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(Circulation. 2005;111:871-878.)
© 2005 American Heart Association, Inc.

Heart Failure

Hyperparathyroidism and the Calcium Paradox of Aldosteronism

Vikram S. Chhokar, MD; Yao Sun, MD, PhD; Syamal K. Bhattacharya, PhD; Robert A. Ahokas, PhD; Linda K. Myers, MD; Zhiqing Xing, MD, PhD; Richard A. Smith, PhD; Ivan C. Gerling, PhD; Karl T. Weber, MD

From the Divisions of Cardiovascular Diseases (V.S.C., Y.S., K.T.W.) and Endocrinology (I.C.G.), Department of Medicine, and Departments of Surgery (S.K.B.), Obstetrics and Gynecology (R.A.A.), Pediatrics (L.K.M.), and Orthopaedic Surgery (Z.X., R.A.S.), University of Tennessee Health Science Center, Memphis.

Correspondence to Karl T. Weber, MD, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 920 Madison Ave, Ste 300, Memphis, TN 38163. E-mail KTWeber{at}utmem.edu

Received October 6, 2004; revision received November 5, 2004; accepted November 10, 2004.

Background— Aldosteronism may account for oxi/nitrosative stress, a proinflammatory phenotype, and wasting in congestive heart failure. We hypothesized that aldosterone/1% NaCl treatment (ALDOST) in rats enhances Ca²⁺ and Mg²⁺ excretion and leads to systemic effects, including bone loss.

Methods and Results— At 1, 2, 4, and 6 weeks of ALDOST, we monitored Ca²⁺ and Mg²⁺ excretion, ionized [Ca²⁺]_o and [Mg²⁺]_o, parathyroid hormone and ₁-antiproteinase activity in plasma, bone mineral density, bone strength, Ca²⁺ and Mg²⁺ content in peripheral blood mononuclear cells (PBMCs) and ventricular tissue, and lymphocyte H₂O₂ production. A separate group received spironolactone (Spiro), an aldosterone receptor antagonist. Age- and gender-matched unoperated and untreated rats served as controls. ALDOST induced a marked (P<0.05) and persistent rise in urinary and fecal Ca²⁺ and Mg²⁺ excretion, a progressive reduction (P<0.05) in [Ca²⁺]_o and [Mg²⁺]_o, and an elevation in parathyroid hormone (P<0.05) with a fall (P<0.05) in bone mineral density and strength. An early, sustained increase (P<0.05) in PBMC Ca²⁺ and Mg²⁺ was found, together with an increase (P<0.05) in tissue Ca²⁺. Plasma ₁-antiproteinase activity was reduced (P<0.05), whereas lymphocyte H₂O₂ production was increased (P<0.05) at all time points. Spiro cotreatment attenuated (P<0.05) urinary and fecal Ca²⁺ and Mg²⁺ excretion, prevented the fall in [Ca²⁺]_o and [Mg²⁺]_o, rescued bone mineral density and strength, and prevented Ca²⁺ overloading of PBMCs and cardiomyocytes.

Conclusions— In aldosteronism, Ca²⁺ and Mg²⁺ losses lead to a fall in [Ca²⁺]_o and [Mg²⁺]_o with secondary hyperparathyroidism and bone resorption. Ca²⁺ overloading of PBMCs and cardiac tissue leads to oxi/nitrosative stress and a proinflammatory phenotype.

Key Words: aldosterone • calcium • magnesium • osteoporosis • parathyroid hormone

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