Research

Overview

The major focus of the Division of Cardiovascular Diseases is in the pathogenesis and optimal management of heart failure, a major health problem of ever increasing proportions particularly amongst the elderly and African-Americans.  Basic and applied studies in heart failure are featured.  Each are funded from federal and nonfederal sources.

Basic Science

One major theme of cellular and molecular science-based studies conducted in the Division's experimental laboratories (Coleman Building) centers on the regulation of tissue architecture and cellular composition, termed structural remodeling.  It focuses primarily on turnover of the extracellular matrix, the heart’s fibrillar collagen matrix, and myofibroblasts, phenotypically transformed fibroblasts integral to fibrous tissue formation.  Our findings have challenged long-held dogma that infarct scar is dead tissue.  Instead, we now know that the infarct scar is a dynamic tissue with resident, metabolically-active myofibroblasts nourished by a neovasculature.  Where they come from and what we should do about them are ongoing questions.

A second major theme addresses the integrative physiology that accompanies aldosteronism in rats.  This includes:  pathophysiologic responses leading to the induction of oxidative stress; an immunostimulatory state involving circulating lymphocytes and monocytes; and a wasting of soft tissues and bone.  An interdisciplinary team of basic and applied scientists working together in a culture of cooperation and common purpose to unravel the mysteries responsible for the appearance of the systemic illness that accompanies aldosteronism, an integral feature of the complex neurohormonal profile found in human CHF.

A third theme addresses the identification of components to a mitochondriocentric pathway to cardiomyocyte necrosis and subsequent replacement fibrosis, or scarring.  This includes:  the role played by calcium overloading of the subsarcolemmal population of cardiac mitochondria; the induction of oxidative stress in these organelles which overwhelms endogenous antioxidant defenses provided largely by Zn2+- and Se2+-based metalloenzymes; and the opening of the mitochondria’s inner membrane permeability transition pore.  Mitochondria-targeted interventions which may serve as cardioprotective strategies are under investigation.

Clinical Science

Clinical investigations, conducted at the Regional Medical Center, the VAMC, and the Methodist University Hospital, broadly focus on the pathogenic origins, the pathophysiologic expressions and management of chronic heart failure.  Several areas of interest are highlighted here.  First, the cellular origins and management of cytokine imbalance that contributes to generalized wasting, termed cardiac cachexia, and which includes a loss of bone mineral density as well as lean body and fat mass.  Cells responsible for the cytokine “storm” seen in heart failure have not been identified.  Challenging current wisdom and the heart’s role in their production, we have targeted cells of the monocyte-phagocyte system for investigation.  Novel management strategies have been targeted to interrupt proinflammatory cytokine production and reverse wasting.  Second, the relationship between heart failure (whether mild or severe), plasma cytokines, and reduced bone mineral density.  Third, our search for a “physiologic diuretic” to overcome avid sodium retention that characterizes advanced heart failure and which would prove useful in its home management.  This includes specific projects that address the utility of the following to enhance sodium excretion:  timed recumbency, with and without loop diuretic; and support stockings.  Each project is based on promoting more favorable relationships between effector hormones of the renin-angiotensin-aldosterone system and the heart’s family of natriuretic peptides.

The importance of cation dyshomeostasis in CHF, including K+, Mg2+, Ca2+ and Zn2+, are also under investigation, together with macro- and micronutrient deficiencies that include hypovitaminosis D.  The impact of hypokalemia, ionized hypcalcemia and hypomagnesemia, and hypozincemia on the heart, its repolarization and the propensity for supra- and ventricular arrhythmias are currently under investigation in patients with CHF or acute bodily injury.

Below is a listing of recent publications in basic and applied research in heart failure.

  1. Zia AA, Komolafe BO, Moten M, Ahokas RA, McGee JE, Rosenberg EW, Bhattacharya SK, Weber KT. Supplemental vitamin D and calcium in the management of African-Americans with heart failure having hypovitaminosis D. Am J Med Sci 2011;341:113-118. PMID: 21239963
  2. Shahbaz AU, Zhao T, Zhao W, Johnson PL, Ahokas RA, Bhattacharya SK, Sun Y, Gerling IC, Weber KT. Calcium and zinc dyshomeostasis during isoproterenol-induced acute stressor state. Am J Physiol Heart Circ Physiol 2011;300:H636-H644. PMID: 21076021
  3. Shahbaz AU, Kamalov G, Zhao W, Zhao T, Johnson PL, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC, Weber KT. Mitochondria-targeted cardioprotection in aldosteronism. J Cardiovasc Pharmacol 2011;57:37-43. PMID: 20966765
  4. Kamalov G, Ahokas RA, Zhao W, Zhao T, Shahbaz AU, Johnson PL, Bhattacharya SK, Sun Y, Gerling IC, Weber KT. Uncoupling the coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria seen in aldosteronism. J Cardiovasc Pharmacol 2010;55:248-254. PMID: 20051880
  5. Kamalov G, Ahokas RA, Zhao W, Johnson PL, Shahbaz AU, Bhattacharya SK, Sun Y, Gerling IC, Weber KT. Temporal responses to intrinsically coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria during aldosteronism. Am J Physiol Heart Circ Physiol 2010;298:H385-H394. PMID: 19915175
  6. Battin DL, Ali S, Shahbaz AU, Massie JD, Munir A, Davis RC, Jr., Newman KP, Weber KT. Hypoalbuminemia and lymphocytopenia in patients with decompensated biventricular failure. Am J Med Sci 2010;339:31-35. PMID: 20057275
  7. Weber KT, Weglicki WB, Simpson RU. Macro- and micronutrient dyshomeostasis in the adverse structural remodeling of myocardium. Cardiovasc Res 2009;81:500-508. PMID: 18835843
  8. Shook MS, Zafarullah H, Nelson MD, Bhattacharya SK, Davis RC, Newman KP, Weber KT. Normoglycemia in nondiabetic African Americans hospitalized with heart failure. Am J Med Sci 2009;338:255-258. PMID: 19707112
  9. Kamalov G, Deshmukh PA, Baburyan NY, Gandhi MS, Johnson PL, Ahokas RA, Bhattacharya SK, Sun Y, Gerling IC, Weber KT. Coupled calcium and zinc dyshomeostasis and oxidative stress in cardiac myocytes and mitochondria of rats with chronic aldosteronism. J Cardiovasc Pharmacol 2009;53:414-423. PMID: 19333130
  10. Dishmon DA, Dotson JL, Munir A, Nelson MD, Bhattacharya SK, D’Cruz IA, Davis RC, Jr., Weber KT. Hypovitaminosis D and valvular calcification in patients with dilated cardiomyopathy. Am J Med Sci 2009;337:312-316. PMID: 19322068
  11. Ali S, Shahbaz AU, Nelson MD, Shirwany A, Munir A, D’Cruz IA, Weber KT. Reduced relative lymphocyte count in African-Americans with decompensated heart failure. Am J Med Sci 2009;337:156-160. PMID: 19174692
  12. Zafarullah H, Shahbaz AU, Alturkmani R, LaGuardia SP, Paulus BM, Battin DL, Afzal MO, Davis RC, Smith JL, Weber KT. Elevated serum cobalamin in patients with decompensated biventricular failure. Am J Med Sci 2008;336:383-388. PMID: 19011393
  13. Selektor Y, Parker RB, Sun Y, Zhao W, Bhattacharya SK, Weber KT. Tissue 65zinc translocation in a rat model of chronic aldosteronism. J Cardiovasc Pharmacol 2008;51:359-364. PMID: 18427278
  14. Selektor Y, Ahokas RA, Bhattacharya SK, Sun Y, Gerling IC, Weber KT. Cinacalcet and the prevention of secondary hyperparathyroidism in rats with aldosteronism. Am J Med Sci 2008;335:105-110. PMID: 18277117
  15. Gandhi MS, Deshmukh PA, Kamalov G, Zhao T, Zhao W, Whaley JT, Tichy JR, Bhattacharya SK, Ahokas RA, Sun Y, Gerling IC, Weber KT. Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism. J Cardiovasc Pharmacol 2008;52:245-252. PMID: 18806605
  16. Carbone LD, Rosenberg EW, Tolley EA, Holick MF, Hughes TA, Watsky MA, Barrow KD, Chen TC, Wilkin NK, Bhattacharya SK, Dowdy JC, Sayre RM, Weber KT. 25-Hydroxyvitamin D, cholesterol, and ultraviolet irradiation. Metabolism 2008;57:741-748. PMID: 18502255
  17. Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ, Dhawan S, Khan BQ, Gupta M, Ahmad K, Khouzam RN, Dishmon DA, Nesheiwat JP, Hajjar MA, Chishti WA, Nasser W, Khan M, Womack CR, Cho T, Haskin AR, Weber KT. Fracture risk in men with congestive heart failure. Risk reduction with spironolactone. J Am Coll Cardiol 2008;52:135-138. PMID: 18598893
  18. Alsafwah S, LaGuardia SP, Nelson MD, Battin DL, Newman KP, Carbone LD, Weber KT. Hypovitaminosis D in African Americans residing in Memphis, Tennessee with and without heart failure. Am J Med Sci 2008;335:292-297. PMID: 18414068
  19. Ahmad K, Gandhi MS, Smith WC, Weber KT. Bilateral pleural effusions in congestive heart failure. Am J Med Sci 2008;335:484-488. PMID: 18552580
  20. Thomas M, Vidal A, Bhattacharya SK, Ahokas RA, Sun Y, Gerling IC, Weber KT. Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone. Am J Physiol Heart Circ Physiol 2007;293:H2361-H2366. PMID: 17616752
  21. Zhao W, Ahokas RA, Weber KT, Sun Y. ANG II-induced cardiac molecular and cellular events: role of aldosterone. Am J Physiol Heart Circ Physiol 2006;291:H336-H343. PMID: 16489102
  22. Vidal A, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC, Weber KT. Calcium paradox of aldosteronism and the role of the parathyroid glands. Am J Physiol Heart Circ Physiol 2006;290:H286-H294. PMID: 16373592
  23. LaGuardia SP, Dockery BK, Bhattacharya SK, Nelson MD, Carbone LD, Weber KT. Secondary hyperparathyroidism and hypovitaminosis D in African-Americans with decompensated heart failure. Am J Med Sci 2006;332:112-118. PMID: 16969139
  24. Khouzam RN, Nelson MD, Klemis JE, Wall BM, Mangold TA, Weber KT. Effect of timed semi-recumbency and furosemide dosing on urinary sodium excretion in patients with compensated heart failure. Am J Med Sci 2006;332:1-5. PMID: 16845234
  25. 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;331:30-34. PMID: 16415661
  26. 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 2006;332:73-78. PMID: 16909053
  27. Arroyo M, LaGuardia SP, Bhattacharya SK, Nelson MD, Johnson PL, Carbone LD, Newman KP, Weber KT. Micronutrients in African-Americans with decompensated and compensated heart failure. Transl Res 2006;148:301-308. PMID: 17162251
  28. Wang B, Ansari R, Sun Y, Postlethwaite AE, Weber KT, Kiani MF. The scar neovasculature after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 2005;289:H108-H113. PMID: 15722410
  29. Runyan AL, Sun Y, Bhattacharya SK, Ahokas RA, Chhokar VS, Gerling IC, Weber KT. Responses in extracellular and intracellular calcium and magnesium in aldosteronism. J Lab Clin Med 2005;146:76-84. PMID: 16099237
  30. 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. PMID: 16020992
  31. Law PH, Sun Y, Bhattacharya SK, Chhokar VS, Weber KT. Diuretics and bone loss in rats with aldosteronism. J Am Coll Cardiol 2005;46:142-146. PMID: 15992648
  32. Kamalov G, Varma BR, Lu L, Sun Y, Weber KT, Guntaka RV. Expression of the multifunctional Y-box protein, YB-1, in myofibroblasts of the infarcted heart. Biochem Biophys Res Commun 2005;334:239-244. PMID: 16002047
  33. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, Weber KT. Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 2005;111:871-878. PMID: 15710759
  34. Campos PC, D’Cruz IA, Johnson LS, Malhotra A, Ramanathan KB, Weber KT. Functional valvular incompetence in decompensated heart failure. Noninvasive monitoring and response to medical management. Am J Med Sci 2005;329:217-221. PMID: 15894862
  35. 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;111:51-57. PMID: 15611366
  36. Sun Y, Zhang J, Lu L, Bedigian MP, Robinson AD, Weber KT. Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart. J Lab Clin Med 2004;143:41-51. PMID: 14749684
  37. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, Weber KT. Loss of bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ Physiol 2004;287:H2023-H2026. PMID: 15475529
  38. Gerling IC, Sun Y, Ahokas RA, Wodi LA, Bhattacharya SK, Warrington KJ, Postlethwaite AE, Weber KT. Aldosteronism: an immunostimulatory state precedes the proinflammatory/fibrogenic cardiac phenotype. Am J Physiol Heart Circ Physiol 2003;285:H813-H821. PMID: 12860567
  39. Ahokas RA, Warrington KJ, Gerling IC, Sun Y, Wodi LA, Herring PA, Lu L, Bhattacharya SK, Postlethwaite AE, Weber KT. Aldosteronism and peripheral blood mononuclear cell activation. A neuroendocrine-immune interface. Circ Res 2003;93:e124-e135. PMID: 14576195
  40. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart. Role of oxidative stress. Am J Pathol 2002;161:1773-1781. PMID: 12414524

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