Oxidative stress in aldosteronism Yao Sun , Robert A. Ahokas

Cardiovascular Research 71 (2006) 300 – 309
www.elsevier.com/locate/cardiores
Review
Oxidative stress in aldosteronism
Yao Sun a, Robert A. Ahokas d, Syamal K. Bhattacharya e, Ivan C. Gerling b,
Laura D. Carbone c, Karl T. Weber a,*
a
b
Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 920 Madison Ave.,
Suite 300, Memphis, TN 38163, USA
Division of Endocrinology, Department of Medicine, University of Tennessee Health Science Center and Veterans Administration Medical Center,
Memphis, TN, USA
c
Division of Connective Tissue Diseases, Department of Medicine, University of Tennessee Health Science Center and
Veterans Administration Medical Center, Memphis, TN, USA
d
Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN, USA
e
Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
Received 5 December 2005; received in revised form 20 February 2006; accepted 6 March 2006
Available online 13 March 2006
Time for primary review 22 days
Congestive heart failure (CHF) is more than a failing heart and salt-avid state. Also present is a systemic illness which features oxidative
stress in diverse tissues, a proinflammatory phenotype, and a wasting of soft tissue and bone. Reactive oxygen and nitrogen species
contribute to this illness and the progressive nature of CHF. Aldosteronism, an integral component of the neurohormonal profile found in
CHF, plays a permissive role in leading to an altered redox state. Because of augmented urinary and fecal excretion of Ca2+ and Mg2+ and
consequent decline in plasma-ionized [Ca2+]o and [Mg2+]o that accompanies aldosteronism, parathyroid glands release parathyroid hormone
(PTH) in an attempt to restore Ca2+ and Mg2+ homeostasis; this includes bone resorption. However, PTH-mediated intracellular Ca2+
overloading, considered a Ca2+ paradox, leads to oxidative stress. This can be prevented by: spironolactone, an aldosterone receptor
antagonist that rescues urinary and fecal cation losses; parathyroidectomy; amlodipine, a Ca2+ channel blocker; N-acetylcysteine, an
antioxidant. In addition to the role played by aldosteronism in the appearance of secondary hyperparathyroidism is the chronic use of a loop
diuretic, which further enhances urinary Ca2+ and Mg2+ excretion, and reduced Ca2+ stores associated with hypovitaminosis D. This broader
perspective of CHF and the ever increasing clinical relevance of divalent cations and oxidative stress raise the question of their potential
management with macro- and micronutrients. An emerging body of evidence suggests the nutritional management of CHF offers an approach
that will be complementary to today’s pharmaceutical-based strategies.
D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Aldosterone; Oxidative stress; Parathyroid hormone; Calcium; Magnesium
1. Introduction
The past decade has witnessed an ever-emerging body of
evidence that implicates oxidative and nitrosative stress in
the pathophysiologic expressions of the clinical syndrome
congestive heart failure (CHF). CHF has its origins rooted in
* Corresponding author. Tel.: +1 901 448 5750; fax: +1 901 448 8084.
E-mail address: KTWeber@utmem.edu (K.T. Weber).
a salt-avid state mediated largely by circulating hormones of
the renin – angiotensin –aldosterone system (RAAS), which
appear in response to reduced renal perfusion [1 –4]. The
interplay between RAAS effector hormones and oxidative
stress and the pathophysiologic importance of reactive
oxygen (ROS) and nitrogen species in CHF can be viewed
from several vantage points. From a cardiovascular perspective, H2O2 in low concentrations contributes to the
signal transduction involved in the regulation of vasomotor
reactivity [5], but which in greater abundance can lead to
0008-6363/$ - see front matter D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2006.03.007
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Abstract
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
2. Oxidative stress in aldosteronism: experimental
studies
2.1. Animal model
A widely used experimental model of aldosteronism
consists of uninephrectomized rats receiving a continuous
infusion of ALDO (0.75 Ag/h) by implanted minipump
together with 1% NaCl/0.4% KCl in drinking water
(ALDOST). This regimen suppresses plasma renin activity
and angiotensin II while raising plasma ALDO levels to
those seen in human CHF and which are inappropriate for
increased or normal dietary Na+. This model of aldosteronism is analogous to the administration of another mineralocorticoid, deoxycorticosterone acetate, with 1% dietary
NaCl (DOCAST), except that plasma renin, AngII, and
ALDO are each suppressed. Oxidative stress is present at a
systemic level throughout weeks 1 – 6 ALDOST as
evidenced by a reduction in plasma a1-antiproteinase
activity, an inverse correlate of global oxidative stress
[13,14].
2.2. The proinflammatory/fibrogenic vascular phenotype
As recently reviewed [8], inflammatory cells invade the
perivascular space of intramural coronary arteries at
> 3weeks of ALDOST and then involve myofibroblasts
expressing types I and III fibrillar collagens, eventuating in
a perivascular/interstitial fibrosis [21,30]. Similar lesions are
also found in the mesentery and intramural vasculature of
the kidneys in rats receiving either ALDOST or DOCAST
[31,32]. Such vascular remodeling in the heart involves both
the normotensive right and left atria, right ventricle, and
pulmonary artery as well as the hypertensive left ventricle
and aorta. Their appearance is not related to: hemodynamic
factors; the hypertrophic growth of cardiomyocytes; ALDO
itself (in the setting of dietary Na+ deprivation); or 1% NaCl
alone. An 8% Na+ diet suppresses renin and ALDO; it too
leads to hypercalciuria and ultimately a fall in plasmaionized Ca2+ with SHPT and the appearance of these
vascular lesions in normo- and hypertensive rats [33,34].
These findings further implicate the permissive role played
by ALDO (for any given level of dietary Na+) in the setting
of SHPT.
The invasion of the coronary and systemic vasculatures
by inflammatory cells occurs in the absence of prior organ
injury, thereby making it unlikely that there is a circulating
self-antigen and antibody response to it that accounts for
this vascular remodeling. Instead, an autoactive immune
system is suggested and referred to as an immunostimulatory state (vide infra).
2.3. The presence of oxi/nitrosative stress
Various lines of evidence, demonstrated by several
independent laboratories, have identified the presence of
oxidative and nitrosative stress in rats receiving ALDOST.
In either case, elevated plasma ALDO is inappropriate for
dietary Na+. Schiffrin and coworkers found an increase in
thiobarbituric acid-reactive substances (TBARs) and 8-isoprostanes in blood, direct indices of oxidative stress, while
increased NADPH-oxidase generation of superoxide by vascular tissue is evidenced by lucigenin chemiluminescence
[35 –37]. By gene chip array technology, the transcriptome
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dysfunction of the endothelium [6] and overwhelm antioxidant defenses to prove cytotoxic, adversely influencing
cardiomyocyte survival in the failing heart [5,7]. A broader
perspective yields the realization that it is the presence of an
altered redox state at a systemic level that is involved in the
wasting of diverse tissues and which contributes to the
progressive nature of CHF [8 –12].
Essentially, a systemic illness accompanies CHF. It has
several prominent features: a) the presence of oxidative stress
in such tissues as skin, skeletal muscle, heart, peripheral
blood mononuclear cells (PBMC; lymphocytes and monocytes), and blood [9 –11,13,14]; b) an immunostimulatory
state with activated circulating lymphocytes and monocytes
and whose transcriptome reveals an upregulated expression
of antioxidant defenses and proinflammatory genes together
with downregulated counter-regulatory or anti-inflammatory
defenses [14 –20]; c) a proinflammatory vascular phenotype,
where CD4+ lymphocytes and ED1+ monocytes/macrophages invade the intramural arterial circulation of systemic
organs and the right and left heart [21]; and d) a catabolic state
with loss of lean tissue, fat, and bone [22 – 25]. Mechanisms
involved in the pathogenesis of this systemic illness and its
pathophysiologic expressions, including the role of oxidative
stress and RAAS effector hormones, are under active
investigation at both the bench and bedside.
Secondary aldosteronism is an integral component of the
neurohormonal profile found in patients with CHF [1–4].
Fiebeler and Luft [26] have suggested that aldosterone–
mineralocorticoid receptor (MR) binding has a direct effect on
PBMC and vascular smooth muscle cells, where it favors the
induction of oxidative stress with ROS regulating MR
behavior. Funder [27] argues ROS generation serves to activate
cortisol–MR complexes in vascular smooth muscle and
cardiomyocytes that normally are tonically inhibited by
cortisol. Under these conditions, it is suggested, glucocorticoids transduce a mineralocorticoid-like excess state. Touyz
and Schiffrin [28] and Li and coworkers [29] implicate
endothelin (ET)-1-induced oxidative stress, via an NADPH
oxidase pathway, with chronic mineralocorticoid excess
(relative to normal or increased dietary Na+). We have
suggested aldosterone (ALDO) and dietary Na+ play a
permissive role while parathyroid hormone (PTH)-mediated
intracellular Ca2+ overloading that accompanies secondary
hyperparathyroidism (SHPT) is integral to the appearance of
oxidative stress [8]. Macro- and micronutrient supplements
may hold the therapeutic potential to regulate these responses.
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Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
2.4. The role of secondary hyperparathyroidism and
intracellular Ca2+ overloading
Iterations in intracellular Ca2+ and Mg2+ concentrations
are found in circulating lymphocytes and platelets in
aldosteronism and contribute to the pathophysiologic basis
for the appearance of oxidative stress [13,14,43– 46]. In
PBMC harvested weekly from rats with ALDOST, an early
and persistent increase in total intracellular Ca2+ (see Fig. 1,
left panel) and a rise in cytosolic-free [Ca2+]i at week 2 and
beyond are found (Fig. 1, right panel) which is prevented by
parathyroidectomy (Fig. 1, right panel) or amlodipine; an
associated fall in [Mg2+]i is attenuated by a Mg2+supplemented diet [13,14,47,48]. The excessive intracellular
Ca2+ accumulation is also found in myocardium and skeletal
muscle and is prevented by parathyroidectomy (see Fig. 2)
[48]. In keeping with Ca2+ overloading is a loss of
mitochondrial potential with apoptosis of cardiac and
skeletal muscle myocytes [12,49]. An increase in PBMC
production of H2O2 is prevented by cotreatment with either
amlodipine or N-acetylcysteine [13]. Thus in PBMC,
organelles such as mitochondria and endoplasmic reticulum
are first saturated by Ca2+, followed by a rise in their
cytosolic-free concentrations. Others have reported increased intracellular [Ca2+]i in many different cell types in
response to SHPT [50]. The Ca2+ overloading of diverse
cells is accompanied by systemic evidence of oxidative
stress. There is an increased rate of production of H2O2 by
PBMC and upregulation of their relevant antioxidant
defense genes [14]. The importance of intracellular Ca2+
overloading to the induction of oxidative stress is further
supported by the protective effects of parathyroidectomy or
a Ca2+ channel blocker [13,48].
Based on metabolic studies conducted in patients with
primary aldosteronism [51 – 56], 24 h urinary and fecal
excretion of these divalent cations was monitored in rats
receiving ALDOST for 1 – 6weeks [47,48,57]. A fourfold
increase ranging in microgram quantities of Ca2+ and Mg2+
excreted in urine at week 1 ALDOST was seen and which
was persistent thereafter. The stimulus to hypercalciuria and
hypermagnesuria that accompanies ALDOST is not well
understood. However, the probable mechanism is thought to
be related to an expansion of the extravascular space,
resulting in decreased proximal tubular resorption, thereby
increasing distal delivery of Na+, Mg2+ and Ca2+ with the
mineralocorticoid promoting distal tubular Na+ resorption
Fig. 1. Total intracellular Ca2+ (left panel) and cytosolic-free [Ca2+]i (right panel) in peripheral blood mononuclear cells (PBMC) in controls (C) and with weeks
of aldosterone/salt treatment (ALDOST) without (hatched bar) or with (dark bar) prior parathyroidectomy. Broken and dotted lines (right panel) connote
mean T S.E.M. for controls. Left panel adapted from Chhokar VS, et al. Circulation 2005; 111: 871 – 878; right panel reproduced from Vidal A, et al. Am J
Physiol Heart Circ Physiol 2006; 290: H286 – H294, with permission.
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of circulating lymphocytes and monocytes (PBMC) revealed
a heightened mRNA expression of antioxidant defenses,
such as glutathione peroxidase (GSH-Px) and Mn-superoxide dismutase (SOD), while H2O2 production by these
PBMC is increased [13 – 15]. Inflammatory cells that invade
the vasculature reveal immunohistochemical evidence of
gp91phox activation, a subunit of NADPH oxidase; the
presence of 3-nitrotyrosine, a stable product of short-lived
peroxynitrite, derived from the reaction of nitric oxide with
superoxide; and the activation of a redox-sensitive nuclear
transcription factor (NF)-nB [21]. Furthermore, in situ
hybridization revealed an increased mRNA expression of a
proinflammatory gene cascade in these invading cells and
which is regulated by NFnB. This includes intercellular
adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1
and tumor necrosis factor (TNF)-a [21,35,36,38].
Further evidence in support of a role played by oxidative
stress in the vascular remodeling found in aldosteronism are
vasculoprotective responses to: antioxidants, pyrrolidine
dithiocarbamate and N-acetylcysteine [21]; tempol, a
superoxide dismutase mimetic [37]; and apocynin, an
NADPH oxidase inhibitor [39,40]. When spironolactone
(Spiro), an ALDO receptor antagonist, is coadministered
with ALDOST these lesions are not seen [21,41]. Cotreatment with a Ca2+ channel blocker is also vasculoprotective [13,42].
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
303
Fig. 2. Total Ca2+ content in myocardium and skeletal muscle in controls, and during 4 – 6 weeks of ALDOST without or with prior parathyroidectomy and a
Ca2+-supplemented diet (Ca2+ PTx). Reproduced from Vidal A, et al. Am J Physiol Heart Circ Physiol 2006; 290: H286 – H294, with permission.
promoting the loss of thiamine, a micronutrient [67].
Hydrochlorothiazide promotes Ca2+ reabsorption without
altering hypermagnesuria [68]. Spiro co-treatment rescues
Ca2+ and Mg2+ losses associated with furosemide use and
the hypermagnesuria seen with hydrochlorothiazide, thus
preserving bone mineral density under either scenario
[67,68].
2.5. Macro- and micronutrients in preventing SHPT and
oxidative stress
Reduced levels of extracellular Ca2+ and Mg2+, reflected
by their fallen ionized levels in the presence of accentuated
urinary and fecal excretion of these cations, accompany
aldosteronism that account for elevations in plasma PTH and
PTH-mediated intracellular Ca2+ overloading and global
oxidative stress. The efficacy of dietary supplements of these
macronutrients in preventing such responses is called into
question. In rats with DOCAST, co-treatment with dietary
Mg2+ supplements attenuated elevations in cytosolic-free
Ca2+ that appear in lymphocytes and platelets, and prevented
increased H2O2 production by PBMC and ET-1 overproduction by the heart and vasculature [13,45,69,70]. A
regimen of calcitriol and dietary Ca2+ and Mg2+ supplements
prevented the fall in plasma-ionized [Ca2+]o and rise in
plasma PTH, which, in turn, prevented Ca2+ loading of
PBMC and rise in PBMC H2O2 production [71].
Micronutrients include such trace minerals as Zn and Se.
Zn and Se are each integral to the activity of endogenous
antioxidant defenses, including Cu/Zn-SOD and Se-GSHPx. Diets deficient in Zn or Se are accompanied by a
reduction in the activities of these oxireductases, which can
be restored with dietary replacements [72,73]. Hypozincemia has been found in rats with ALDOST and who were
receiving standard laboratory chow that satisfies minimal
daily requirements of this mineral together with an
associated fall in the Cu/Zn-SOD activity of PBMC [74].
Hyposelenemia is also found in these rats and its impact on
Se-GSH-Px is under investigation. The origins of hypo-
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without influencing increased Mg2+ and Ca2+ excretion
[53,58 –61]. A similar response was also found in feces;
however, here milligram quantities of Ca2+ and Mg2+ were
lost through this route. Spiro cotreatment attenuated the loss
of these divalent cations at each site [47]. The early and
persistent excretion of Ca2+ and Mg2+ led to a fall in their
plasma-ionized concentrations throughout weeks 1 – 6
ALDOST. Fig. 3 depicts this sequence of events. The
decline in plasma [Ca2+]o and [Mg2+]o are each major
stimuli to the parathyroid glands’ secretion of PTH. Plasma
PTH levels increased at week 1 and remained so over
ensuing weeks with continued ALDOST [47]. In keeping
with elevated PTH, bone resorption ensued to restore
extracellular Ca2+ and Mg2+ homeostasis. Bone mineral
density of tibia and femur, as evidenced by dual-energy Xray absorptiometry (DXA), reduced by 10% at week 4 and
50% by week 6 of ALDOST; a corresponding reduction in
Ca2+ and Mg2+ concentrations of these bones was found by
atomic absorption spectroscopy [47,57]. The fall in mineral
density was accompanied by a decline in bone strength as
evidenced by a reduced resistance to flexor stress [47]. The
decline in bone mineral density provided biologic evidence
of a persistent state of SHPT.
Whether given orally or intravenously, Na+ loading leads
to increased urinary Ca2+ excretion and this holds true for
normotensive young adults, hypertensive elderly patients,
and salt-sensitive, hypertensive African-Americans [62 – 64].
Chronic Na-related hypercalciuria, especially when the diet is
deficient in Ca2+, leads to increased serum PTH with
increased Ca2+ and reduced Mg2+ concentrations in various
cell types [64,65]. PTH-mediated renal formation of
1,25(OH)2D provides for a compensatory increment in
gastrointestinal Ca2+ absorption, which is not seen in patients
with hypoparathyroidism following PTx [62,66]. In chronic
aldosteronism, Ca2+ losses from gut dominate over such
compensatory resorption, but can be attenuated by Spiro [47].
Diuretics modify urinary Ca2+ and Mg2+ excretion in
aldosteronism. Spiro attenuates such losses while furosemide, a loop diuretic, augments these events, as well as
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Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
elevated circulating PTH that mediates an excessive
accumulation of intracellular Ca2+ in diverse cells. SHPT
accompanies aldosteronism because of the urinary and fecal
losses of Ca2+ and Mg2+ and consequent decline in their
plasma-ionized concentrations. Spiro prevents SHPT and
rescues bone mineral density by attenuating these losses and
fall in plasma-ionized [Ca2+]o and [Mg2+]o. Reactive oxygen
species, as evidenced by the heightened PBMC production
of H2O2, function as intracellular messengers to activate
downstream signaling molecules that either up- or downregulate genes of the PBMC transcriptome and which
account for their proinflammatory phenotype. These autoactivated circulating immune cells likely contribute to the
systemic illness that accompanies PTH-mediated Ca2+
overloading of diverse cells and the proinflammatory
vascular phenotype. SHPT represents an obligatory covariant responsible for the generalized wasting that accompanies the secondary aldosteronism of CHF, including bone
resorption and the apoptosis of cardiac and skeletal muscle
myocytes.
3.1. The CHF syndrome
Fig. 3. A paradigm depicting the appearance of secondary hyperparathyroidism (SHPT) in rats receiving aldosterone (ALDO) and 1% NaCl in
drinking water. Elevations in circulating parathyroid hormone (PTH)
promote an excessive accumulation of intracellular Ca2+ and induction of
oxidative stress in PBMC via NADPH oxidase with generation of
superoxide, peroxynitrite (OONO ) and H2O2, which overwhelm antioxidant defenses such as superoxide dismutase (SOD). H2O2 participates in
signal transduction, activation of a redox-sensitive nuclear transcription
factor (NF)-nB, transcription and cell activation leading to an immunostimulatory state. Various interventions which interrupt this sequence of
events at different stages of progression are shown by a horizontal wavy
line. Spiro, spironolactone; PTx, parathyroidectomy; CCB, Ca2+ channel
blocker; apocynin, an NADPH oxidase inhibitor; tempol, an SOD mimetic;
and antioxidants, N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate
(PDTC).
zincemia and hyposelenemia in rats with aldosteronism
remain to be thoroughly explored as does the protective
impact of dietary supplements.
A dietary flavonoid, quercetin, prevents increased
TBARS in plasma and heart while raising total glutathione
levels in liver and heart and GSH-Px activities at these sites
in rats with DOCAST [75]. Furthermore, sesamin, a lignin
derived from sesame oil, inhibits increased superoxide
production by the aorta in rats receiving DOCAST [76].
2.5.1. Summary
Thus, in rats with aldosteronism, the presence of
oxidative stress at a systemic level is in keeping with
Characteristic signs and symptoms comprise the CHF
syndrome, where expanded intra- and extravascular volumes are rooted in a salt-avid state mediated, in part, by
secondary aldosteronism [4]. Serum ALDO levels are
increased in patients who are decompensated with salt and
water retention (NYHA Class III and IV heart failure),
which is not the case for those asymptomatic patients with
compensated (NYHA Class I and II) heart failure unless
potent loop diuretics usage reduces intravascular volume
and renal perfusion to activate the circulating RAAS [1 –3].
3.2. Proinflammatory CHF phenotype
Elevations in circulating IL-6 and TNF-a accompany the
proinflammatory CHF phenotype [22,23,77,78]. The extent
to which cytokines and chemokines (e.g., MCP-1) are
elevated relates to the severity of heart failure, but not its
etiologic origins. This suggests neurohormonal activation is
likely contributory to the phenotype, not the cardiomyopathic process itself. The source of circulating cytokines in
CHF remains uncertain. Candidate cellular sources include
activated lymphocytes and monocytes, as well as osteoblasts
under the influence of PTH to promote osteoclastogenesis
[19,20,79,80].
Circulating lymphocytes and monocytes, harvested from
patients with CHF and studied ex vivo, demonstrated
increased chemokine production in response to provocation
with lipopolysaccharide and which was greater than that
seen with cells obtained from healthy volunteers [17,18].
Serum from patients with CHF raises superoxide generation
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3. Secondary aldosteronism in CHF: clinical studies
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
by cultured monocytes obtained from healthy blood donors
and which may relate to increased serum MCP-1 levels that
could be blocked by neutralizing antibody to this chemokine. A role for PTH in mediating these responses has not
been examined. An upregulated PBMC transcriptome has
been found in CHF with increased expression of cytokines
and chemokines and their receptors [17,18].
3.3. Oxidative stress in CHF
During June 1 – August 31, 2005, we addressed the
presence of SHPT and hypovitaminosis D in 25 AA: 20 who
were hospitalized because of their CHF; and 5 who were
ambulatory and asymptomatic with compensated heart
failure with comparable reductions in ejection fraction
< 35% [93]. Patients were stratified, on historical grounds,
as protracted CHF ( 4weeks) in 11 and short-term CHF
(1 –2 weeks) in 9. All had been treated with an ACE
inhibitor or AT1 receptor antagonist, furosemide and in
many cases low-dose spironolactone. Serum PTH (mean
T S.E.M.; range) was elevated in all those with protracted
CHF (127 T 13; 82– 243 pg/mL) and in 3 of 9 with shortterm CHF (59 T 8; 18 – 99pg/mL); none of the compensated
patients had SHPT (42 T 5, 17 –53 pg/mL). Ionized hypocalcemia and hypomagnesemia was present in both groups
with CHF. We found hypovitaminosis D (< 30 ng/mL) in: all
11 with protracted CHF; 8 of 9 with short-term CHF; and 4
of 5 with compensated failure. Melanin is a natural
sunscreen. Thus, hypovitaminosis D is prevalent in AA
even during summer months and especially when housebound with symptomatic heart failure. The aldosteronism of
protracted CHF and chronic furosemide usage each exaggerate Ca2+ and Mg2+ losses to compromise cation balance
to lead to ionized hypocalcemia and hypomagnesemia with
SHPT in AA, where hypovitaminosis D has already
compromised Ca2+ balance. Reduced serum 25(OH)D has
been previously reported in some Caucasian patients with
CHF followed during winter months in Germany [91]. A
role for restoring 25(OH)D levels to >30 ng/mL in preventing SHPT and oxidative stress in the overall management of
CHF remains to be addressed.
3.4. Secondary hyperparathyroidism in CHF
3.5. Secondary hyperparathyroidism and the failing heart
Elevations in serum PTH have been found in 18 –40% of
predominantly Caucasian patients awaiting cardiac transplantation in the United States and western Europe
[24,25,88 –91]. In addition to aldosteronism in mediating
urinary and fecal Ca2+ and Mg2+ excretion is the contribution of furosemide, a potent loop diuretic that further
accentuates urinary Ca2+ and Mg2+ excretion. Many of these
patients with advanced CHF were found to have osteopenia
and osteoporosis likely due to SHPT [24,25].
In 9 patients (8 African-Americans, AA), consecutively
admitted to the Regional Medical Center Hospital in
Memphis this past winter (February, 2005) because of their
CHF with systolic dysfunction (ejection fraction <35%), we
found elevated serum PTH (mean T S.E.M.; range; normal
12 –65 pg/mL) was documented. This included 5 who were
medically untreated (204 T 60; 86– 393pg/mL) and 4 with
treated CHF (134 T 14; 105 – 164 pg/mL) that included
furosemide [92]. However, abnormalities in albumin-corrected serum Ca2+, serum Mg2+ or phosphorus were not
present. Calculated creatinine clearance in untreated and
treated patients with CHF was 74 T 15 and 83 T 21mL/min,
respectively, and did not differ between them. In this
preliminary study, 25(OH)D was not monitored.
As noted earlier, a proinflammatory vascular phenotype
accompanies the SHPT of aldosteronism. This includes a
perivascular/interstitial fibrosis of the right and left ventricle
which will adversely influence myocardial stiffness [94]. PTx
attenuates the appearance of such reactive fibrosis [48,95].
Microscopic scars, a reparative fibrosis replacing cardiomyocytes lost to necrosis, are also seen in the right and left heart in
aldosteronism [94]. The pathogenic origin of cardiomyocytic
necrosis is uncertain, but could relate to excessive intracellular Ca2+ overloading and oxidative stress.
In addition to an adverse structural remodeling of
myocardium found in SHPT are direct effects of PTH on
cardiomyocyte metabolism and function [96,97]. These
include (see Fig. 4) impaired mitochondrial phosphorylation
and reduced ATP synthesis, which accompany Ca2+ overloading and reduced Ca2+ efflux as a result of impaired
Ca2+-ATPase activity [96]. An inverse correlation exists
between PTH and ejection fraction in end-stage renal failure
[98]. Correction of SHPT by PTx or calcitriol treatment is
associated with improved systolic function [99,100]. Diastolic dysfunction found in primary HPT is improved by
PTx [101]. Finally, PTH-mediated bone resorption involves
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Oxidative stress has been found to be an integral feature
of the illness that accompanies CHF and which involves
diverse tissues. The presence of oxidative stress therefore
appears at a systemic level, irrespective of the etiologic
origins of CHF, and which correlate with its clinical severity
[81 – 83]. Furthermore, evidence of reduced antioxidant
defenses has also been reported [84 – 86]. Such endogenous
defenses, provided by Cu/Zn-SOD and Se-GSH-Px, respectively, scavenge superoxide and H2O2, and are upregulated
in stressed tissues [22]. These endogenous defenses,
however, may be overwhelmed in CHF, thus creating an
antioxidant deficit [23]. In addition, the activity of these
oxireductases is dependent on Zn and Se, respectively,
which may be reduced if the bioavailability of these trace
minerals is compromised [24,25].
Consequences of oxidative stress in CHF are thought to
be concentration-dependent and include: signal transduction
and cell signaling in low concentration [87]; and
programmed cell death with activation of apoptotic pathways and ultimately necrotic pathways [5,7].
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Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
setting of reduced extracellular Ca2+, a Ca2+ paradox, has
the potential to lead to the appearance of oxidative stress.
SHPT is an important covariant involved in the systemic
illness that accompanies CHF.
4. Conclusions and future directions
Fig. 4. Several factors can contribute to the appearance of secondary
hyperparathyroidism (SHPT) in human CHF. These include: hypovitaminosis D; aldosteronism; and chronic use of furosemide, a loop diuretic. PTH
has direct and indirect effects that compromise ventricular function. These
respectively include: Ca2+ overload, decreased energy stores, and mitochondrial phosphorylation; and increased cytokine production by osteoblasts with increased circulating IL-6 and TNF-a having a negative impact
on cardiomyocyte contractility.
3.6. Macro- and micronutrients in CHF
In recognizing the importance of oxidative stress and its
potential role in the progressive nature of heart failure,
attention has been drawn to macro- and micronutrients as
contributors and combatants. Deficits of extracellular Ca2+
and Mg2+ and hypovitaminosis D, accompanied by SHPT
with intracellular Ca2+ overloading, are associated with the
induction of oxidative stress. Deficiencies of zinc and
selenium, related to inadequate dietary sources or promoted
by their urinary losses that accompany ACE inhibitors or
AT1 receptor blockers, reduce the activities of Cu/Zn-SOD
and Se-GSH-Px which serve as antioxidant defenses, thus
augmenting the susceptibility and severity of oxidative
stress. The contribution of micronutrients to the pathophysiology of heart failure and its management is beginning to
receive much deserved attention [91,106 – 110].
3.6.1. Summary
SHPT accompanies the aldosteronism of CHF. Elevations
in circulating PTH occur in response to falling plasmaionized [Ca2+]o and [Mg2+]o that result from aldosterone/
Na+-mediated urinary and fecal excretion of these cations.
Chronic furosemide treatment is also contributory as is the
case for reduced sunlight exposure with hypovitaminosis D.
SHPT with intracellular Ca2+ overloading of cells in the
Acknowledgements
We acknowledge the invaluable contribution of Richard
A. Parkinson, MEd, Assistant Director for Scholastic
Services, in presenting these materials.
This work was supported, in part, by NIH/NHLBI grant
R01-HL73043.
References
[1] Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones
regulating cardiovascular function in patients with severe congestive
Downloaded from by guest on October 28, 2014
osteoblast formation of IL-6 and TNF-a to induce osteoclastogenesis [102]. These cytokines are known to inhibit
mitochondrial energy production and impair cardiomyocyte
contractility [103 –105]. Elevations in circulating IL-6 and
TNF-a found in CHF [23] may represent surrogate
biomarkers of SHPT.
The CHF syndrome is more than a failing heart and a
state of salt and water retention. A broader perspective takes
into account the importance of neurohormonal activation
and its contribution to an accompanying systemic illness
that features oxidative stress, a proinflammatory phenotype,
and tissue wasting. The road to wasting in CHF is paved
with lost minerals. The accompanying decline in extracellular Ca2+ and Mg2+ and consequent elaboration of PTH
seeks to restore homeostasis of these cations. SHPT is a
covariant of CHF; it has far-reaching consequences involving diverse tissues and which is mediated by intracellular
Ca2+ overloading.
Not unlike patients with chronic renal failure, where
issues related to the prevention and management of SHPT
are integral to optimal management, today’s treatment of
patients with CHF must also take into account Ca2+ and
Mg2+ balance. This includes: the urinary and fecal loss of
these cations that occurs in response to aldosteronism,
which can be attenuated by an aldosterone receptor
antagonist; medications which further threaten their balance
(e.g., loop diuretics); adequate dietary intake; the presence
of hypovitaminosis D that occurs as a result of a
housebound lifestyle, especially in AA who require more
sunlight to maintain their 25(OH)D stores; and skeletal
health, particularly amongst the elderly, where SHPT may
threaten already reduced bone mineral density.
The importance of oxidative stress in CHF calls into
question the capacity of antioxidant defenses, such as Cu/ZnSOD and Se-GSH-Px. Zn and Se balance in patients with
CHF needs to be addressed more comprehensively, including
the potential efficacy of dietary supplements with these
micronutrients. In coming years, the nutritional management
of CHF, including macro- and micronutrients, will undoubtedly receive greater and well-deserved attention.
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21] Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosteroneinduced inflammation in the rat heart. Role of oxidative stress. Am J
Pathol 2002;161:1773 – 81.
[22] Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox
WJ, et al. Hormonal changes and catabolic/anabolic imbalance in
chronic heart failure and their importance for cardiac cachexia.
Circulation 1997;96:526 – 34.
[23] Anker SD, Clark AL, Teixeira MM, Hellewell PG, Coats AJ. Loss of
bone mineral in patients with cachexia due to chronic heart failure.
Am J Cardiol 1999;83:612 – 5.
[24] Lee AH, Mull RL, Keenan GF, Callegari PE, Dalinka MK, Eisen HJ,
et al. Osteoporosis and bone morbidity in cardiac transplant
recipients. Am J Med 1994;96:35 – 41.
[25] Shane E, Mancini D, Aaronson K, Silverberg SJ, Seibel MJ,
Addesso V, et al. Bone mass, vitamin D deficiency, and
hyperparathyroidism in congestive heart failure. Am J Med 1997;
103:197 – 207.
[26] Fiebeler A, Luft FC. The mineralocorticoid receptor and oxidative
stress. Heart Fail Rev 2005;10:47 – 52.
[27] Funder JW. RALES, EPHESUS and redox. J Steroid Biochem Mol
Biol 2005;93:121 – 5.
[28] Touyz RM, Schiffrin EL. Reactive oxygen species in vascular
biology: implications in hypertension. Histochem Cell Biol
2004;122:339 – 52.
[29] Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, et
al. Endothelin-1 increases vascular superoxide via endothelinA –
NADPH oxidase pathway in low-renin hypertension. Circulation
2003;107:1053 – 8.
[30] Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin converting
enzyme and myocardial fibrosis in the rat receiving angiotensin II or
aldosterone. J Lab Clin Med 1993;122:395 – 403.
[31] Sun Y, Zhang J, Zhang JQ, Ramires FJA. Local angiotensin II and
transforming growth factor-h1 in renal fibrosis of rats. Hypertension
2000;35:1078 – 84.
[32] Schiffrin EL, Larivie´re R, Li JS, Sventek P, Touyz RM. Deoxycorticosterone acetate plus salt induces overexpression of vascular
endothelin-1 and severe vascular hypertrophy in spontaneously
hypertensive rats. Hypertension 1995;25(Part 2):769 – 73.
[33] Yu HC, Burrell LM, Black MJ, Wu LL, Dilley RJ, Cooper ME, et al.
Salt induces myocardial and renal fibrosis in normotensive and
hypertensive rats. Circulation 1998;98:2621 – 8.
[34] Takeda Y, Yoneda T, Demura M, Furukawa K, Miyamori I, Mabuchi
H. Effects of high sodium intake on cardiovascular aldosterone
synthesis in stroke-prone spontaneously hypertensive rats. J Hypertens 2001;19(3 Pt 2):635 – 9.
[35] Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL.
Spironolactone improves angiotensin-induced vascular changes and
oxidative stress. Hypertension 2002;40:504 – 10.
[36] Pu Q, Neves MF, Virdis A, Touyz RM, Schiffrin EL. Endothelin
antagonism on aldosterone-induced oxidative stress and vascular
remodeling. Hypertension 2003;42:49 – 55.
[37] Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL. Involvement
of oxidative stress in the profibrotic action of aldosterone.
Interaction with the renin – angiotensin system. Am J Hypertens
2004;17:597 – 603.
[38] Yoshida K, Kim-Mitsuyama S, Wake R, Izumiya Y, Izumi Y,
Yukimura T, et al. Excess aldosterone under normal salt diet induces
cardiac hypertrophy and infiltration via oxidative stress. Hypertens
Res 2005;28:447 – 55.
[39] Li L, Chu Y, Fink GD, Engelhardt JF, Heistad DD, Chen AF.
Endothelin-1 stimulates arterial VCAM-1 expression via NADPH
oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension 2003;42:997 – 1003.
[40] Park YM, Park MY, Suh YL, Park JB. NAD(P)H oxidase inhibitor
prevents blood pressure elevation and cardiovascular hypertrophy in
aldosterone-infused rats. Biochem Biophys Res Commun 2004;313:
812 – 7.
Downloaded from by guest on October 28, 2014
[11]
heart failure and their relation to mortality. CONSENSUS Trial Study
Group. Circulation 1990;82:1730 – 6.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang
C, et al. Comparison of neuroendocrine activation in patients with
left ventricular dysfunction with and without congestive heart failure:
a substudy of the Studies of Left Ventricular Dysfunction (SOLVD).
Circulation 1990;82:1724 – 9.
Rousseau MF, Gurne O, Duprez D, Van Mieghem W, Robert A, Ahn
S, et al. Beneficial neurohormonal profile of spironolactone in severe
congestive heart failure: results from the RALES neurohormonal
substudy. J Am Coll Cardiol 2002;40:1596 – 601.
Weber KT. Aldosterone in congestive heart failure. N Engl J Med
2001;345:1689 – 97.
Cai H. Hydrogen peroxide regulation of endothelial function: origins,
mechanisms, and consequences. Cardiovasc Res 2005;68:26 – 36.
Struthers AD. Aldosterone escape during angiotensin-converting
enzyme inhibitor therapy in chronic heart failure. J Cardiac Failure
1996;2:47 – 54.
Kumar D, Jugdutt BI. Apoptosis and oxidants in the heart. J Lab Clin
Med 2003;142:288 – 97.
Weber KT. The proinflammatory heart failure phenotype: a case of
integrative physiology. Am J Med Sci 2005;330:219 – 26.
Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, NadalGinard B, et al. Oxidative stress-mediated cardiac cell death is a
major determinant of ventricular dysfunction and failure in dog
dilated cardiomyopathy. Circ Res 2001;89:279 – 86.
Miyamoto M, Kishimoto C, Shioji K, Lee JD, Shimizu H, Ueda T, et
al. Cutaneous arteriolar thioredoxin expression in patients with heart
failure. Circ J 2003;67:116 – 8.
Tsutsui H, Ide T, Hayashidani S, Suematsu N, Shiomi T, Wen J, et al.
Enhanced generation of reactive oxygen species in the limb skeletal
muscles from a murine infarct model of heart failure. Circulation
2001;104:134 – 6.
Burniston JG, Saini A, Tan LB, Goldspink DF. Aldosterone induces
myocyte apoptosis in the heart and skeletal muscles of rats in vivo.
J Mol Cell Cardiol 2005;39:395 – 9.
Ahokas RA, Sun Y, Bhattacharya SK, Gerling IC, Weber KT.
Aldosteronism and a proinflammatory vascular phenotype. Role of
Mg2+, Ca2+ and H2O2 in peripheral blood mononuclear cells.
Circulation 2005;111:51 – 7.
Ahokas RA, Warrington KJ, Gerling IC, Sun Y, Wodi LA, Herring PA,
et al. Aldosteronism and peripheral blood mononuclear cell activation.
A neuroendocrine-immune interface. Circ Res 2003;93:e124.
Gerling IC, Sun Y, Ahokas RA, Wodi LA, Bhattacharya SK,
Warrington KJ, et al. Aldosteronism: an immunostimulatory state
precedes the proinflammatory/fibrogenic cardiac phenotype. Am J
Physiol, Heart Circ Physiol 2003;285:H813 – 21.
Aukrust P, Ueland T, Mu¨ller F, Andreassen AK, Nordøy I, Aas H, et
al. Elevated circulating levels of C – C chemokines in patients with
congestive heart failure. Circulation 1998;97:1136 – 43.
Dama˚s JK, Gullestad L, Aass H, Simonsen S, Fjeld JG, Wikeby L, et
al. Enhanced gene expression of chemokines and their corresponding
receptors in mononuclear blood cells in chronic heart failuremodulatory effect of intravenous immunoglobulin. J Am Coll
Cardiol 2001;38:187 – 93.
Dama˚s JK, Gullestad L, Ueland T, Solum NO, Simonsen S, Frøland
SS, et al. CXC-chemokines, a new group of cytokines in congestive
heart failure-possible role of platelets and monocytes. Cardiovasc
Res 2000;45:428 – 36.
Yndestad A, Dama˚s JK, Eiken HG, Holm T, Haug T, Simonsen S, et
al. Increased gene expression of tumor necrosis factor superfamily
ligands in peripheral blood mononuclear cells during chronic heart
failure. Cardiovasc Res 2002;54:175 – 82.
Yndestad A, Holm AM, Mu¨ller F, Simonsen S, Frøland SS,
Gullestad L, et al. Enhanced expression of inflammatory cytokines
and activation markers in T-cells from patients with chronic heart
failure. Cardiovasc Res 2003;60:141 – 6.
307
308
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
[62] Breslau NA, McGuire JL, Zerwekh JE, Pak CY. The role of
dietary sodium on renal excretion and intestinal absorption of
calcium and on vitamin D metabolism. J Clin Endocrinol Metab
1982;55:369 – 73.
[63] Imaoka M, Morimoto S, Kitano S, Fukuo F, Ogihara T. Calcium
metabolism in elderly hypertensive patients: possible participation of
exaggerated sodium, calcium and phosphate excretion. Clin Exp
Pharmacol Physiol 1991;18:631 – 41.
[64] Zemel MB, Kraniak J, Standley PR, Sowers JR. Erythrocyte
cation metabolism in salt-sensitive hypertensive blacks as affected
by dietary sodium and calcium. Am J Hypertens 1988;1(4 Pt 1):
386 – 92.
[65] Haller H, Thiede M, Lenz T, Ludersdorf M, Harwig S, Distler A, et
al. Intracellular free calcium and ionized plasma calcium during
mineralocorticoid-induced blood pressure increase in man. J Hypertens Suppl 1985;3(Suppl 3):S41 – 3.
[66] Zikos D, Langman C, Gafter U, Delahaye B, Lau K. Chronic DOCA
treatment increases Ca absorption: role of hypercalciuria and vitamin
D. Am J Physiol 1986;251(3 Pt 1):E279 – 84.
[67] Law PH, Sun Y, Bhattacharya SK, Chhokar VS, Weber KT. Diuretics
and bone loss in rats with aldosteronism. J Am Coll Cardiol
2005;46:142 – 6.
[68] Runyan AL, Chhokar VS, Sun Y, Bhattacharya SK, Runyan JW,
Weber KT. Bone loss in rats with aldosteronism. Am J Med Sci
2005;330:1 – 7.
[69] Suzuki H, Sano H, Fukuzaki H. Decreased cytosolic free calcium
concentration in lymphocytes of magnesium-supplemented DOCA –
salt hypertensive rats. Clin Exp Hypertens, A 1989;11:487 – 500.
[70] Berthon N, Laurant P, Hayoz D, Fellmann D, Brunner HR,
Berthelot A. Magnesium supplementation and deoxycorticosterone
acetate – salt hypertension: effect on arterial mechanical properties
and on activity of endothelin-1. Can J Physiol Pharmacol 2002;
80:553 – 61.
[71] Goodwin KD, Ahokas RA, Bhattacharya SK, Sun Y, Gerling IC,
Weber KT. Preventing oxidative stress in rats with aldosteronism by
calcitriol and dietary calcium and magnesium supplements. Am J
Med Sci in press.
[72] Johnson F, Giulivi C. Superoxide dismutases and their impact upon
human health. Mol Aspects Med 2005;26:340 – 52.
[73] Thomson CD. Assessment of requirements for selenium and
adequacy of selenium status: a review. Eur J Clin Nutr 2004;58:
391 – 402.
[74] Thomas M, Vidal A, Bhattacharya SK, Ahokas RA, Johnson PL, Sun
Y, et al. Hypozincemia and oxidative stress in rats with chronic
aldosteronism. J Investig Med 2006;54(Suppl 1):S264.
[75] Galisteo M, Garcia-Saura MF, Jimenez R, Villar IC, Zarzuelo A,
Vargas F, et al. Effects of chronic quercetin treatment on antioxidant
defence system and oxidative status of deoxycorticosterone acetate –
salt-hypertensive rats. Mol Cell Biochem 2004;259:91 – 9.
[76] Nakano D, Itoh C, Ishii F, Kawanishi H, Takaoka M, Kiso Y, et al.
Effects of sesamin on aortic oxidative stress and endothelial
dysfunction in deoxycorticosterone acetate – salt hypertensive rats.
Biol Pharm Bull 2003;26:1701 – 5.
[77] Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, et
al. Interleukin-6 spillover in the peripheral circulation increases with
the severity of heart failure, and the high plasma level of interleukin6 is an important prognostic predictor in patients with congestive
heart failure. J Am Coll Cardiol 1998;31:391 – 8.
[78] Janssen SP, Gayan-Ramirez G, Van den Bergh A, Herijgers P,
Maes K, Verbeken E, et al. Interleukin-6 causes myocardial
failure and skeletal muscle atrophy in rats. Circulation 2005;111:
996 – 1005.
[79] Grey A, Mitnick MA, Shapses S, Ellison A, Gundberg C, Insogna K.
Circulating levels of interleukin-6 and tumor necrosis factor-alpha
are elevated in primary hyperparathyroidism and correlate with
markers of bone resorption-a clinical research center study. J Clin
Endocrinol Metab 1996;81:3450 – 4.
Downloaded from by guest on October 28, 2014
[41] Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and
the prevention of myocardial fibrosis in primary and secondary
hyperaldosteronism. J Mol Cell Cardiol 1993;25:563 – 75.
[42] Ramires FJA, Sun Y, Weber KT. Myocardial fibrosis associated with
aldosterone or angiotensin II administration: attenuation by calcium
channel blockade. J Mol Cell Cardiol 1998;30:475 – 83.
[43] Nickerson PA, Yang F. Calcium distribution in aortic smooth muscle
cells of deoxycorticosterone-hypertensive rats. A quantitative cytochemical study. J Submicrosc Cytol Pathol 1988;20:317 – 24.
[44] Wuorela H. The effect of high calcium intake on intracellular free
[Ca2+] and Na+ – H+ exchange in DOC – NaCl-hypertensive rats.
Pharmacol Toxicol 1992;71:376 – 82.
[45] Kh R, Khullar M, Kashyap M, Pandhi P, Uppal R. Effect of oral
magnesium supplementation on blood pressure, platelet aggregation
and calcium handling in deoxycorticosterone acetate induced
hypertension in rats. J Hypertens 2000;18:919 – 26.
[46] Delva P, Pastori C, Degan M, Montesi G, Brazzarola P, Lechi A.
Intralymphocyte free magnesium in patients with primary aldosteronism: aldosterone and lymphocyte magnesium homeostasis. Hypertension 2000;35:113 – 7.
[47] Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing
Z, et al. Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 2005;111:871 – 8.
[48] Vidal A, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC, Weber
KT. The calcium paradox of aldosteronism and the role of the
parathyroid glands. Am J Physiol, Heart Circ Physiol 2006;290:
H286 – 94.
[49] Duchen MR. Mitochondria and Ca2+ in cell physiology and
pathophysiology. Cell Calcium 2000;28:339 – 48.
[50] Massry SG, Smogorzewski M. Mechanisms through which parathyroid hormone mediates its deleterious effects on organ function in
uremia. Semin Nephrol 1994;14:219 – 31.
[51] Conn JW. Aldosteronism in man. Some clinical and climatological
aspects: Part I. JAMA 1963;183:775 – 81.
[52] Conn JW. Aldosteronism in man. Some clinical and climatological
aspects: Part II. JAMA 1963;183:871 – 8.
[53] Horton R, Biglieri EG. Effect of aldosterone on the metabolism of
magnesium. J Clin Endocrinol Metab 1962;22:1187 – 92.
[54] Rastegar A, Agus Z, Connor TB, Goldberg M. Renal handling of
calcium and phosphate during mineralocorticoid ‘‘escape’’ in man.
Kidney Int 1972;2:279 – 86.
[55] Gehr MK, Goldberg M. Hypercalciuria of mineralocorticoid escape:
clearance and micropuncture studies in the rat. Am J Physiol
1986;251(5 Pt 2):F879 – 88.
[56] Cappuccio FP, Markandu ND, MacGregor GA. Renal handling of
calcium and phosphate during mineralocorticoid administration in
normal subjects. Nephron 1988;48:280 – 3.
[57] Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK,
Xing Z, et al. Loss of bone minerals and strength in rats with
aldosteronism. Am J Physiol, Heart Circ Physiol 2004;287:
H2023 – 6.
[58] Bhattacharya SK, Williams JC. Modified method of urinary calcium
and magnesium determinations by atomic absorption spectrophotometry using nitrous oxide-acetylene flame. Anal Lett 1979;12:
397 – 414.
[59] Bhattacharya SK, Williams JC, Palmieri GMA. Determination of
calcium and magnesium in cardiac and skeletal muscles by atomic
absorption spectroscopy using stoichiometric nitrous oxide-acetylene
flame. Anal Lett 1979;12:1451 – 75.
[60] Nagy TR, Prince CW, Li J. Validation of peripheral dual-energy Xray absorptiometry for the measurement of bone mineral in intact and
excised long bones of rats. J Bone Miner Res 2001;16:1682 – 7.
[61] Combs NR, Kornegay ET, Lindemann MD, Notter DR, Wilson JH,
Mason JP. Calcium and phosphorus requirement of swine from
weaning to market weight: II. Development of response curves for
bone criteria and comparison of bending and shear bone testing.
J Anim Sci 1991;69:682 – 93.
Y. Sun et al. / Cardiovascular Research 71 (2006) 300 – 309
[96] Smogorzewski M, Massry SG. Uremic cardiomyopathy: role of
parathyroid hormone. Kidney Int Suppl 1997;62:S12.
[97] Schlu¨ter KD, Piper HM. Cardiovascular actions of parathyroid
hormone and parathyroid hormone-related peptide. Cardiovasc Res
1998;37:34 – 41.
[98] Nasri H, Baradaran A, Naderi AS. Close association between
parathyroid hormone and left ventricular function and structure in
end-stage renal failure patients under maintenance hemodialysis.
Acta Med Austriaca 2004;31:67 – 72.
[99] McGonigle RJ, Fowler MB, Timmis AB, Weston MJ, Parsons V.
Uremic cardiomyopathy: potential role of vitamin D and parathyroid
hormone. Nephron 1984;36:94 – 100.
[100] Lemmila¨ S, Saha H, Virtanen V, Ala-Houhala I, Pasternack A. Effect
of intravenous calcitriol on cardiac systolic and diastolic function in
patients on hemodialysis. Am J Nephrol 1998;18:404 – 10.
[101] Na¨ppi S, Saha H, Virtanen V, Limnell V, Sand J, Salmi J, et al. Left
ventricular structure and function in primary hyperparathyroidism
before and after parathyroidectomy. Cardiology 2000;93:229 – 33.
[102] Grey A, Mitnick MA, Masiukiewicz U, Sun BH, Rudikoff S, Jilka
RL, et al. A role for interleukin-6 in parathyroid hormone-induced
bone resorption in vivo. Endocrinology 1999;140:4683 – 90.
[103] Tatsumi T, Matoba S, Kawahara A, Keira N, Shiraishi J, Akashi K, et
al. Cytokine-induced nitric oxide production inhibits mitochondrial
energy production and impairs contractile function in rat cardiac
myocytes. J Am Coll Cardiol 2000;35:1338 – 46.
[104] Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A,
et al. Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit Care Med
1999;27:1309 – 18.
[105] Joe EK, Schussheim AE, Longrois D, Ma¨ki T, Kelly RA, Smith TW,
et al. Regulation of cardiac myocyte contractile function by inducible
nitric oxide synthase (iNOS): mechanisms of contractile depression
by nitric oxide. J Mol Cell Cardiol 1998;30:303 – 15.
[106] de Lorgeril M, Salen P, Accominotti M, Cadau M, Steghens JP,
Boucher F, et al. Dietary and blood antioxidants in patients with
chronic heart failure. Insights into the potential importance of
selenium in heart failure. Eur J Heart Fail 2001;3:661 – 9.
[107] Witte KK, Clark AL, Cleland JG. Chronic heart failure and
micronutrients. J Am Coll Cardiol 2001;37:1765 – 74.
[108] Chmielinska JJ, Tejero-Taldo MI, Mak IT, Weglicki WB. Intestinal
and cardiac inflammatory response shows enhanced endotoxin
receptor (CD14) expression in magnesium deficiency. Mol Cell
Biochem 2005;278:53 – 7.
[109] Polidori MC, Pratico´ D, Savino K, Rokach J, Stahl W, Mecocci P.
Increased F2 isoprostane plasma levels in patients with congestive
heart failure are correlated with antioxidant status and disease
severity. J Card Fail 2004;10:334 – 8.
[110] Houston MC. Nutraceuticals, vitamins, antioxidants, and minerals in
the prevention and treatment of hypertension. Prog Cardiovasc Dis
2005;47:396 – 449.
Downloaded from by guest on October 28, 2014
[80] Takahashi S, Hakuta M, Aiba K, Ito Y, Horikoshi N, Miura M, et al.
Elevation of circulating plasma cytokines in cancer patients with high
plasma parathyroid hormone-related protein levels. Endocr Relat
Cancer 2003;10:403 – 7.
[81] Molavi B, Mehta JL. Oxidative stress in cardiovascular disease:
molecular basis of its deleterious effects, its detection, and
therapeutic considerations. Curr Opin Cardiol 2004;19:488 – 93.
[82] Ungvari Z, Gupte SA, Recchia FA, Batkai S, Pacher P. Role of
oxidative-nitrosative stress and downstream pathways in various
forms of cardiomyopathy and heart failure. Curr Vasc Pharmacol
2005;3:221 – 9.
[83] Wykretowicz A, Furmaniuk J, Smielecki J, Deskur-Smielecka E,
Szczepanik A, Banaszak A, et al. The oxygen stress index and levels
of circulating interleukin-10 and interleukin-6 in patients with
chronic heart failure. Int J Cardiol 2004;94:283 – 7.
[84] Shioji K, Nakamura H, Masutani H, Yodoi J. Redox regulation by
thioredoxin in cardiovascular diseases. Antioxid Redox Signal
2003;5:795 – 802.
[85] Takano H, Zou Y, Hasegawa H, Akazawa H, Nagai T, Komuro I.
Oxidative stress-induced signal transduction pathways in cardiac
myocytes: involvement of ROS in heart diseases. Antioxid Redox
Signal 2003;5:789 – 94.
[86] Demirbag R, Yilmaz R, Erel O, Gultekin U, Asci D, Elbasan Z. The
relationship between potency of oxidative stress and severity of
dilated cardiomyopathy. Can J Cardiol 2005;21:851 – 5.
[87] Reth M. Hydrogen peroxide as second messenger in lymphocyte
activation. Nat Immunol 2002;3:1129 – 34.
[88] Stefenelli T, Pacher R, Woloszczuk W, Glogar D, Kaindl F.
Parathyroid hormone and calcium behavior in advanced congestive
heart failure [German]. Z Kardiol 1992;81:121 – 5.
[89] Christ E, Linka A, Junga G, Odermatt M, Steinert H, Kiowski W, et
al. Bone density and laboratory parameters of bone metabolism in
patients with terminal heart disease [German]. Schweiz Med
Wochenschr 1996;126:1553 – 9.
[90] Schmid C, Kiowski W. Hyperparathyroidism in congestive heart
failure. Am J Med 1998;104:508 – 9.
[91] Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R,
Stehle P. Low vitamin D status: a contributing factor in the
pathogenesis of congestive heart failure? J Am Coll Cardiol
2003;41:105 – 12.
[92] Khouzam RN, Dishmon DA, Farah V, Flax SD, Carbone LD, Weber
KT. Secondary hyperparathyroidism in patients with untreated and
treated congestive heart failure. Am J Med Sci 2006;331:30 – 4.
[93] LaGuardia SP, Dockery BK, Bhattacharya SK, Nelson MD, Carbone
LD, Weber KT. Hyperparathyroidism and hypovitaminosis D in
African-Americans with heart failure [abstract]. J Investig Med
2006;54(Suppl 1):S302.
[94] Weber KT, Brilla CG, Janicki JS. Myocardial fibrosis: functional
significance and regulatory factors. Cardiovasc Res 1993;27:341 – 8.
[95] Nickerson PA, Conran RM. Parathyroidectomy ameliorates vascular
lesions induced by deoxycorticosterone in the rat. Am J Pathol
1981;105:185 – 90.
309