Doctor of Philosophy, The Ohio State University, 2018, Biomedical Sciences

Heart disease is the leading cause of death in the United States. Heart failure is a disease in which the heart fails to pump sufficient amount of blood to the body. It is a serious health burden that claims the lives of 58,000 Americans per year with a grim 5-year mortality rate of 50%. Over the years, the field of cardiovascular medicine has produced improved treatment options for patients with heart failure, such as beta blockers and angiotensin converting enzyme (ACE) inhibitors. However, the field has not yet been able to produce treatments to reverse the pathophysiology of heart failure, as the mechanism of disease has not been fully elucidated. We have obtained human non-failing and failing hearts and isolated intact trabeculae from left and right ventricle. We first utilized right ventricular intact trabeculae to characterize baseline twitch force and kinetics and found that non-failing and failing trabeculae do not have different developed force or contraction kinetics. However, failing trabeculae had slower relaxation kinetics. In addition, we found evidence that suggests trabeculae from males trend towards having greater developed force compared to trabeculae from females. After baseline twitch characterization, we investigated changes in their contractile and relaxation capacities at different lengths, stimulation frequencies, and beta-adrenergic activation levels. We found that length-dependent activation is present in both non-failing and failing trabeculae. Moreover, the slowing of contraction and relaxation kinetics at longer lengths was observed in both non-failing and failing trabeculae. Non-failing trabeculae exhibited positive force-frequency relationship, meaning that their developed force increases as stimulation frequency is increased. On the other hand, failing trabeculae displayed negative force-frequency. Upon maximal beta-adrenergic stimulation, developed force was increased by ~ 5 fold in non-failing trabeculae and ~3 fold in failing t (open full item for complete abstract)

Committee: Paul Janssen (Advisor); Jonathan Davis (Committee Member); Bryan Whitson (Committee Member); Noah Weisleder (Committee Member) Subjects: Biomedical Research; Biophysics; Medicine

Doctor of Philosophy, The Ohio State University, 2008, Integrated Biomedical Sciences

Heart failure is the leading cause of death in much of the western world. Progressive deterioration of cardiac contractility and/or relaxation, resulting in cardiac output below metabolic demands is the central theme in heart failure. Although treatments are improving, we still do not have a full understanding of the fundamental pathophysiology that impairs contractility and relaxation. The force frequency relationship (FFR) is ubiquitously altered in failing myocardium regardless of the etiology. The FFR, which is normally positive (greater contractile force at higher contraction frequency) in healthy myocardium, is blunted, flat, or negative in dysfunctional myocardium. While the FFR has been studied extensively, the role myofilament properties play in this effect is unknown. To address deficiencies in our understanding of cardiac contraction, we worked from the following hypothesis: Alterations in myofilament calcium sensitivity significantly contribute to blunted force frequency response, contractile dysfunction, and impairment of myocardial relaxation of failing myocardium. First, we set out to develop a method which would enable quantitative analysis of shifts in myofilament calcium sensitivity due to changes in frequency in isolated, yet intact muscles at physiologic temperature. We found that we could induce slowly forming contractures by superfusing the intact isolated rat trabeculae with a solution of high potassium and lower sodium. The contractures allowed for development of a myofilament calcium sensitivity curve sensitive to interventions known to shift myofilament calcium sensitivity (beta adrenergic simulation and pH). We then aimed at determining if myofilament calcium sensitivity shifted with changes in frequency. We found that myofilament calcium sensitivity did decrease with frequency in intact rabbit trabeculae. This effect correlated with an increase in the phosphorylation status at Troponin I and Myosin Light Chain-2, as well as relaxation acc (open full item for complete abstract)

Committee: Paul M.L. Janssen PhD (Advisor); Jack Rall PhD (Committee Member); William Carson MD (Committee Member); David Feldman MD,PhD (Committee Member); George Billman PhD (Committee Member) Subjects: Health