Research

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 One Health, 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.