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Cardiovascular Research 2006 71(2):300-309; doi:10.1016/j.cardiores.2006.03.007
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Copyright © 2006, European Society of Cardiology

Oxidative stress in aldosteronism

Yao Suna, Robert A. Ahokasd, Syamal K. Bhattacharyae, Ivan C. Gerlingb, Laura D. Carbonec and Karl T. Webera,*

aDivision of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 920 Madison Ave., Suite 300, Memphis, TN 38163, USA
bDivision of Endocrinology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
cDivision of Connective Tissue Diseases, Department of Medicine, University of Tennessee Health Science Center and Veterans Administration Medical Center, Memphis, TN, USA
dDepartment of Obstetrics and Gynecology, University of Tennessee Health Science Center and Veterans Administration Medical Center, Memphis, TN, USA
eDepartment of Surgery, University of Tennessee Health Science Center and Veterans Administration Medical Center, Memphis, TN, USA

* Corresponding author. Tel.: +1 901 448 5750; fax: +1 901 448 8084. Email address: KTWeber{at}utmem.edu

Received 5 December 2005; revised 20 February 2006; accepted 6 March 2006


   Abstract
Top
 Abstract
1. Introduction
 2. Oxidative stress in...
 3. Secondary aldosteronism in...
 4. Conclusions and future...
 References
 
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.

KEYWORDS Aldosterone; Oxidative stress; Parathyroid hormone; Calcium; Magnesium


   1. Introduction
Top
 Abstract
 1. Introduction
2. Oxidative stress in...
 3. Secondary aldosteronism in...
 4. Conclusions and future...
 References
 
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 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 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.


   2. Oxidative stress in aldosteronism: experimental studies
Top
 Abstract
 1. Introduction
 2. Oxidative stress in...
3. Secondary aldosteronism in...
 4. Conclusions and future...
 References
 
2.1 Animal model
A widely used experimental model of aldosteronism consists of uninephrectomized rats receiving a continuous infusion of ALDO (0.75µg/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 {alpha}1-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 plasma-ionized 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 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)-{kappa}B [21]. Furthermore, in situ hybridization revealed an increased mRNA expression of a proinflammatory gene cascade in these invading cells and which is regulated by NF{kappa}B. This includes intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-{alpha} [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]. Co-treatment with a Ca2+ channel blocker is also vasculoprotective [13,42].

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].


Figure 1
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  		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±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.

 

Figure 2
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  		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.

 
Based on metabolic studies conducted in patients with primary aldosteronism [51–56], 24h 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 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 X-ray 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.


Figure 3
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  		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)-{kappa}B, 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).

 
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 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-GSH-Px. 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 hypozincemia 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 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. Secondary aldosteronism in CHF: clinical studies
Top
 Abstract
 1. Introduction
 2. Oxidative stress in...
 3. Secondary aldosteronism in...
4. Conclusions and future...
 References
 
3.1 The CHF syndrome
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-{alpha} 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 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
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].

3.4 Secondary hyperparathyroidism in CHF
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±S.E.M.; range; normal 12–65pg/mL) was documented. This included 5 who were medically untreated (204±60; 86–393pg/mL) and 4 with treated CHF (134±14; 105–164pg/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±15 and 83±21mL/min, respectively, and did not differ between them. In this preliminary study, 25(OH)D was not monitored.

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 (leg4weeks) in 11 and short-term CHF (1–2weeks) 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±S.E.M.; range) was elevated in all those with protracted CHF (127±13; 82–243pg/mL) and in 3 of 9 with short-term CHF (59±8; 18–99pg/mL); none of the compensated patients had SHPT (42±5, 17–53pg/mL). Ionized hypocalcemia and hypomagnesemia was present in both groups with CHF. We found hypovitaminosis D (<30ng/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 >30ng/mL in preventing SHPT and oxidative stress in the overall management of CHF remains to be addressed.

3.5 Secondary hyperparathyroidism and the failing heart
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 osteoblast formation of IL-6 and TNF-{alpha} 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-{alpha} found in CHF [23] may represent surrogate biomarkers of SHPT.


Figure 4
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  		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-{alpha} 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 plasma-ionized [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 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
Top
 Abstract
 1. Introduction
 2. Oxidative stress in...
 3. Secondary aldosteronism in...
 4. Conclusions and future...
References
 
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/Zn-SOD 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.


   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.


   Notes
 
Time for primary review 22 days


   References
Top
 Abstract
 1. Introduction
 2. Oxidative stress in...
 3. Secondary aldosteronism in...
 4. Conclusions and future...
 References
 

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