Karl T. Weber

The pathologic hypertrophy of hypertensive heart disease is related to the quality, not the quantity, of myocardium; the presence of fibrosis is inevitably linked to structural and functional insufficiencies with increased cardiovascular risk. Elevations in plasma aldosterone that are inappropriate relative to dietary sodium, or relative aldosteronism, are accompanied by suppressed plasma renin activity, elevation in arterial pressure, and dyshomeostasis of divalent cations. The accompanying hypocalcemia, hypomagnesemia, and hypozincemia of aldosteronism contribute to the appearance of secondary hyperparathyroidism. Parathyroid hormone-mediated intracellular calcium overloading of cardiac myocytes and mitochondria leads to the induction of oxidative stress and molecular pathways associated with cardiomyocyte necrosis and scarring of myocardium, whereas the dyshomeostasis of zinc compromises antioxidant defenses. This dyshomeostasis of calcium and zinc, intrinsically coupling prooxidant calcium and antioxidant zinc, raises the prospect for therapeutic strategies designed to mitigate intracellular calcium overloading while enhancing zinc-mediated antioxidant defenses, thus preventing adverse myocardial remodeling with fibrosis, associated diastolic dysfunction, and cardiac arrhythmias.

Hypertension and heart failure are worldwide health problems of ever-increasing proportions. A failure of the heart, during either systolic and/or diastolic phases of the cardiac cycle, has its origins rooted in an adverse structural, biochemical, and molecular remodelling of myocardium that involves its cellular constituents, extracellular matrix, and intramural coronary vasculature. Herein we focus on the pathogenic role of a dyshomeostasis of several macro- (i.e. Ca²⁺ and Mg²⁺) and micronutrients (i.e. Zn²⁺, Se²⁺, and vitamin D) in contributing to adverse remodelling of the myocardium and its failure as a pulsatile muscular pump. An improved understanding of how these macro- and micronutrients account for the causes and consequences of adverse myocardial remodelling carries with it the potential of identifying new biomarkers predictive of risk, onset and progression, and response to intervention(s), which could be monitored non-invasively and serially over time. Moreover, such incremental knowledge will serve as the underpinning to the development of novel strategies aimed at preventing and/or regressing the ongoing adverse remodelling of myocardium. The time is at hand to recognize the importance of macro- and micronutrient dyshomeostasis in the evaluation and management of hypertension and heart failure.

Iterations in Ca²⁺ and Mg²⁺ balance accompany aldosteronism (inappropriate for dietary Na⁺ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined. (1) To study the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO₃^- excretion. (2) To assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn²⁺]_i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress were examined. (3) Oxidative stress and cardiac pathology in response to ZnSO₄ supplement (40 mg/d) were also studied. Comparison of controls and rats receiving 4 weeks ALDOST revealed the following: (1) an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; (2) a rise in cardiac Zn, including increased [Zn²⁺]_i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91^phox, coupled with oxidative stress in plasma and urine; (3) ZnSO₄ prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO₄ attenuated cardiomyocyte necrosis; however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contributes to cardiac pathology.