napoca, Romania
Telephone: +0264591942, e-mail: luciacoldea@yahoo.com
REFERENCES
1.
MARTIN, L.G., RUNDBACK, J.H., SACKS, D. et al., Society of Interventional Radiology Standards of Practice Committee:
Quality improvement guidelines for angiography angioplasty, and stent placement in the diagnosis and treatment of renal artery
stenosis in adults. J. Vasc. Intervent. Radiol., 2003, 14:297–310.
2. SAFIAN R.D., TEXTOR S.C., Renal-artery stenosis. N. Engl. J. Med., 2001, 344:431–442.
3. SLOVUT D.P., OLIN J.W., Fibromuscular dysplasia. N. Engl. J. Med., 2004, 350:1862–1871.
4. BOFINGER A., HAWLEY C., FISHER P. et al., Polymorphisms of the renin-angiotensin system in patients with multifocal
renal arterial fibromuscular dysplasia. J. Hum. Hypertens., 2001, 15:185–190.
5. VÖLK M., STROTZER M., LENHART M. et al., Time-resolved contrast-enhanced MR angiography of renal artery stenosis:
diagnostic accuracy and interobserver variability. Am. J. Roentgenol., 2000, 174:1583–1588.
6. SOULEZ G., PASOWICZ M., BENEA G. et al., Renal Artery Stenosis Evaluation: Diagnostic Performance of Gadobenate
Dimeglumine-enhanced MR Angiography-Comparison with DSA. Radiology, 2008, 247:273–285.
7. BIRRER M., DO D.D., MAHLER F. et al., Treatment of renal artery fibromuscular dysplasia with balloon angioplasty: a
prospective follow-up study. Eur. J. Vasc. Endovasc. Surg., 2002, 23:146–152.
8. RUNDBACK J.H., SACKS D., KENT K.C. et al., Guidelines for the Reporting of Renal Artery Revascularization in Clinical
Trials. J. Vasc. Intervent. Radiol., 2003, 14:S477–S492.
9. TRINQUART L., MOUNIER-VEHIER C., SAPOVAL M. et al., Efficacy of Revascularization For Renal Artery Stenosis
Caused by Fibromuscular Dysplasia. A Systematic Review and Meta-Analysis. Hypertension, 2010, 110.152918v1.
10. CHONCHOL M., LINAS S., Diagnosis and Management of Ischemic Nephropathy. Clin. J. Am. Soc. Nephrol., 2006, 1:72–181.
Received August, 27, 2010
POINTS OF VIEW
At the Dawn of a New Era in Treating Angina Pectoris,
or just Another Antianginal Drug?
Some Considerations About Ranolazine
H. BĂLAN
“Carol Davila” University of Medicine and Pharmacy, Medical Clinic,
Clinical Emergency Hospital Ilfov County, Bucharest, Romania
Ranolazine is a new compound that has been approved by the FDA for use in patients who
have chronic stable angina refractory to conventional antianginal medications.
Ranolazine proved to be effective also as monotherapy in patients with stable angina and as
part of a combination regimen.
This review is inspired by the presentation that legendary figures in contemporary cardiology,
such as Braunwald, Komajda and Camm made recently at the Congress of the European Society of
Cardiology held in Stockholm, Sweden, last September [1].
Key words: chronic stable angina, ranolazine.
The modern life can be considered as a bunch
of risk factors for a rapid journey to the end of the
cardio-vascular continuum. An intervention at any
stage of this continuum can be viewed as a possible
prolongation of this journey. The material support
of this continuum is represented by atherosclerosis,
the leading cause of coronary vessels narrowing.
As a clinical sign, the imbalance between the
reduced oxygen supply and the increased oxygen
demand during efforts or other causes generating
increased cardiac frequency, the symptoms of
angina occur at the end of the ischaemic cascade.
Kern [2] proposed the following succession
of events, with a duration of about 30 seconds:
cellular alterations > decreased relaxation (dyastolic
dysfunction) > systolic dysfunction > decrease of
the diastolic filling > the appearance of ST
alterations > angina.
Angina, as other symptomps of CVD, can be
considered as what can be called “the tip of the
iceberg” that is a summum of risk factors (dyslipidaemia, smoking, obesity, age, etc.) and subclinical
organ damage.
The ACC/AHA Guidelines on stable angina,
released in 2002 [3], stated that the basis of medical
management remains the pharmacological approach
(with the exception of a few high risk situations),
that includes what can be called: life saving drugs;
drugs maintaining/ameliorating the quality of life,
by relieving angina related discomfort.
ROM. J. INTERN. MED., 2010, 48, 4, 361–369
Among patients with a history of angina,
the frequency of exacerbations is the most important determinant of quality of life [4].
The recent ESC Congress in Stockholm,
Sweden offered an overview about the benefic
capacity of a novel substance, a late Na+ inhibitor
of offering anti-ischemic efficacy in subjects suffering from stable angina (either in monotherapy, or
in combination therapy).
The clinical proofs are consistent, summarizing the results obtained in the following trials
(their presentation in detail will follow): MARISA:
chronic angina (n = 191)[5]; CARISA: chronic
angina (n = 829)[5], ERICA: chronic angina (n =
565) [6], ROLE: chronic angina (n = 746)[7],
MERLIN – TIMI – 36 Non – STEMI ACS (n =
6.560) [8] [9], in a consistent number of patients.
In the first place, it is worth mentioning that
the severity of angina is in a direct and close
relationship with the mortality, conclusion that was
highlighted by using the Seattle Angina Questionnaire (SAQ) [10] – item disease-specific health
status measure for patients with coronary artery
disease. The different predictor variables in SAQ
were the scores for: physical limitation; angina
stability; angina frequency; quality of life, and the
primary outcome was the 1-year all cause mortality
and a secondary one: hospitalization for an ACS.
The 1-year mortality rate ranged from 2% in
patients with minimal physical limitation to over
12% in those with severe physical limitation.
362
H. Bălan
The principal two aims of the management of
stable angina pectoris are:
1) To improve prognosis by preventing myocardial infarction and death;
2) To diminish/abolish the symptoms.
The armamentarium considered to play an
active role in the conservative management of stable
angina is composed by: anti-thrombotic drugs, statins,
angiotensin converting enzyme inhibitors (ACEI),
beta-blockers (BB), nitrates, calcium channel blockers/
calcium antagonists (CCB/CA), potassium channel
offerers, sinus node inhibitors, metabolic agents.
On top of that came the new therapeutical
agent that represents the subject of this review:
a late sodium channel blocker, ranolazine.
First, why it is so important to have new
therapeutic agent in chronic angina: because the
incidence and prevalence of patients with angina is
anticipated to increase in the coming decades, due
to evident and increasing cardio-vascular burden:
the aging of the population, the “tsunamy” of
obesity/“diabesity”, the increasing use of lifeprolonging therapies.
Ranolazine, a piperazine derivative, the first
member of a new class of drugs (that have antiischemic effects through antagonism of the late
phase of the inward sodium current, significantly
increased in myocardial ischemic and also significantly contributing to calcium overload [11–13],
received the approval for the following benefits
that she proved to generate: improved exercise
performance; reduced angina frequency; reduced
use of sublingual nitroglycerin.
MERLIN-TIMI 36 trial [8] [9] enrolled 6.560
patients, of which 3.565 (54%) had a history of
prior chronic angina (the mean duration of the
angina was 5.2 years), the majority of patients were
in Canadian Cardiovascular Society Class (CCSC)
class 2 (41%), 32% reporting were severe anginal
symptoms (a non–ST–segment elevation ACS).
Study patients with an ACS had at least 1 indicator
of moderate to high risk of death on recurrent
ischemic events.
First, Ranolazine was tested as monotherapy
in patients with exercise – limiting angina and
significant ST-segment depression between 3 and
9 minutes, on an exercise tolerance test (ETT), using
the Bruce protocol [14] [15].
Also, Ranolazine was tested in combination
with other antianginal agents in patients with the
same ETT criteria [16] or in patients with at least
3 episodes of angina/week (although they used the
maximal dose of amlodipine) [17].
2
NB. On the basis of this evidence (the results
on over 1.500 patients of this randomized, doubleblind, placebo-controlled trial MERLIN-TIMI 36),
ranolazine is an effective antianginal and antiischemic agent, but it is not useful as a diseasemodifying secondary preventive therapy or for prophylaxis of recurrent angina in asymptomatic patients
stabilized after an ACS.
Active medications for secondary prevention
were used in a high proportion: aspirin 95%; betablockers 89%; statins 78%.
More than one third of the patients had a
history of prior revascularization (448 had a percutaneous coronary intervention – PCI) in the prior
24 months, of which 315 in the past 12 months
before study coronary angiography was undertaken
in 49% of patients.
The results of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive
Drug Evaluation) [18] which showed no difference
between aggressive secondary preventive pharmacotherapy plus PCI compared with optimal medical
therapy is reasonable for most patients with stable
CAD and that medical therapy and PCI are important
complementary options for managing angina.
But, even with aggressive pharmacotherapy
and revascularization, approximatively 25% of patients
with chronic angina continue to experience attacks
with contemporary therapy [19] [20].
In addition, use of traditional antianginal
agents is limited in some patients by side effects.
The median duration of follow-up was 350 days.
The mean number of antianginal agents administered at hospital discharge to patients with prior
angina was 1.9 (with no difference between treatment
groups).
Over the entire duration of follow-up, the
mean number of antianginals used / patient was 2.9
(67.5% of the patients were treated with 2 or more
medication).
Efficacy of ranolazine as antianginal therapy
The primary end-point (cardiovascular death,
AMI or recurrent ischemia) was lower in patients
treated with ranolazine compared with placebo
(25.2% vs. 29.4%; p < 0.017); this difference is due
only to the impact of ranolazine on recurrent
ischemia. One should note that ranolazine had
no effect on the risk of cardiovascular death or
AMI in the patients with prior angina.
But, it is worth mentioning that ranolazine
significantly reduced the incidence of each of the
major end points, with respect to its antianginal
3
Another anginal drug?
efficacy: reduction of the incidence of recurrent
ischemia (HR: 0.78%; 95% CI; p < 0.002); worsening
angina (HR = 0.77; 95% CI; p < 0.048); intensifycation of antianginal therapy (HR = 0.77; 95% CI;
p < 0.005).
Ranolazine improved severe recurrent ischemia
in patients with prior angina [defined as ischemia
associated with new electrocardiographic changes
or leading to hospital stay or revascularization
(11.9% vs 14.4%; HR = 0.81; 95% CI; p < 0.026)].
In patients without prior angina there was no
detectable benefit of ranolazine, with respect to
recurrent ischemia (HR = 1.03; 95% CI; p < 0.83).
And, finally, this effect of ranolazine on the
primary end point and recurrent ischemia was
consistent in patients with prior angina who were
treated with an early invasive management strategy
(n = 1.184; HR = 0.75; 95% CI; p < 0.013 and HR =
0.71; 95% CI; p < 0.015, respectively).
Ranolazine slightly reduced also the number
of traditional antianginal drugs (2.8 vs. 2.9; p <
0.045).
In an analysis conducted to evaluate the chronic
effect of ranolazine after the first 30 days, ranolazine
reduced the incidence of recurrent ischemia (HR =
0.80; 95% CI; p < 0.015), reduced worsening
angina (HR = 0.76; 95% CI; p < 0.044), reduced
the intensification of other antianginal therapy (HR =
0.77; 95% CI; p < 0.007).
At 8 months (or the final visit, if sooner),
ranolazine significantly improved all metrics of
exercise performance on ETT or bicycle exercise
testing: exercise duration (514 ± 7s vs. 482 ± 7s)
(p < 0.002), the time to onset of angina (508 ± 7s vs.
477 ± 7s) (p < 0.002), the time to onset of 1-mm
ST-segment depression (509 ± 7s vs. 479 ± 7s) (p <
0.003).
Among patients undergoing treadmill testing
(n = 1.459) (the primary study assessment in prior
studies of ranolazine) the mean difference in
exercise duration compared with placebo was 44 s
(589 ± 10s vs. 545 ± 10s, p < 0.001).
There was no significant impact of ranolazine
on exercise duration (p < 0.14) or time to ischemia
on exercise testing (p < 0.17) in those without a
history of stable angina, consistent with the anterior
mentioned lack of effect on recurrent ischemia in
patients without prior angina [8] [9] [17].
Safety and tolerability. Ranolazine was
generally welltolerated in patients with prior angina.
The few mentioned adverse effects were: dizziness
(12.4% vs. 7.4%), nausea (9.7% vs. 6.1%), constipation (8.5% vs. 3.3%).
363
In 8.1% patients ranolazine was discontinued
due to an adverse effect (vs. 4.1% in the placebo
group) (p < 0.001).
The dose of ranolazine had to be decreased
in: 190 (10.6%) patients for renal dysfunction; 10
(0.6%) patients for persistant prolongation of the
corrected QT interval; 154 (8.6%) patients for
adverse events; 8 patients for unknown cause.
There was no difference in the incidence of
the major safety end points in patients with prior
angina treated with ranolazine vs. placebo. Death
from any cause did not differ between treatment
groups (HR = 1.01; 95% CI; p < 0.96).
No significant increase in frequency of
symptomatic documented arrhythmias; clinically
significant arrhythmias on Holter evaluation were
significantly lower (73.9% vs. 83.1%; p < 0.0001).
There were no differences regarding the
incidence of discontinuation of ranolazine for an
adverse effect in those treated with calcium antagonists (diltiazem and verapamil have inhibitory
effect on the clearance of ranolazine).
Ranolazine was effective as an antianginal,
reducing the incidence of recurrent ischemia by
22% with a corresponding 24% reduction in the
incidence of worsening angina and improvement in
exercise performance on treadmill testing.
No evident effect on: the incidence of
cardiovascular death or MI, outcomes or symptoms
in patients with CAD without chronic angina,
although its efficacy as an antianginal drug is clear
and significant.
Ranolazine is an effective antianginal and
antiischemic agent but there were no benefits
considering a disease-modifying secondary preventive therapy or the prophylaxis of recurrent
angina in asymptomatic patients stabilized after
an acute coronary syndrome (ACS).
But, we must remember that the frequency of
exacerbations is the most important determinant of
quality of life [4].
That’s why the guidelines from the American
Heart Association and American College of
Cardiology are stating clearly the dual goals for the
management of patients with chronic CAD: the
secondary prevention of cardiovascular death and
AMI and the amelioration of angina [3].
The tablets should be swollen without chewing
or dividing them. The absorption is not influenced
by the meals.
The antianginal action of ranolazine may be
related to partial inhibition of fatty acid oxidation
[21] [22], which can produce anti-ischemic effects
364
H. Bălan
without depressing hemodynamic function, but it
was later proved that this effect is obtained only at
much higher serum levels than the ones clinically
used.
Inhibition of fatty acid oxidation reciprocally
increases glucose oxidation which generates more
adenosine triphosphate for each molecule of oxygen
consumption [23].
This shift may reduce myocardial oxygen
supply needed to support a given level of coronary
flow, resulting that ischemia should be less likely.
The Monotherapy Assessment of Ranolazine
in Stable Angina (MARISA) trial was the first
placebo-controlled trial to establish the antianginal
and anti-ischemic effects of ranolazine monotherapy,
demonstrating increased exercise tolerance and
prolonged times to exercise-induced angina and
ischemic ST-segment depression with twice-daily
ranolazine doses ranging from 500 mg to 1.500 mg
[5].
The main tendency in treating angina pectoris,
because myocardial oxygen extraction is maximal
at rest, was to minimize O2 demand (preload,
afterload, heart rate, myocardial contractility).
By its capacity of reducing myocardial O2
demand by a novel mechanism, ranolazine is
effective to reduce manifestations of ischemia and
angina, and raised new hopes for having benefic
effects in the management in left ventricular
dysfunction (especially diastolic dysfunction),
arrhythmias (especially chronic atrial fibrillation).
The actual data are indicating that the real
mechanism of action is represented by the
inhibition of the late inward sodium channel (late
INa) [1] [6] [11] [12], which remains opened (pathologically) in many situations, allowing to many
adverse stimuli to influence myocardium.
In normal situations, the inward sodium
channels rapidly inactivate after a short activation,
remaining closed during the plateau phase of the
action potential.
Following electrical activation other ion
channels open; among them, calcium channels: the
calcium ions that enter the cell during the plateau
phase will trigger the release of large quantities of
calcium ions from the endoplasmic reticulum.
In many pathological situations that can be
considered myocardial insults: myocardial ischemia,
ventricular hypertrophy, oxidative stress the late
sodium channels fail to inactivate/to close or fail to
reopen, so that the sodium ions continue to enter
the cell, generating an intracellular overload of
sodium, and thus leading to significant electro-
4
physiological disturbances: in contractility, in
metabolic environment.
The balance of sodium/calcium is disturbed
in such a manner that the elevation of the intracellular sodium concentration will promote an
increased exchange of intracellular sodium for
extracellular calcium through the Na+/Ca++ exchanger
mechanism, the initial sodium overload (at microscopic level the condition that will expose permanently
the contractile elements: actin and myosin, to the
calcium ions, that mean a continuous tonic
contracture.
A continuous tonic contracture is the functional
basis for an increased diastolic stiffness, associated
with an abnormal elevation in myocardial contractile work, which is leading to exactly the
opposite that is desired by any antianginal treatment:
increased oxygen consumption and the compression
of the vascular space during diastole [20] [22].
This late one effect determines a reduction in
myocardial blood flow, thus supplementarily reducing it.
By reducing the late sodium influx (in a
concentration, voltage- and frequency-dependent
manner) ranolazine has the capacity to prevent
the intracellular sodium overload and the subsequent calcium overload, a cascade of benefic
events that promotes: the facilitation of diastolic
relaxation, the preservation of the myocardial
blood flow during ischemia and reperfusion, the
reduction of oxygen consumption, the restauration
of the electrical stability.
At therapeutic plasmatic concentrations ranolazine has not any significant effect on the
cardiovascular performances of the non-ischemic
myocytes.
Ranolazine is an active piperazine derivative
available in oral and intravenous forms. Its major
metabolic biotransformation is through the cytochrome P4503A4-mediated pathway [23], an
important clue to remember, because drugs like
ketoconazole (diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, grapefruit juice),
which inhibit the Cyp3A isoenzymes increase
ranolazine levels (from 2.5 to 4.5 times).
It is also important to mention that ranolazine
increases digoxin levels.
Ranolazine showed a dose-related benefic
effect in myocardial ischemia at submaximal and
maximal exercise in patients who had stable coronary
artery disease attributable to an improvement in
myocardial blood flow without significantly
influencing heart rate or blood pressure.
5
Does that mean a new era in antianginal
treatment or just a useful complementary help,
by reducing the O2 demand?
For answering this important question, studies
have been made using both immediate-release
formulation and sustained-release formulation.
The anti-ischemic effect of ranolazine appeared
without a significant change in myocardial O2
demand; in comparison with placebo it was noted:
a significant reduction of anginal episodes, a significant reduction of nitroglycerin use, a significant
improvement in exercise duration and time to
exercise-induced myocardial ischemia.
MARISA (the Monotherapy Assessment of
Ranolazine in Stable Angina) trial, using the
sustained-release formulation in 500 mg twice a
day, 1.000 mg twice a day, 1.500 mg twice a day
versus placebo in 191 patients [5] showed a
significant, dose-dependent increase in: exercise
duration (maximal increase: 56 seconds), exercise
time to angina, exercise time to 1-mm ST segment
depression compared to placebo (maximal increase
69 seconds).
CARISA (Combination Assessment of
Ranolazine in Stable Angina) trial highlighted the
supplementary benefit of adding ranolazine to a
combination of antianginal drugs (atenolol 50 mg
every day, diltiazem 180 mg every day or
amlodipine 5 mg every day [5] in 823 patients).
The addition of ranolazine was followed by: a
significant reduction in antianginal frequency and
nitroglycerin consumption, an increase in exercise
duration (115.6 seconds above baseline), an
increase of the period of time to angina, an increase
of the period of time to 1-mm ST segment
depression compared to placebo (also at trough, as
at peak drug effect), without a significant
difference between the two doses used: 750 mg
twice a day and 1.000 mg twice a day.
The benefic, above-mentioned effects were
not connected to any change in blood pressure or
heart rate.
The most common dose-related adverse effects
were constipation, dizziness, nausea and asthenia
(that appeared in less than 7% of the ranolazinetreated patients, compared to less than 1% of the
placebo-treated subjects).
The higher doses (up to 2.000 mg twice a
day) can be followed by postural hypotension and
syncope (probably due to alpha 1-adrenergic
receptor blocking activities) [24].
The diabetics in CARISA trial showed a
significant (by an unknown mechanism) improvement in HbA1c [5].
365
ERICA trial (Efiicacy of Ranolazine in Chronic
Angina) [6] investigated the antianginal effects of
ranolazine vs. placebo in 565 patients with
persistent angina symptoms despite maximal dosing
(10 mg daily) of amlodipine.
And, what should be especially noted is that
those patients, who had more frequent angina per
week (over 4.5 episodes) had a much more marked
beneficial response to ranolazine addition to
baseline treatment, expressed in: angina frequency,
nitroglycerin consumption, seattle Angina Questionnaire.
The MERLIN-TIMI-36 trial studied the effects
of ranolazine (first administered by intravenous
infusion, followed by oral ranolazine) in patients
who had a non-ST segment elevation acute
coronary syndrome (ACS) [8] [9] – a total of 6.560
patients who had either unstable angina or
NSTEMI (enrolled within 48 hours of ischemic
symptoms and were treated, as mentioned with
ranolazine, first by i.v. infusion, after oral administration, that were followed for a median of 348 days).
The primary efficacy end-point was a
composite of: cardio-vascular death, myocardial
infarction, recurrent ischemia; no difference was
noted between the two treatment groups, with the
exception of recurrent ischemia.
Concerning this effect, a trend toward the
reduction of recurrent ischemic complications
(13.9% in the ranolazine-treated patients vs. 16.1%
in the placebo-treated group) (HR = 0.75; p =
0.03).
Besides the above-mentioned long-term effect
of the treatment with ranolazine: the worsening
angina by: at least one Canadian Cardiovascular
Society class requiring intensification of medical
therapy, less frequent escalation in antianginal
medication, improvement in anginal frequency
using the SAQ, another benefic longterm effect of
ranolazine was the prevention of atrial and
ventricular arrhythmias in this class of high-risk
subject (with non-ST elevation ACS) [9].
In a substudy analysis ranolazine was
associated with a significant reduction in the
composite primary end-point in the high-risk
subgroup of patients (characterized by elevated
levels of brain natriuretic peptide [BNP]: greater
than 80 pg/ml (p = 0.009), showing no beneficial
effect in those considered low-risk (those with a
normal BNP value).
Such a large trial demonstrated convincingly
the safety of ranolazine: no difference in mortality
in those treated with ranolazine vs. placebo; no
366
H. Bălan
difference in the incidence of sudden death; no
difference in the incidence of symptomatic
documented arrhythmias.
Discontinuation of treatment because an
adverse effect occurred in 28% in the ranolazine
group and in 22% in the placebo group (p < 0.01),
the most frequent adverse effects, occurring in
more than 4% were: dizziness (13% vs. 7%),
nausea (9% vs. 6%), syncope (3.3% vs. 2.3%) in
placebo in placebo (p = 0.01).
Regarding the electrophysiological effects
and antiarrhythmic properties of ranolazine,
although its effects: inhibition of the late INa and the
late ICa are modest (5–10 miliseconds) regarding
the duration of the action potential, this means the
shortening or normalization of a prolonged action
potential (due to ischemia or to exposure to
arrhythmogenic compounds).
His minimal effect on prolongation of QT
interval is considered as another source of potential
effects:
In drug-induced “torsades des pointes”, in
reduction in the incidence of early after depolarization, to not exacerbate the transmural dispersion
of repolarization (associated with ischemic and
exposure to arrhythmogenic drugs).
In all the trials conducted until now there
were very rare cases of torsdes des pointes, each
time the same incidence as in the placebo group.
Although not used as an antiarrhythmic drug,
his efficacy in this domain was proven in the
MERLIN-TIMI 36, where 97% of the 6.560
patients with an ACS were contiuously ECGmonitored, so it was possible to make a very solid
analysis.
The results of this analysis showed that
ranolazine was associated with a significant reduction
in ventricular arrhythmias (with no effect on sustained ventricular tachycardia greater than 30 seconds);
a reduction of the incidence of supraventricular
arrhythmias; a trend toward reducing the incidence
of new-onset atrial fibrillation (p = 0.08); a very
significant reduction of the ventricular tachycardias
lasting 8 beats or more in the high-risk patients:
those who had prior heart failure, reduced left
ventricular function, prolonged QTc interval at
baseline and a high [25–27] TIMI risk score; and
with a reduction of the incidence of bradycardia
less than 45 bpm for at least 4 beats.
Although it is not clear if these antiarrhythmic effects are secondary to prevention of
ischemia-associated arrhythmias or from a primary
antiarrhythmic effect (maybe related to its effect on
Na and Ca ions channels.
6
The actual data show promising results of
ranolazine in the management of diastolic LV
dysfunction, especially associated with ischemic
cardiomyopathy and left ventricular hypertrophy
(LVH) (conditions associated with abnormal late
INa and secondary Na and Ca overload, associated
with oxidative stress).
Hayashida et al. [28], by intravenous administration of ranolazine in 15 patients with a previous
transmural MI in whom were demonstrated
ischemic or infarcted segments observed a significantly increased regional peak filling rate and the
regional wall lengthening in the ischemic segments
(p < 0.05).
The echo Doppler analysis of the left
ventricular filling dynamics [29] showed an improved
peak filling rate.
In patients with documented genetic defect in
the late sodium channel, the hereditary long QT
syndrome LQT3-delta KPQ, intravenous administration of ranolazine managed to shorten the
prolonged QTc and to improve the associated
diastolic dysfunction.
ROLE trial (Ranolazine Open Label Experience) [7] studied the safety and tolerability of
ranelazine (n = 746).
The ROLE program involved patients who
completed MARISA and CARISA trial, so all
ROLE participants were having severe functional
limitations due to angina.
All the subjects had severe functional
impairment from angina and adverse events (AE)
reporting was performed periodically.
Investigators could titrate to optimal ranolazine
dosages between 500 and 1.000 mg b.i.d. on the
basis of clinical responses at up to 6 initial weekly
visits.
Patients who experienced recurrent angina or
adverse events (AE) during the maintenance phase
could be titrated to higher or lower drug doses.
The optimal addition of other antianginal
effects was permitted.
Safety and tolerability assessments included
vital signs, electrocardiograms (ECGs), AE evaluation,
with physical examination and laboratory analyses
(hematology, chemistry and plasma ranolazine
concentrations) were conducted at baseline and all
maintainance-phase visits; urinanalysis and serum
lipids were assessed at baseline and every 6 months
during maintenance.
All the reasons for study drug discontinuation
were recorded.
Every new drug is considered, at the beginning,
with hopeful feelings and some concerns, the last
ones being justified by the relatively recent cases of
mibefradil and nesiritide (agents that received
7
regulatory approval for the symptomatic relief that
they offered, and were subsequently withdrawn/
kept under strict observation after the release of
safety data.
The results of this observational trial can be
summarized as follows: 23.2% of the patients did
not complete 2 years of therapy, but only less than
one half (9.7%) stopped the ranolazine administration due to AE.
Predictive modeling showed a significantly
increased likelihood of AE-discontinuation only with
the variable represented by an age of over 64 years.
Some previous data that showed improvement of the left ventricular function in animals [9]
[17] are, possibly, sustaining the good tolerance of
ranolazine in those with CHF.
Their mortality (all of them, with a mean
Duke Treadmill Score [TDS] [30] of – 14.4 was
considered at high risk (category characterized by
TDS score < –10) was compared with the Duke
Treadmill Score (DTS) predictive model and other
contemporary cohorts of high-risk CHD patients
(during a mean follow-up of 2.82 years).
Although the open-label methodology of this
trial is not a perfect tool for a rigorous analysis in
this sense, the data offered by this trial are
consistent: the mean DTS would imply a poor
prognosis and a yearly mortality estimate above
5%; at the end of the study the 2 year mortality of
5.6%, with a yearly mortality of approximately
one-half the DTS predicted rate, a very supportive
data in favor of ranolazine.
It is also useful to mention that these data are
an answer regarding the very negative impact of the
QTc interval prolongation (a mean of 2.4 msec), a
previous study regarding the Bazzett’s corrected
interval [31] showed a prolongation of less than
10 msec (and, it is worth mentioning that is now
demonstrated [32] that QTc interval prolongation
alone is not sufficient to cause torsades des pointes,
it is mandatory that induction of early after
depolarizations and an increase in transmural
dispersion be present. Finally, there were no
investigator-ordered discontinuations related to
QTc interval prolongation or cases of torsade des
pointes [33].
A populational analysis of data from patients
and healthy volunteers demonstrated that the
increase of the QTc duration as function of the
plasmatic concentration was estimated to 2.4 msec
at 1.000 ng/ml, that means an increase of 2–7 msec
over the interval of the plasmatic concentration of
ranolazine in doses ranging from 500 mg twice a
day to 1.000 mg twice a day. This prolongation of
QTc must be cautiously considered when ranolazine is intended to be administered in: patients
367
with an inherited prolongation of QTc, in patients
with acquired QT prolongation, or in patients that
are concomitantly treated with QTc prolongating-drugs:
some antihistaminic drugs (terfenadine, astemizole,
mizolastine), some antiarrhythmic drugs (quinidine,
disopiramide, procainamide), tricyclic antidepressive drugs (imipramine, amitryptiline, doxepine).
It is also mandatory to carefully establish the
dosing in: congestive heart failure, renal failure,
hepatic failure, third age subjects, those with reduced
weight; it is not recommended to administer
ranolazine in children and adolescents.
Regarding the AE 72 patients (9.7%) they
discontinued ranolazine due to AE, only the age of
over 64 years being highly predictive for high
withdrawal rates.
Mean QTc interval was prolonged by 2.4 msec
(without any treatment discontinuation due to this
prolongation) and with no torsades des pointes
reported.
The total mortality (by extending observations to all patients in the double-blind trials
(preceding the ROLE program) was 2.8%
compared with > 5% as predicted by DTS.
Long-term safety and tolerability of ranolazine
in patients with chronic stable angina seems favorable without indication of increased long-term cardiac
mortality compared with reference populations.
So, there are solid arguments sustaining that
ranolazine is well tolerated in high-risk CHD
patients and survival analysis suggests that symptommatic improvements attributable to ranolazine
are important, compared to the absence of an
increase of the mortality.
As conclusions:
• myocardial ischaemia is associated with a
pathological increase of the late cardiac Na+
current (INa);
• this increase in late INa causes Ca2+ overload, generating increased diastolic wall
tension and, respectively, a worsening of
ischaemia;
• by these effects, the anti-anginal/antiischaemic effects are not secondary to any
modification in the haemodynamic parameters;
• the well-demonstrated improvement in exercise
performance (MARISA, CARISA, MERLINTIMI 36), the significant decrease in weekly
attacks and in nitrates consumption
(CARISA, ERICA) and the benefic effects
on angina/ischaemia (MERLIN-TIMI 36)
are solid arguments for this new and well-tolerated
anti-anginal agent, that can, possibly, have also
benefic antiarrhythmic properties.
368
H. Bălan
8
Ranolazine este un medicament nou, recent aprobat de Food and Drug
Administration (FDA) pentru tratamentul pacienţilor cu angină pectorală stabilă
refractară la terapia antianginoasă convenţională.
Ranolazine s-a dovedit a fi eficace atât ca monoterapie, cât şi în combinaţie
cu alte principii terapeutice.
Această trecere în revistă este inspirată de prezentarea pe care figuri
legendare ale cardiologiei contemporane, precum Braunwald, Komajda, Camm au
făcut-o recent acestui medicament la ultimul Congres al Societăţii Europene de
Cardiologie, desfşurat la Stockholm, în Suedia, anul acesta.
Corrresponding author: H. Bălan
Medical Clinic, Clinical Emergency Hospital Ilfov County,
49–51, Bucharest, Basarabia Blvd.
e-mail: drhoriabalan@yahoo.com
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Stress Vulnerability in Patients with Drug Allergy –
Psychological Aspects Revealed from some Personal Studies
I.B. IAMANDESCU, LILIANA DIACONESCU
“Carol Davila” University of Medicine and Pharmacy, Department of Medical Psychology, Bucharest, Romania
Previous studies revealed the fact that patients with allergic-type reactions to drugs display
very frequently psychical disturbances, possibly in relation to the large amount of stress perceived by
them. Some of these patients with psychiatric comorbidity show a disproportionate reaction,
manifested as extensive psychosomatic disturbances, mimicking the psychic and somatic symptoms
of a previous anaphylactic or anaphylactoid reaction, when a new drug or even when placebo
preparations are given. The neurotic symptoms, very frequently encountered in patients with allergictype reactions to drugs (including asthma patients) appear to be secondarily-induced by the anxious
experience of the drug-provoked accident.
The vulnerability to psychic stress, together with many life stressors events may represent a
potential risk for developing drug allergy. Their main problem is the risk of repeating the allergic
accidents, especially in patients with various comorbidity which need medication.
Key words: drug allergy, psychotomatic disease.
Belonging to allergic diseases, drug allergy is
considered a psychosomatic disease with multifactorial
etiology with a psychogenic component binding [1].
In iatrogenic pathology, patients with allergic
reactions to drugs are a specific subpopulation both
in terms of allergic mechanisms of allergic reactions
to medicines and of the site of these reactions –
skin and mucous membranes (especially respiratory
and digestive) as tissues with a barrier role.
Together with allergic reactions to drugs can
be considered a fairly large group of “pseudoallergic” reactions included under the term “nonallergic hypersensitivity” [2] whose mechanism
does not “appeal” to allergic antibodies or to the
sensitized cells, but other “non-allergic” mechanisms
(e.g., cyclooxygenase inhibition by NSAIDs, direct
action on mast cell as polymixine). These nonallergic mechanisms “use” the effector link of allergic
reaction represented by mast cell degranulation and
other blood cells, as eosinophils, resulting in the
release of allergic mediators (histamine, leukotriene,
PAF, etc.).
Therefore, since both allergic reactions and
non-allergic reactions to drugs have same causes,
one of us (Iamandescu) grouped both types of
reactions as “allergic-type reactions to drugs
(medicines)” (AtRD). Since the psychological effects
of these reactions are the same, the references to
drug allergy presented in this article will actually
refer AtRD term, which is less used in the
literature.
ROM. J. INTERN. MED., 2010, 48, 4, 371–375
Psychological vulnerability to stress may be
regarded as a particular feature of individuals
which respond in an easy manner to psychological
stress in a wide range of stress agents [3] and
appears as an element favoring psychosomatic
disease in which an organ vulnerability is associated
[4]. Meanwhile, any psychosomatic disease generates
somato-psychic disorders, which are enhanced by
this type of personality with an increased vulnerability (especially in the field of affective-emotional)
[5]. We can speak about a double vulnerability:
psychological and physical.
In selected cases, may consider the presence
of a constitutional vulnerability to stress (generated
by inducing genes of such vulnerabilities, which
coexist with genes bearing immunological characteristics of future allergic). But no matter whether
we speak about an acquired or constitutional
vulnerability, patients who experienced an allergic
reaction to medication, especially if it was severe
(anaphylactic shock, glottis edema), may submit a
series of psychological symptoms, arising from the
allergic reaction recurrence [6] [7]:
– a high degree of anxiety in the event of an
illness requiring medical treatment;
– fear of a new allergic accident, resulting in
anxious expectation of possible allergic reactions;
– disease phobia and drug phobia especially
to drugs;
– (in surgery) assumption of increased suffering
due to fear of developing allergy after anesthesia;
372
I.B. Iamandescu and Liliana Diaconescu
– extrapolation of allergic reactions from
certain drugs to all drugs;
– excessive neuro-vegetative reactions (headache, dizziness, palpitations, tachycardia) at the
administration of medicines, and some-times even
in placebo-prepared (in which case we speak about
nocebo effect).
These symptoms may be a clinical expression
of a state of extreme anxiety.
Personality type and psychic symptoms of
patients with allergic reactions to drugs
Two sub-populations can be distinguished,
from the viewpoint of personality features, corresponding to the two clinical-pathogenic groups
defined above [8]:
1) Patients with pure allergy or with pseudoallergy to drugs (group A)
From the 79 patients that we investigated,
55.7% had T values over 70 percentile on the Hs
(Hipocondria), D (Depression) and Hy (Hysteria)
scales, constituting together the so-called “neurotic
triad”. Also, a record of events on the Holmes and
Rahe scale showed that 82.3% of these patients had
a total score over 300 points, with regard to the
summation of psycho-traumatizing events occurred
in the last 6 months preceding the allergic-type
reactions to drugs.
2) Patients with psychosomatic disturbances –
mimicking drug allergy – on repeated administration of drugs (other than the initial ones, that
had triggered allergic-type reactions) (group B).
This subgroup included 40 patients with
characteristics indicating coexistence of a true
neurosis, both by the large number of neurotic
symptoms (> 5) found in almost each patient (90%
of all cases), and by the high values of T levels on
the neurotic triad scales as evaluated with the
MMPI Questionnaire (96% of all cases).
All the patients had been submitted to psychical
stress, and had scores above 300 points on the
Holmes and Rahe Scale over the last 6 months that
had preceded the first episode of allergic-type
intolerance to certain drugs.
Concluding on these relationships mentioned
above the following can be inferred:
• The permeability factor for the onset of
allergic-type reactions to drugs, as well as
of neurotic disturbances secondary to these
reactions was the overall vulnerability to
stress of most of the patients, as demonstrated with the psychological MMPI test,
which showed values characteristic for
2
neurotic patients(the neurotic triad: Hs +
Hy + D) in 55.7% of the cases in the first
group (A) (with lower neurotic disturbances), and in 90% of the patients in the
second group (B) (with chronic neurotic
disturbances and “noisy” psychosomatic
reactions to placebo testing).
• In the vast majority of patients with
allergic-type reactions to drug – 82.3% of
the 79 patients with exclusive allergic or
pseudo-allergic reactions to drugs group and
in 100% of the 40 patients with initial allergic
reactions followed by psychosomatic disturbances to placebo administration – the
presence of major stresses was noted,
before the onset of first allergic-type
manifesttations, and these stresses were
later exacerbated by the psychologicallytraumatizing experience of drug-induced
accidents, including the fear for their
possible recurrence.
• Neurotic symptoms evidenced by us in
patients with allergic-type reactions to drugs
(considered at present to be “neurotic
disturbances of personality”) were present
in these patients, either in an isolated form
of 1–2 symptoms (for instance: anxiety and
depression), with a transient evolution, or
as “true neurotic syndromes” with a chronic
evolution.
To conclude (Table I):
• Patients with allergic-type reactions to
drugs display very frequently psychical
disturbances, possibly in relation to the
large amount of stress perceived by them;
• Many of these patients are neurotic and a
large part of them show a disproportionate
reaction, manifested as extensive psychosomatic disturbances, mimicking the psychic
and somatic symptoms of a previous
anaphylactic or anaphylactoid reaction, when
a new drug or even when placebo preparations are given;
• The neurotic symptoms, very frequently
encountered in patients with allergic-type
reactions to drugs (including asthma patients),
appear to be secondarily-induced by the
anxious experience of the drug-provoked
accident. This authentic somato-psychic
reaction to drug allergy can be conditioned
in some patients (see group B), but it
achieves this secondary “neurotic state”
only when certain personality features already
exist (that can even reflect personality
3
Stress vulnerability and drug allergy
disturbances!), making these patients highly
vulnerable to psychical stress;
• The vulnerability to psychic stress, together
with many life stressors events may repre-
373
sent a potential risk for developing drug
allergy in a predisposed patient, but this
hypothesis – emerged from our studies –
has still to be demonstrated.
Table I
Psychotic parameters
1. Stresors of life events
Subpopulations of patients with drug
induced symptoms
Allergy or pseudo-allergy
Mimicking allergy
(Group A)
(Group B)
↑ ↑ ↑
↑ ↑ ↑ ↑
2. High vulnerability to stress (MMPI)
3. Neurotic symptoms
- absent
- few (< 5)
- many (> 5)
(real neurotic patients)
Depression and anxiety
Allergic patients have a high rate of anxiety
disorders and/or depression [9] [10]. Furthermore,
studies on patients with affective and anxiety
disorders [11] showed a high prevalence of allergic
reactions. In these patients a higher percentage of
affective disorders, anxiety, depression and panic
have been present. Anxiety is characterized by
excessive anxiety and vegetative hyperexcitation
associated with distorted perceptions of symptoms,
leading to an increased number and severity of
complaints/symptoms [12] [13] and avoidant behaviour [14].
Somato-psychic recoil
In addition to somatic or psychological terrain
favorable to allergic reactions, a definite contribution to the perpetuation of an allergy is somatopsychic recoil [9]. In this regard, the doctor should
discover the individual representations of allergic
reaction to medication which are related to issues
such as [15]:
– a correct identification of allergy;
– identifying the consequences (physical,
emotional, social, economic);
– the patient knowledge about the real causes
of allergy;
– the control of drug allergy (the extent to
which the patient identifies the allergic reaction as
a problem that can be controlled).
If drug allergy has or has not vital risk, patients
with allergic-type reactions will use adaptive
strategies, such as [15]:
↑ ↑
↑ ↑ ↑ ↑
↑ ↑ ↑
↑ ↑
↑
0
↑
↑ ↑ ↑ ↑
– reorganization of the relationship with others;
– reorganization of the self image;
– affective and behavioral regression;
– emotional reactions (anxiety, depression);
– problem-centered coping (e.g., analyzing,
resolving/minimizing the situation) or emotioncentered coping (e.g. denying, resignation, fatalism).
We conducted a recent study (2009) in order
to highlight some psychodiagnostic and experimental aspects in drug allergy.
MATERIAL AND METHOD
In the study 30 subjects with drug allergy and
30 healthy subjects were included. In both groups
of subjects psychological tests were applied:
• Anxiety and Depression Scale – HADS [16].
It is a brief self-report questionnaire (14
items) which assesses anxiety (HADS-A)
and depression (HADS-D) as two distinct
dimensions in non-psychiatric populations.
It has been used widely in clinical settings
where anxiety and depression can co-occur
with physical pathology.
• Perceived Stress Scale [17]. It is a psychological instrument (10 items) which measures
a global perception of stress. The questions
ask about feelings and thoughts during the
last month. Items were designed to tap how
unpredictable, uncontrollable and overloaded
respondents find their lives.
• Stress Vulnerability Scale [18]. It is a self
report questionnaire (20 items) which
374
I.B. Iamandescu and Liliana Diaconescu
measures how vulnerable is someone to
stress. It refers to a number of factors that
affect one’s vulnerability to stress – among
them are eating and sleeping habits, caffeine
and alcohol intake, and how people express
their emotions.
Considering the finding that emotional stimuli
modify the sudor secretion [19], the subjects were
submitted to a musical-test diagnostic (MTD,
Iamandescu) including 3 sets of music as a psychosomatic stimulus that induces changes in the
moisture of skin which was measured with the
Multi Skin Test Center MC 750.
4
RESULTS (shown in Table II)
Levels of anxiety, depression and perceived
stress were significantly elevated in patients with
drug allergy compared with the control group.
Increased scores at the stress vulnerability (with
values between 32 and 65 points) correlated with
high scores on perceived stress scale (.408, p <
0.01).
Sudor secretion was increased in patients with
drug allergy after hearing each music fragment, but
especially after the sad music pieces (perceived as
a distressing stimulus).
Table II
Anxiety
Depression
Perceived stress
Stress vulnerability
Patients with drug allergy
9.25
5.72
41.55
38.97
Healthy subjects
6.73
3.80
28.80
31.46
Considering those issues is useful and necessary
a psychosomatic approach of patients with drug
allergy, an approach that focuses on items like:
1. High levels of anxiety and depression that
– the evolution of allergy, although disconpatients have presented underline the somatic-psychic
tinuous
and sometimes with the possibility of
recoil and psychological impact of allergic reactions.
avoiding allergic episodes remains often unpre2. High scores on scales of perceived stress
dictable;
and vulnerability to stress indicate that these
– the risk of occurrence of episodes which
patients are characterized by a particular psychocan endanger life (shock, glottis edema);
logical profile, with personality traits that imply the
– personality traits dominated by the presence
existence of a psychological vulnerability to stress.
of anxiety, depression;
3. Higher value of perceived stress and
– psychological stress vulnerability that entails
vulnerability to stress in patients with drug allergy
which can maximize the role of stressful life
(comparing with healthy subjects) may indicate
context and enhance the appearance of somatothat these patients would have limited capacity to
psychic recoil with anticipatory anxiety and phobia
cope with stressful events), generated either by
towards drugs and any condition that requires
acquired or constitutional vulnerability.
treatment, the feeling of helplessness and hope4. The increasing of sweat secretion level
lessness or neuro-vegetative reactions that mimic
especially after the sad music passage (as a psychoan allergic reaction;
– the utility of psychotherapeutic interventions,
somatic stimulus) is an objective proof of the
at least supportive or relaxant therapies.
influence of psychic stress.
___________________________________________________________________
DISCUSSION
Studiile precedente au relevat faptul că pacienţii cu reacţii de tip alergic la
medicamente prezintă tulburări psihice foarte frecvent, eventual în relaţie cu
încărcătura de stres perceput. Unii dintre aceşti pacienţi cu comorbiditate
psihiatrică au o reacţie disproporţionată, manifestată prin tulburări psihosomatice
extinse, ce pot mima simptome psihice şi somatice ale unei reacţii anafilactice sau
anafilactoide anterioare, atunci când este administrat un nou medicament sau
chiar un preparat placebo. Simptomele nevrotice, foarte frecvent întâlnite la
pacienţii cu reacţii de tip alergic la medicamente (inclusiv la pacienţii cu astm),
par a fi induse în mod secundar şi de experienţa anxioasă a unui accident provocat
de medicamente.
5
Stress vulnerability and drug allergy
375
Vulnerabilitatea la stres psihic, împreună cu evenimentele stresante de viaţă,
poate reprezenta un risc potenţial pentru apariţia reacţiilor alergice la medicamente.
Problema principală este reprezentată de riscul repetării accidentelor alergice, în
special la pacienţii cu diferite comorbidităţi şi care necesită medicaţie.
___________________________________________________________________
Corresponding author: Liliana Diaconescu
Email: idiac2002@yahoo.com
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Protein Aggregation in Inclusion Body Myositis, a Sporadic Form Among Protein
Aggregate Myopathies, and in Myofibrillar Myopathies – a Comparative Study
ALEXANDRA BASTIAN1, H.H. GOEBEL2
1
“Colentina” University Hospital, Department of Pathology, Bucharest, Romania
Johannes Gutenberg University Clinical Hospital, Department of Neuropathology, Mainz ,Germany
2
Protein aggregation has been identified in muscle fibres and, thus, in certain neuromuscular
disorders. There are certain similarities between IBM and DRM: midlife or late-onset clinical symptoms,
apparently of both sporadic and genetic background, morphologically autophagocytosis by vacuole
formation, which is frequent in IBM though rare in DRM, and presence of tubulofilamentous aggregates,
which is almost regular in IBM but scantily found in DRM as β-amyloid components have been
identified as accruing proteins, both in IBM and DRM.
Previous studies pointed to the hypothesis that clear morphological borders between the two
types of diseases – hereditary inclusion body myopathies/myositis and desmin-related myopathies
may not exist. Therefore, we analysed and morphologically characterised the spectrum of proteins
accumulating in both types of disorders in order to compare them and more clearly define similarities
and dissimilarities between these two different groups of protein aggregate myopathies. Previous
studies [7] showed that there is an overlap among some of the proteins accruing in these diseases , but
there might also be differences in that a large number of proteins found aggregated in desmin-related
myopathies had not yet been described in IBM. The aim of describing the comparative protein
profiles is to give more insights into the mechanism of protein aggregation within muscle fibres.
Material & Methods. We studied diagnostic muscle biopsies from 10 sIMB patients and 6 MM
patients with histological, histochemical, enzyme histochemical, ultrastructural and immunohistochemical techniques using a large number of antibodies.
Results. We noticed a partial overlap of protein expression in the two cohorts of patients for
sarcomeric, chaperone and mostly for cytoskeletal proteins. In both of the cohorts, the nuclear proteins
were absent in the cytoplasmic bodies. A different pattern of immunolabelling was noted for transsarcolemmal proteins, constantly enhanced in the inclusion bodies in MM, but never found in IBM,
except for δ-sarcoglycan, dysferlin and caveolin.
Conclusions. The partial overlap among some of the proteins accruing in these diseases raise
the hypothesis that clear nosological borders between s-IBM and MM may not always exist. There are
also dissimilarities in the pattern of protein aggregation, suggesting that other additional factors are
involved in the pathogenesis.
Keywords: myofibrillar myopathies, desmin-related myopathies (DRM), inclusion body myositis
(IBM), rimmed vacuoles.
Sporadic inclusion body myositis (s-IBM) is
an inflammatory myopathy, morphologically characterized by varying degrees of inflammatory infiltrates
and rimmed vacuoles with or without inclusion
bodies made by abnormal aggregates of proteins in
muscle fibres. Myofibrillar myopathies (MM)/
desmin-related myopathies (DRM), a subgroup in
the family of protein aggregates myopathies, are a
clinically and genetically heterogeneous group of
muscular diseases marked by abnormal accumulation
of proteins in muscle fibres. We compared the
spectrum of proteins accumulating in both types of
disorders.
We studied diagnostic muscle biopsy specimens from ten unrelated patients with s-IBM. In all
ROM. J. INTERN. MED., 2010, 48, 4, 377–384
the cases, the diagnosis was established following
combined clinical and morphopathological criteria
[1–3]. Three patients were women and seven were
men. The age of onset varied from 40 to 75 years.
Symptoms at the time of diagnosis consisted of
slowly progressing proximal and distal muscle
weakness and wasting with depressed or absent
tendon reflexes especially in the lower limbs. The
pattern of muscle weakness was variable, but
mostly distal and asymmetric. In all of the cases the
skeletal muscle biopsies were characterized by
variable numbers of atrophic or normally sized
fibers containing one or more rimmed vacuoles,
often associated with a nucleus and best seen by
modified Gömöri trichrome stain and muscle fibers
378
Alexandra Bastian and H.H. Goebel
with cytoplasmic inclusions. The vacuolated muscle
fibres were ultramorphologically characterised by
intracytoplasmic and, though less frequently, also
intranuclear, tubulofilaments with diameters of
around 16–21 nm which appeared as paired helical
filaments, a morphologic hallmark of IBM. Other
common findings at electron microscopic level
were myelin-like bodies (membranous whorls) of
varying size and shape disrupting the myofibrils
and aggregates of mitochondria and occasionaly
honeycomb structures. A constant feature at light
microscopy level were varying degrees of inflammatory infiltrates consisting of large numbers of autoaggressive CD8 + T lymphocytes and CD68 +
macrophages, the latter reacting histochemically for
acid phosphatase, surrounding and partially invading
non-necrotic muscle fibres, while other regions of
the muscle fiber appeared intact. Muscle fibers
showed upregulation of MHC class I antigen
(major histocompatibility complex). Endomysial
inflammatory infiltrates, in the form of linear
distribution of cells among muscle fibers or as
larger collections around muscle fibers, were mostly
T lymphocytes around vessels and mainly macrophages near and within muscle fibres. Variation in
myofiber diameters, endomysial fibrosis, occasional
necrotic and regenerating fibers, angulated atrophic,
rarely grouped muscle fibers and ragged red and
cytochrome – C-oxidase – negative fibers were
further myopathic features.
The second cohort of patients with the
diagnosis of myofibrillar myopathy (MM) established
after examination of the muscle biopsies by light
and electron microscopy included six cases.
Two of these were brothers, aged 52 and
42 years. The older brother noticed increased muscle
weakness first in the left and then in the right leg,
followed by marked gait disturbances and distal
paresis of peroneal distribution. In the last six
months he had also noted weakness in his left hand,
and in the past two months weakness in his right
hand. At the time of examination he had conspicuous distal muscle atrophy in both legs and
arms, asymmetric deep tendon reflexes, decreased
knee jerks on the left and absent Achilles tendon
reflexes on both sides. He also had cardiac arrythmia
with atrial fibrillation and considerably enlarged
atria and a history of two myocardial infarcts at the
ages 44 and 46 years. His brother, 10 years
younger, developed restrictive cardiomyopathy at
the age of 20 years, which required cardiac transplantation at the age of 41 years. Their sister and an
uncle were said to have had myocardial infarcts.
2
We studied biopsied skeletal muscle specimens of
the older brother obtained from gastrocnemius and
deltoid muscles, as well as from his heart tissue and
also from the explanted heart of his younger
brother. In the skeletal muscle tissues, the pathological features consisted in variation in fibre size,
considerable increase in internally located nuclei
and muscle fibres showing irregular densities within
the sarcoplasm, in subsarcolemmal or centrally
located areas, as eosinophilic masses on hematoxylin-eosin stain and dark-blue on modified Gömöri
trichrome stain, often devoid of oxidative and
ATPase enzyme activities. Phagocytosis, necrosis
and basophilia of muscle fibres were absent, as well
as COX-negative fibres and inflammatory infiltrates.
One ragged red fibre was noted in the deltoid
muscle specimen. There was no upregulation of
MHC-I on muscle fibres. Immunohistochemically,
desmin and other proteins were focally expressed
within numerous muscle fibres. Electron microscopy
of deltoid and gastrocnemius muscle tissues revealed
granulofilamentous material beneath the sarcolemma as well as among the muscle fibrils. In both
muscles autophagic vacuoles contained some pseudomyelin lamellae and debris as well as – deposited
as aggregates – tubulofilaments of the helicalfilament type. The brother’s explanted heart muscle
showed variation in muscle cell diameters and
numerous densities within muscle fibres which, by
immunohistochemistry, contained desmin and numerous other proteins. By electron microscopy,
these patches within cardiac myocytes were
composed of granular and filamentous material or
electron dense material, very similar to the granulofilamentous material within skeletal muscle fibres.
Molecular analysis based on DNA extracted from
nucleated blood cells revealed a heterozygous novel
GAG-GAC mutation in exon 3 of the desmin gene
at 2q35 chromosome, resulting in amino acid
change Glu245Asp in the desmin molecule, confirmed
the morphological diagnosis of desminopathy. This
case, published by us in 2005 [6], enlarged the
spectrum of known mutations in the desmin gene,
but also the molecular spectrum of desmin-related
myopathies as well as genotype-morphotype correlations.
The third case of MM was a 67-year old man
with proximal and distal muscle atrophy of the
lower limbs, difficulty climbing stairs and getting
out a chair for the past few years, and a cardiomyopathy with an ejection fraction reduced at 25%.
He was clinically diagnosed with a distal myopathy
of the Markesbery-Griggs-Udd type. His five year-
3
Protein aggregation in inclusion body myositis
younger brother had a ten to twelve year history of
slowly progressive weakness first in the feet,
subsequently involving his distal upper extremities
and carried the diagnosis of s-IBM. On the muscle
biopsy, he had numerous rimmed vacuoles, but no
endomysial inflammation and no invasion of nonnecrotic muscle fibres. The muscle biopsies of our
patient, from quadriceps and triceps suralis, showed
numerous cytoplasmic inclusion bodies containing
desmin and other proteins, necrotic and angular
atrophic fibres and many rimmed vacuoles.
Patient 4 was a 42 year-old man with a rigidspine syndrome, muscle weakness when climbing
stairs or walking long distances, myopathic EMG
and elevated CK level. He had a younger brother
also affected. The biopsy from biceps brachialis
muscle revealed numerous cytoplasmic bodies and
autophagic-rimmed vacuoles with tubulofilamentous
aggregates. The cytoplasmic bodies stained positive
with anti-desmin antibodies and others. The molecular
analysis showed no mutations in desmin, αB-Crystallin or Selenoprotein N1 genes.
The fifth patient was a woman aged 62 years
with weakness in her lower limbs for two years, a
myopathic EMG and elevated CK level. Her biopsy
muscle specimen from triceps suralis muscle showed
atrophic and hypertrophic fibres, increased number
of internal nuclei and areas of condensation of the
sarcoplasm indicating myofibrillary myopathy,
reacting with numerous antibodies.
Patient 6 was a 74 year-old woman clinically
diagnosed with a proximal myopathy of the lower
limbs. Her skeletal muscle biopsy from quadriceps
femoris muscle revealed abnormal deposits in the
muscle fibres, located mainly subsarcolemmaly, but
also in the center of the fibres, as well as lobulated
muscle fibres, numerous core-targetoid lesions and
rare ragged red fibres. By electron microscopy, she
had areas of Z-disk streaming and granulofilamentous material between the myofibrils in her
muscle biopsy tissue specimen.
RESULTS
EXPRESSION OF TRANSSARCOLEMMAL PROTEINS
In eight of the ten patients with s-IBM we found
normal subsarcolemmal staining for dystrophin,
only two cases showing mild sarcoplasmic increase
as granular deposits. In all the cases with MM we
found ectopic cytoplasmic expression of dystrophin
379
in structurally abnormal fibres, that clearly indicate
dystrophin as a useful immunocytochemical marker
for abnormal regions in MM.
In normal adult muscle, utrophin is located
at the neuromuscular synapse and myotendinous
junctions, where it participates in post-synaptic
membrane maintenance and acetylcholine receptor
clustering. In four of our six patients with MM,
utrophin was found aggregated within cytoplasmic
bodies, as well as along the membrane in some of
the regenerated fibres. Only four of our ten s-IBM
cases showed areas of increased DRP 2 expression
along the sarcolemmal surface, but utrophin was
not found aggregated in the cytoplasm of the muscle
fibres.
We studied the profiles of four members of
the sarcoglycans complex, as part of the dystrophin-based membrane cytoskeleton of muscle fibre.
Its normal function being the stabilisation of the
transmembrane β-dystroglycan protein with dystrophin, we were interested in their pattern in the two
types of diseases.We found varriable expression of
the four sarcoglycans in the MM cases, more
consistent, among them, for δ-sarcoglycan in the
sarcoplasmic inclusions and all the cases showed
normal sarcolemmal expression. In the s-IBM cohort
α, β and γ sarcoglycans were never found accruing
in inclusion bodies or elsewhere in the sarcoplasm
of vacuolated or normal appearing fibres, but were
constantly positive along the sarcolemmal surface.
Surprisingly, δ sarcoglycan was expressed not only
at the periphery of the fibres, but in seven of the ten
cases also in cytoplasmic bodies and at the rim of
vacuoles as granular deposits
Laminin α 2 (merosin), major component of
the myofibre basal lamina, interacts in normal
muscle fibre with the plasma membrane and
mediates interactions between the basal lamina and
the endomysial connective tissue. In our patients
with s-IBM, the two isoforms of merosin were never
found aggregated elsewhere than in the normal
location at the basal lamina. On the contrary, we
found abnormal accumulation of merosin within
the muscle fibres in five of the six cases of MM.
The expression of α and β dystroglycans,
that bind dystrophin intracellularly and laminin
extracellularly, thus forming a critical link between
the extracellular matrix and the cytoskeleton, was
found normal in all our studied patients from the sIBM lot. In five of the six cases of MM, abnormal
accumulations of α and β dystroglycans were detected
in cytoplasmic bodies within muscle fibres.
380
Collagen 6, component of the extracellular
matrix, with its important role in anchoring basal
lamina to the endomysial connective tissue, was
normally expressed in all our s-IBM cases, as well
as in all cases with MM. In two of the latter group
of patients we found several additional foci of
immunopositivity in the sarcoplasmic inclusions.
Normal expression of β and γ laminins was
found in all s-IBM specimens; two of the six patients
with MM showed limited areas of abnormal
accumulation in the sarcoplasm.
The study of dysferlin showed in all cases,
from both cohorts, apart from normal immunostain
on the plasma membrane, constant increased expression. In muscle fibres of patients with s-IBM,
dysferlin was expressed in small and large vacuolated
fibres, appearing as granular deposits bordering
vacuoles, as diffuse accumulation in the sarcoplasm
and even inside the vacuoles. Immunoreactivity of
dysferlin was observed as positive subsarcolemmal
aggregates and intracytoplasmic inclusions in all
MM cases.
Caveolin, a major protein of plasmalemmal
microdomain caveolae, is a proven intracellular
transporter of cholesterol, thus influencing its
homeostasis. In IBM muscle fibres, caveolin
immunoreactive inclusions were observed in
vacuolated fibres as plaque-like deposits or diffuse
accumulation, but were also noticed in regenerated
and necrotic fibres. In the muscle fibres of the MM
cohort, caveolin showed focal increased immunostain
under the sarcolemma and in centrally located areas
in all the cases.
The expression of n NOS (neural nitric
oxide synthase) in the muscle fibres was found
increased in all patients from MM cohort as part of
the cytoplasmic bodies and in eight of ten patients
with IBM as granular or compact foci of immunopositivity in the cytoplasm of vacuolated muscle
fibres, more pronounced at the rim of the vacuoles.
EXPRESSION OF NUCLEAR PROTEINS
Emerin is a nuclear membrane protein which
is missing or defective in Emery-Dreifuss muscular
dystrophy (EDMD). It is one member of a family
of lamina-associated proteins which includes
LAP1, LAP2 and lamin B receptor (LBR). Lamins
are nuclear intermediate filaments, which form a
network-like structure underneath the nuclear
membrane, the nuclear lamina, as well as complexes
in the nuclear interior. Lamins associate with
4
numerous proteins in the inner nuclear membrane,
including emerin, and lamina-associated polypeptides.
In our study, nuclear membrane proteins were
never found expressed in muscle fibres of patients
with IBM in other location than perinuclear. Only
one patient of the MM cohort had additional focal
increased emerin expression in cytoplasmic deposits
of his cardiomyocytes, but these were not stained
with antibodies against lamins A/C.
EXPRESSION OF THE SARCOMERIC PROTEINS
Actin, the major component of thin myofilaments, has been previously found in lesions of
desminopathies by some investigators [14]. In our
study, actin was found accumulated in cytoplasmic
bodies in all cases with MM and in nine of ten
cases with s-IBM as diffuse accumulation in the
cytoplasm, but more consistently expressed at the
border areas of the vacuoles.
α actinin is a physiological protein component
of the Z-bands, cross-linking actin filaments.
Electron microscopic findings showed excessive
involvement of Z bands and so of α actinin in the
hyaline structures of desminopathies, but in another
extensive study this was only occasionally expressed
by immunohistochemistry [14]. All our MM cases
showed consistent expression of α actinin in the
sarcoplasmic inclusions, simmilar to the positive
immunostaining found in all ten IBM cases in
vacuolated muscle fibres, mostly at the periphery
of vacuoles and as patchy cytoplasmic deposits.
In our comparative study we were especially
interested in the expression of myotilin as a
recently discovered Z-disk-associated key protein
localized along the sarcolemmal membrane and
within I bands that control sarcomere assembly,
cross-links actin filaments and binds to α actinin
and γ-filamin. Recently, mutations in myotilin were
found in myofibrillar myopathy [4]. An extensive
study on 63 patients of MM described, for the first
time in the literature, increased myotilin expression
in 90% of the fibres that were abnormal in
trichrome-stained sections and suggested that
myotilin is the most reliable immunocytochemical
marker for abnormal fibre regions in MM [4]. In
fact, all our muscle biopsy fibres from MM patients
expressed myotilin in the sarcoplasmic inclusions,
as all the cases with IBM had increased myotilin
immunostain in the cytoplasm of vacuolated fibres
in the vicinity of vacuoles and even in normal
appearing fibres as irregular areas of deposition.
5
EXPRESSION OF CYTOSKELETAL PROTEINS
Desmin is located in mature skeletal muscle
between the subsarcolemmal region and the nuclear
membrane, associated with lamin B and around the
myofibrillar Z discs, encircling and interconnecting
myofibrils at this level, thus aligning myofibrils
and linking them to nuclei, to the plasma membrane,
especially in the region of the costameres and to
cytoplasmic organelles such as mitochondria. In
the heart, desmin is increased in Purkinje fibres, as
a major component, and at the level of intercalated
discs. In our immunohistochemical study we found
in each muscle specimen of patients with MM a
markedly increased expression of desmin in intrasarcoplasmic deposits, ultrastructurally with a
granulofilamentous aspect. The accumulation of
desmin in IBM is still controversial in the literature;
desmin has been shown to accumulate abnormally,
among other proteins [7]. Other study found normal
expression of desmin in hypertrophic and normal
sized muscle fibres in all patient biopsies [16]. Our
study showed in all patients strong expression of
desmin, more obvious at the rim of vacuoles, as
diffuse or patchy accumulation in the cytoplasm of
vacuolated and even normal appearing muscle
fibres, as well as in small regenerated fibres.
Plectin is a highly conserved and ubiquitously
expressed intermediate filament – associated
protein concentrated at sites of mechanical stress,
such as the hemidesmosomes in skin, the Z disk of
skeletal muscle fibers and the intercalated disks in
cardiac muscle cells. Plectin is also normally
associated with the sarcolemma, the postsynaptic
membrane, the nuclear membrane, and the intermyofibrillar network of skeletal muscle. Plectin is
known to associate with vimentin, integrin, desmin,
lamin B, myosin II, vimentin and actin. Plectin is
also associated with mitochondria and is important
in the localization of intracytoplasmic organelles.
We analysed the expression of plectin in three MM
cases and we found in all of them increased immunostain in abnormal fibres. All the patients with sIBM had conspicuous plectin deposits in inclusion
bodies of vacuolated muscle fibres, as well as in
focal accumulations in nonvacuolated fibres.
Vimentin, a member of the intermediate
filament family, is absent in healthy mature muscle
fibres, being expressed only in developing muscle,
colocalized with desmin, and in regenerating
muscle fibres. We found increased expression of
vimentin in five of the six MM cases in the
381
sarcoplasmic inclusions as well as in regenerated
fibres. Nine of ten patients with IBM also showed
increased expression of vimentin in small and
degenerated fibres, but also in vacuolated fibres.
EXPRESSION OF CHAPERONE PROTEINS
αB-crystallin is a member of the small heat
shock protein family , which exerts a role as
molecular chaperones by binding unfolded or
denatured proteins, suppressing irreversible protein
aggregation and consecutive cell damage, their
essential role in neuromuscular disorders being
corroborated by the observation that a mutation of
the human αB-crystallin gene causes an autosomal
dominant myofibrillar myopathy morphologically
characterized by αB-crystallin and desmin accumulation and granulofilamentous material by electron
microscopy. We found strong expression of αBcrystallin in sarcoplasmic inclusions in all MM
cases, colocalized with desmin, as well as in all
IBM cases, in the vacuolated muscle fibres at the
border of vacuoles and in inclusion bodies, but also
in normal appearing fibres, as previously suggested.
The selective degradation of many short-lived
proteins in eukaryotic cells is carried out by the
ubiquitin system. Abnormalities in ubiquitinmediated processes have been shown to cause
pathological conditions. In our study we observed
accumulation of ubiquitin in all cases with MM,
two of them showing strong aggregation in the
cytoplasmic bodies, in the other the increase was
only mild. Muscle biopsy specimens from IBM
patients also revealed enhanced expression of
ubiquitin in vacuolated fibres and, focally, also in
nonvacuolated ones. These findings indicate that
muscle fibres contained undesirable protein material
targeted for non-lysosomal degradation, but the
mild ubiquitin positivity in some of the cases
suggest operation of an alternative pathway of
protein degradation.
Heat shock proteins play an important role
in protein-protein interactions, including folding
and assisting in establishing proper protein conformation, and prevention of inappropriate protein
aggregation. Heat shock proteins are synthesized
under different stress conditions and act as molecular
chaperones for protein molecules. We found increased expression of HSP 72/73 in all our MM
cases as well as in all IBM muscle biopsy specimens.
In the first group, HSP 72/73 was mainly found at
382
subsarcolemmal and central sites in muscle fibres;
in the latter group, HSP 72/73 was enhanced in
degenerated and regenerated muscle fibres and in
inflammatory infiltrates invading muscle fibres, as
well as in vacuolated fibres, more conspicuous
around vacuoles.
DISCUSSION
Our study shows, as previously expected,
some similarities and partial overlaps in protein
expression between MM and IBM, but also some
dissimilarities.
The mechanisms responsible for formation of
the multiprotein inclusions in IBM muscle are not
understood, although the histopathology of s-IBM
has been well described, but it seems that unfolding
and misfolding of proteins probably play a role, as
well as the cellular aging that promotes accumulation
of abnormal proteins and slows degradation of
normal and abnormal proteins.
Only a minority of MM cases were, up to
now, shown to be caused by mutations in desmin,
alpha B-crystallin, myotilin and selenoprotein N1
genes, suggesting that the majority of them are due
to yet unidentified gene defects or are non-genetic
at all, also requiring further mutational analyses of
other genes such as for paranemin, synemin and
syncoilin. On the contrary, IBM is a sporadic
disease. Both disorders share accumulation of
different types of proteins, indicating a partially
common pathogenesis.
Accumulation of extrasarcomeric cytoskeletal
proteins was a common feature in both diseases.
We found increased expression of desmin, alpha B
crystallin and plectin in all the muscle biopsies,
showing a marked disturbance of filamentous intermyofibrillar cytoskeleton, with its important role in
structural and functional maintenance of striated
muscle fibres in response to stress. Thus, we
amplified the findings of other investigators [9]
who described desmin and alpha B crystallin accumulation in both MM/DRM and IBM. We found
accretion of plectin, with its essential role in the
proper spacing, stabilization and subcellular
attachement of intermediate filaments. We also
confirmed the occurrence of increased immunomarcation of alpha B crystallin in abnormal
vacuolated muscle fibres, as well as in the normal
appearing fibres in IBM, as described by Banwell
et al., [9]. Heat shock protein 72/73, a “stress marker”,
was also found overexpressed in both disorders.
6
We observed a similar expression of sarcomeric proteins in both diseases, as actin and alpha
actinin aggregates. Concerning the expression of
myotilin, a recently discovered protein that, when
mutated, causes MM, we found in all the cases
increased accumulation in the cytoplasm of vacuolated fibres in IBM patients, as well as in the
sarcoplasmic inclusions in our DRM/MM specimens,
thus supporting the suggestion that myotilin is the
most reliable immunocytochemical marker for
abnormal regions in the muscle fibres in MM [4].
Our study shows additional abnormal myotilin
immunomarcation in the vacuolated muscle fibres
in IBM.
Only normal immunolabelling of nuclear
membrane proteins was encountered in both diseases,
but there are data that these proteins may be found
aggregated in sarcoplasmic bodies in MM. Further
studies may eventually correlate these accretions
with a particular genetic profile.
The pattern of transsarcolemmal protein
immunolabelling showed, in our studied cases,
consistent dissimilarities. We found prominent
dystrophin colocalisation with desmin aggregates
in MM cases, our IBM cases always showing a
normal immunolabelling at the sarcolemmal level.
The same pattern was found for alpha and beta
dystroglycans. The sarcoglycans alpha, beta and
gamma were always normally expressed in the
muscle fibres of IBM patients, but occasionally
aggregated in the cytoplasmic bodies in MM. Delta
sarcoglycan was markedly increased in MM specimens, and occasionally also in IBM specimens.
Merosin showed normal expression in IBM, but
was frequently found coaggregated with desmin in
MM cases, as were beta and gamma laminin.
Dysferlin and caveolin were overexpressed in both
MM and IBM cases. These observations point to a
more severe impairment of the sarcolemmal architecture in MM than in IBM.
CONCLUSIONS
1. There is considerable aggregation of
proteins in both IBM and DRM.
2. A large number of same proteins accrue
in both groups of conditions.
3. In each of the two groups, however, there
are proteins aggregated only in one group,
not in the other.
4. In both groups of disorders, impairment in
extralysosomal protein degradation is an
important pathogenetic principle, high-
7
383
lighted by the common involvement of the
no such mutant proteins have been identified in
h-IBM.
chaperone protein α-B crystallin and by
While s-IBM is considered a sporadic and
the involvement in both groups of disorders
acquired condition, among patients with DRM, a
of proteins engaged in the ubiquitin pronon-hereditary form has also been suggested but,
teasomal degradative pathway of proteins
perhaps, will be more difficult to prove as a fair
While DRM consist of both desminopathies,
number of genes in DRM may indicate that there
i.e. desmin-accumulating myopathies, and other
are still unidentified genes involved as well and,
forms related to mutations in other genes such as
thereby, recognizing true acquired DRM most
selenoprotein N1, and myotilin, suggesting that
exclusively by exclusion of any hereditary form.
mutant proteins form part of the protein aggregates,
__________________________________________________________________
Miozita cu incluzii- forma sporadica(s-IBM) este o miopatie inflamatorie
caracterizată morfologic prin variate grade de infiltrate inflamatorii si prezenţa de
vacuole tivite cu sau fără corpi de incluzie compuşi din agregate anormale de
proteine în fibrele musculare. Miopatiile miofibrilare/miopatiile legate de desmină,
un subgroup în familia miopatiilor cu aggregate proteice, reprezintă un grup de
afecţiuni musculare clinic şi genetic heterogene caracterizate prin prezenţa de
acumulări proteice anormale în fibrele musculare. Am comparat spectrul proteinelor
acumulate în ambele tipuri de afecţiuni.
__________________________________________________________________
Acknowledgment: A.B. was supported by a fellowship of the European Neurological Society (ENS).
Corresponding author: Alexandra Bastian
“Colentina” Clinical Hospital, 19, Şos. Ştefan cel Mare, Bucharest
E-mail: aleca.bastian@yahoo.com
REFERENCES
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Askanas V., Engel W.K., Nogalska A., Inclusion-body myositis: a degenerative muscle disease associated with intramusclefiber multiprotein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation. Brain
Pathology, 2009, 19:493–506.
ENGEL W.K., ASKANAS V., Inclusion-body myositis:clinical, diagnostic and pathologic aspects. Neurology, 2006, 66: S 20–S 29.
SELCEN D., ENGEL A.G., Mutations in myotilin cause myofibrillar myopathy. Neurology, 2004, 62:1363–1371.
SELCEN D., ENGEL A.G., Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain, 2004, 127,
439–451.
VRABIE A., GOLDFARB L.G., SHATUNOV A., NAGELE A., FRITZ P., KACZMAREK I., GOEBEL H.H., The enlarging
spectrum of desminopathies: new morphological findings, eastward geographic spread, novel exon 3 desmin mutation. Acta
Neuropathologica, 2005, 109:411–417.
FERRER I., MARTÍN B., CASTAÑO J.G., LUCAS J.J., MORENO D., OLIVÉ M., Proteasomal expression, induction of
immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis.
J.Neuropathol.Exp Neurol., 2004, 63:484–498.
FIDZIANSKA A., DRAC H., KAMINSKA A., Familial inclusion body myopathy with desmin storage. Acta Neuropathol.,
1999, 97:509–514.
BANWELL B.L., ENGEL A.G., A-B-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology,
2000, 54:1033–1041.
FERREIRO A., CEUTERICK-DE GROOTE C., MARKS J.J., GOESMANS N., SCHREIBER G., HANEFELD F. et al., Desminrelated myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol., 2004,
55:676–686.
GOEBEL H.H., WARLO I.A., Surplus protein myopathies. Neuromuscul.Disord., 2001, 11:3–6.
GOEBEL H.H., Congenital myopathies at their molecular dawning. Muscle Nerve, 2003, 27:527–548.
GOLDFARB L.G., VICART P., GOEBEL H.H., DALAKAS M.C., Desmin myopathy. Brain, 2004, 127:723–734.
DE BLEECKER J.L., ENGEL A.G., ERTL B.B., Myofibrillar myopathy with abnormal foci of desmin positivity. II.
Immunocytochemical analysis reveals accumulation of multiple other proteins. J.Neuropathol.Exp.Neurol., 1996, 55:563–577.
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15. SHARMA M.C., GOEBELL H.H., Protein aggregate myopathies. Neurol.India, 2005, 53, 273–279.
16. GOUDEAU B., DAGVADORJ A., RODRIGUES-LIMA F., NEDELLEC P., CASTERAS-SIMON M., PERRET E., Structural
and functional analysis of a new desmin variant causing desmin-related myopathy. Hum Mutat., 2001, 18:388–396.
17. ARNADOTTIR S., BORG K., ANSVED T., Sporadic inclusion body myositis: morphology, regeneration, and cytoskeletal
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Received August 8, 2010
NEW BOOKS
Dilemmas and Certainties in a Cardiology Textbook
Although time passing, technological developments, the apparent exit
from the Gutenberg galaxy and entry in an area of visual dominance could
have pushed away the written pages – medical literature continues to occupy
a central place on the scale of values of the medical world. Through their own
education – doctors perceive the textbooks as possible keys for their professional
existence.
In this context the newly published Romanian monograph “Textbook of
Cardiology” edited by Carmen Ginghină (Romanian Academy Publishing
House) poses a particular interest.
The book brings together elements of classical structure with a modern
approach.
In a classic, almost ultra-conservative approach, the anatomy and
physiology of the cardio-vascular system is included together with the
presentation of the detailed clinical evaluation of the cardiac patient, the
paraclinical evaluation, the presentation of cardiovascular diseases and the
description of cardiac involvement in other pathological conditions. Classic is
also the constant findings of definitions (detailed) and the presence of short “dictionary of terms”at the
beginning of the chapters with subjects more distant to the clinical cardiologist.
The modern view is represented by the addopted approach (e.g., anatomical images are shown along
with images obtained through echocardiography, computed tomography, magnetic resonance imaging,
coronary angiography), the presence of chapters focusing on genetics (for cardiologists!) and epidemiology
of cardiovascular diseases (with data from Romania), the attention towards cardiac biomarkers, the chapter
dedicated to the choice of method of evaluation. Modern is also the continuous reference to the guidelines –
predominantly the European ones and frequently the American ones (as unique recent guidelines for some
subjects or difference of opinions from the European ones) or even national guidelines (Canadian, British)
when they are of particular interest.
The most consistent part of the book includes the description of the main cardiovascular diseases; it
includes up to date information and reference data (well-known monographs, articles) filtered through the
experience of the authors. This section contains 51 case reports (short ones – only one page) with comments
that complete the topic in an attractive manner. All cases are “experienced” by the authors and the
atmosphere of “real life” is a plus for the publication.
It is a book full of life which includes dilemmas and certainties. Dilemmas are inherent to the trends
of modern cardiology to promote guided, preformed medical decisions. The Greek term dilemma (the main
source for the current international word) is composed of di –“two or twice” and lemma – “premise”.
However, in cardiology – and the book illustrates this – we are facing more than two possibilities. Dilemmas
arise in the book not only as a matter of logic and reasoning but also as an act of reflection in particular
cases. Certainties derive from the immutable truths of clinical cardiology tested during time, from the
certitude of modern laboratory data and the confidence in medical common sense.
The monograph is clearly written, deliberately ordered and the explanations are often accompanied by
drawings and diagrams that facilitate the understanding.
The “visible” authors of this book are mainly cardiologists from the Cardiology Clinic of the Institute
for Emergency in Cardiovascular Disorders “Prof. C.C. Iliescu”, most of them with academic background, and in
addition a distinguished anatomist and experts in medical imaging. Other cardiologists, radiologists, surgeons,
pathologists are “non-visible” contributors on the list of authors, but cited in the reference list of each chapter .
The book continues the tradition of Cardiology Clinic ASCAR/FUNDENI for which the publication of
textbooks and manuals appears a “modus vivendi” promoted over the time by all the mentors. In fact Professor
Carmen Ginghină says in the preface of the book: “We have followed the message of our mentors: spoken
language can be brilliant but short-lived in the communication of scientific ideas, while the written page
implies performance and requires rigour and depth of understanding from both author and reader”.
Prof. dr. Tiberiu Nanea
ROM. J. INTERN. MED., 2010, 48, 4, 385

ROMANIAN JOURNAL OF INTERNAL MEDICINE

Transcription

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