Kevin P. Newman

Hypovitaminosis D in African Americans residing in Memphis, Tennessee with and without heart failure

Background:Factors contributing to heart failure (HF) in African Americans (AA) are under investigation. Reduced 25(OH)D confers increased cardiovascular risk, including HF. Methods:We monitored serum 25(OH)D, 1,25(OH)2D3, parathyroid hormone (PTH), and creatinine clearance in 102 AA residing in Memphis: 58 hospitalized with decompensated HF of ≥4 weeks in 34 (21 men; 53.3 ± 1.8 years) or of 1 to 2 weeks in 24 (17 men; 49.6 ± 2.4 years) and associated with a dilated cardiomyopathy and reduced ejection fraction (<35%); 19 outpatients with compensated HF (14 men; 52.6 ± 2.7 years) with comparable ejection fraction; 16 outpatients (9 men; 55.4 ± 2.9 years) with heart disease, but without HF; and 9 healthy volunteers (3 men; 35.8 ± 3.5 years). Results:Serum 25(OH)D ≤30 ng/mL was found in 96% and 90% with protracted or short-term decompensated HF, where it was of moderate to marked severity (<20 ng/mL) in 83% and 76%, respectively. In patients with either compensated or no HF, 25(OH)D <30 ng/mL was found in 95% and 100%, respectively, and in 30% of volunteers. Normal serum 1,25(OH)2D3 did not differ between patients. Serum PTH >65 pg/mL was found in all AA with decompensated HF of ≥4 weeks (132.4 ± 12.0 pg/mL) and 67% with 1 to 2 weeks duration (82.3 ± 7.9 pg/mL), but only 11% with compensated HF (45.8 ± 6.1 pg/mL), 12% without HF (29.6 ± 5.4 pg/mL), and none of the volunteers (31.1 ± 3.9 pg/mL). Creatinine clearance did not differ between patient groups. Conclusions:Hypovitaminosis D is prevalent amongst AA residing in Memphis, with or without HF. Elevations in serum PTH in keeping with secondary hyperparathyroidism are only found in AA with decompensated HF, where hypovitaminosis D and other factors are contributory.

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

Congestive heart failure (CHF) is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensin-aldosterone system. More than this cardiorenal perspective, CHF is accompanied by a systemic illness whose features include an altered redox state in diverse tissues and blood, an immunostimulatory state with proinflammatory cytokines and activated lymphocytes and monocytes, and a wasting of tissues that includes muscle and bone. Based on experimental studies of aldosteronism and clinical findings in patients with CHF, there is an emerging body of evidence that secondary hyperparathyroidism is a covariant of CHF. The aldosteronism of CHF predisposes patients to secondary hyperparathyroidism because of a chronic increase in Ca2+ and Mg2+ losses in urine and feces, with a fall in their serum ionized levels and consequent secretion of parathyroid hormone. Secondary hyperparathyroidism accounts for bone resorption and contributes to a fall in bone strength that can lead to nontraumatic fractures.The long-term use of a loop diuretic with its attendant urinary wasting of Ca2+ and Mg2+ further predisposes patients to secondary hyperparathyroidism and attendant bone loss. Aberrations in minerals and micronutrient homeostasis that includes Ca2+, Mg2+, vitamin D, zinc and selenium appear to be an integral component of pathophysiologic expressions of CHF that contributes to its systemic and progressive nature. This broader perspective of CHF, which focuses on the importance of secondary hyperparathyroidism and minerals and micronutrients, raises the prospect that dietary supplements could prove remedial in combination with the current standard of care.

Hypoalbuminemia and Lymphocytopenia in Patients With Decompensated Biventricular Failure

Background:In patients hospitalized with decompensated biventricular failure having hypoalbuminemia and lymphocytopenia without underlying hepatic or renal disease, we addressed the presence of a protein-losing enteropathy (PLE). Methods:We studied 78 patients having a dilated cardiomyopathy, who were hospitalized with congestive heart failure (CHF) and hypoalbuminemia of uncertain origin. In the first 19 patients, we investigated the presence of PLE using Tc-Dex70 scintigraphy together with serum albumin 2 to 4 weeks later when compensation had been restored. In the next 59 patients, presenting with reduced serum albumin and relative lymphocyte count at admission, these parameters were again monitored (2–4 weeks) later when symptoms and signs of CHF had resolved. Results:PLE, documented by Tc-Dex70 scintigraphy, was found in 10 of 19 patients and whose hypoalbuminemia (2.7 ± 0.1 g/dL, mean ± standard error of mean) were corrected (3.3 ± 0.1 g/dL; P < 0.05) with the resolution of CHF, whereas in the 9 patients without a PLE, reduced baseline serum albumin (2.6 ± 0.1 g/dL) failed to improve on follow-up (2.6 ± 0.2 g/dL) in keeping with malnutrition. Relative lymphocyte count was reduced (14.6 ± 1.5%) in patients with PLE but was normal (21.4 ± 3.3%; P < 0.05) in those without PLE. Serum albumin and relative lymphocyte count were each reduced at admission (2.8 ± 0.1 g/dL and 14.4 ± 1.0%, respectively) in 59 patients and increased (P < 0.05) to normal values (3.5 ± 0.1 g/dL and 24.9 ± 1.0%) 2 to 4 weeks after they were compensated. Conclusions:Enteral losses of albumin and lymphocytes account for the reversible hypoalbuminemia and lymphocytopenia found in patients hospitalized with CHF having splanchnic congestion.

Macro- and micronutrients in African-Americans with heart failure

An emerging body of evidence suggests secondary hyperparathyroidism (SHPT) may be an important covariant of congestive heart failure (CHF), especially in African-Americans (AA) where hypovitaminosis D is prevalent given that melanin, a natural sunscreen, mandates prolonged exposure of skin to sunlight and where a housebound lifestyle imposed by symptomatic CHF limits outdoor activities and hence sunlight exposure. In addition to the role of hypovitaminosis D in contributing to SHPT is the increased urinary and fecal losses of macronutrients Ca2+ and Mg2+ associated with the aldosteronism of CHF and their heightened urinary losses with furosemide treatment of CHF. Thus, a precarious Ca2+ balance seen with reduced serum 25(OH)D is further compromised when AA develop CHF with circulating RAAS activation and are then treated with a loop diuretic. SHPT accounts for a paradoxical Ca2+ overloading of diverse tissues and the induction of oxidative stress at these sites which spills over to the systemic circulation.In addition to SHPT, hypozincemia and hyposelenemia have been found in AA with compensated and decompensated heart failure and where an insufficiency of these micronutrients may have its origins in inadequate dietary intake, altered rates of absorption or excretion and/or tissue redistribution, and treatment with an ACE inhibitor or AT1 receptor antagonist. Zn and Se deficiencies, which compromise the activity of several endogenous antioxidant defenses, could prove contributory to the severity of heart failure and its progressive nature. These findings call into question the need for nutriceutical treatment of heart failure and which is complementary to today’s pharmaceuticals, especially in AA.

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation.

Inappropriately (relative to dietary Na+) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na+ have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca2+ accumulation (EICA), or intracellular Ca2+ overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca2+ and Mg2+. In addition, we found intracellular Ca2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn2+, which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular–molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra- and intracellular Ca2+ and Zn2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.

Oxidative Stress and Cardiomyocyte Necrosis With Elevated Serum Troponins: Pathophysiologic Mechanisms

The progressive nature of heart failure is linked to multiple factors, including an ongoing loss of cardiomyocytes and necrosis. Necrotic cardiomyocytes leave behind several footprints: the spillage of their contents leading to elevations in serum troponins; and morphologic evidence of tissue repair with scarring. The pathophysiologic origins of cardiomyocyte necrosis relates to neurohormonal activation, including the adrenergic nervous system. Catecholamine-initiated excessive intracellular Ca2+ accumulation and mitochondria Ca2+ overloading in particular initiate a mitochondriocentric signal-transducer-effector pathway to necrosis and which includes the induction of oxidative stress and opening of their inner membrane permeability transition pore. Hypokalemia, ionized hypocalcemia and hypomagnesemia, where consequent elevations in parathyroid hormone further account for excessive intracellular Ca2+ accumulation, hypozincemia and hyposelenemia each compromise metalloenzyme-based antioxidant defenses. The necrotic loss of cardiomyocytes and adverse structural remodeling of myocardium is related to the central role played by a mitochondriocentric pathway initiated by neurohormonal activation.

Stressor States and the Cation Crossroads

Neurohormonal activation involving the hypothalamic-pituitary-adrenal axis and adrenergic nervous and renin-angiotensin-aldosterone systems is integral to stressor state–mediated homeostatic responses. The levels of effector hormones, depending upon the degree of stress, orchestrate the concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia. Seemingly contradictory to homeostatic responses wherein the constancy of extracellular fluid would be preserved, upregulation of cognate-binding proteins promotes coordinated translocation of cations to injured tissues, where they participate in wound healing. Associated catecholamine-mediated intracellular cation shifts regulate the equilibrium between pro-oxidants and antioxidant defenses, a critical determinant of cell survival. These acute and chronic stressor-induced iterations in extracellular and intracellular cations are collectively referred to as the cation crossroads. Intracellular cation shifts, particularly excessive accumulation of Ca2+, converge on mitochondria to induce oxidative stress and raise the opening potential of their inner membrane permeability transition pores (mPTPs). The ensuing loss of cationic homeostasis and adenosine triphosphate (ATP) production, together with osmotic swelling, leads to organellar degeneration and cellular necrosis. The overall impact of iterations in extracellular and intracellular cations and their influence on cardiac redox state, cardiomyocyte survival, and myocardial structure and function are addressed herein. Key teaching points: •  Acute and chronic stressor states (e.g., bodily injury and congestive heart failure, respectively) are inextricably linked to homeostatic responses, which include neurohormonal activation.•  Effector hormones of the hypothalamic-pituitary-adrenal axis and the adrenergic nervous and renin-angiotensin-aldosterone systems are elaborated in concert to regulate extracellular and intracellular cation concentrations.•  Regulatory responses converge to culminate in the contemporaneous and concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia, which are integral to pathophysiologic expressions of acute and chronic stressor states.•  The extent to which these cation concentrations decline correlates with the severity of injury and, in turn, the degree of neurohormonal activation; accordingly, they are predictive of patient prognosis.•  Cardiomyocytes and their mitochondria are highly susceptible to cation trafficking, including the inducibility of atrial and ventricular arrhythmias, altered cardiac redox state, threatened cardiomyocyte survival, adverse remodeling of myocardial structure by loss of cardiomyocytes and replacement with fibrous tissue, and, in turn, dysfunction of this normally efficient muscular pump.•  In congestive heart failure, catecholamine and parathyroid hormone–mediated cardiomyocyte calcium overloading, in particular, an adverse accumulation of mitochondrial calcium, leads to the induction of oxidative stress and increased opening potential of mitochondrial permeability transition pores with ensuing organellar degeneration and mitochondria-dependent cellular necrosis.

Normoglycemia in Nondiabetic African Americans Hospitalized With Heart Failure

Background:In nondiabetic patients hospitalized with multiorgan failure, neurohormonal activation can lead to stress-induced hyperglycemia (>140 mg/dL), as could Mg2+ and Zn2+ deficiencies. However, it is currently uncertain whether nondiabetic African Americans (AA) hospitalized with either chronic, decompensated biventricular failure (DecompHF) having hepatic and splanchnic congestion, ionized hypomagnesemia and hypozincemia, or acute left heart failure (LHF) would exhibit hyperglycemia at admission. Methods:We retrospectively examined admission serum glucose in 77 AA patients without a history of diabetes, who were hospitalized with heart failure. This examination included 41 patients admitted during a 4-month period with chronic DecompHF and whose clinical presentation included findings of expanded intra- and extravascular volumes, together with echocardiographic evidence of marked tricuspid regurgitation and distended inferior vena cava, without respiratory variation. These patients were compared with 14 nondiabetic patients hospitalized during the same time period with acute LHF. We also studied admission serum glucose in 22 patients who were admitted with DecompHF having documented hypomagnesemia and hypozincemia. Results:Admission serum glucose (mean ± standard error of mean) in patients with chronic DecompHF was 105.41 ± 4.08 mg/dL and was modestly elevated (140–160 mg/dL) in 3 patients. In those with acute LHF, glucose was 94.86 ± 3.96 mg/dL and did not exceed 140 mg/dL in any patient. Glucose (103.2 ± 4.3 mg/dL) was not elevated in patients having chronic DecompHF and reduced ionized Mg2+ and serum Zn2+ (0.44 ± 0.01 mmol/L and 69.6 ± 3.2 &mgr;g/dL, respectively). Conclusions:Hyperglycemia at admission was infrequent in nondiabetic AA patients hospitalized with either acute LHF or chronic DecompHF, which may have also included hypomagnesemia and hypozincemia. This calls into question the need for intensive insulin therapy in these patients.

The importance of lost minerals in heart failure.

The clinical syndrome congestive heart failure (CHF) has its origins rooted in a salt-avid state mediated largely by effector hormones of the renin-angiotensin-aldosterone system (RAAS). In addition, a systemic illness accompanies chronic RAAS activation. Its features include: the presence of oxidative stress in diverse tissues coupled with a reduction in activity of endogenous oxidoreductases, such as Cu/Zn-superoxide dismutase and Se-glutathione peroxidase; a proinflammatory phenotype with activated immune cells and increased circulating levels of proinflammatory cytokines; and a catabolic state with loss of soft tissues and bone that eventuates in a wasting syndrome termed cardiac cachexia. Pathogenic mechanisms and pathophysiologic expressions of this illness are under active investigation. In this context and less well appreciated is the importance of a dyshomeostasis of various minerals, including Ca2+, Mg2+, Zn, and Se, and their impact on the systemic and progressive nature of CHF. A convergence of multiple factors, some hormonal (e.g., aldosteronism, secondary hyperparathyroidism, hypovitaminosis D), others pharmacologic (e.g., loop diuretics, angiotensin-converting enzyme inhibitors), predispose to the heightened excretion of these minerals in urine and feces while parathyroid hormone promotes intracellular Ca2+ overloading in diverse tissues. The importance of these macro- and micronutrients to the appearance of oxidative stress, compromised antioxidant defenses, an immunostimulatory state and tissue wasting needs to be critically addressed. So, too, must the potential for nutriceuticals, complementary to todays pharmaceuticals, to assist in the overall management of CHF.

Mineralocorticoid receptor antagonism confers cardioprotection in heart failure.

The symptoms and signs constituting the congestive heart failure (CHF) syndrome have their pathophysiologic origins rooted in a salt-avid renal state mediated by effector hormones of the renin-angiotensin-aldosterone and adrenergic nervous systems. Controlled clinical trials, conducted over the past decade in patients having minimally to markedly severe symptomatic heart failure, have demonstrated the efficacy of a pharmacologic regimen that interferes with these hormones, including aldosterone receptor binding with either spironolactone or eplerenone. Potential pathophysiologic mechanisms, which have not hitherto been considered involved for the salutary responses and cardioprotection provided by these mineralocorticoid receptor antagonists, are reviewed herein. In particular, we focus on the less well-recognized impact of catecholamines and aldosterone on monovalent and divalent cation dyshomeostasis, which leads to hypokalemia, hypomagnesemia, ionized hypocalcemia with secondary hyperparathyroidism and hypozincemia. Attendant adverse cardiac consequences include a delay in myocardial repolarization with increased propensity for supraventricular and ventricular arrhythmias, and compromised antioxidant defenses with increased susceptibility to nonischemic cardiomyocyte necrosis.