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Cardiac Myofilament Calcium Sensitivity in Health and Disease

Varian, Kenneth Dean
http://rave.ohiolink.edu/etdc/view?acc_num=osu1211898886

Abstract Details

2008, Doctor of Philosophy, Ohio State University, 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 acceleration. Using staurosporine (non-specific kinase inhibitor), we found inhibition of the myofilament calcium sensitivity shift between 1 and 4 Hz. To examine how inter-beat duration independent of posttranslational modifications occurs, we performed an analysis of twitch contractions in rabbit trabeculae stimulated randomly at 5 different cycle lengths; this was done in order to isolate the effect of cycle time on contractility and relaxation. We found that the primary cycle length correlated positively with force, while the secondary and tertiary cycle lengths correlated negatively with force. Finally, we set out to determine how frequency dependent modulations of force, relaxation, and myofilament calcium sensitivity differed in a model of right ventricular hypertrophy. We used pulmonary artery banded rabbits and examined twitch contractions, intracellular calcium, and myofilament calcium sensitivity (potassium contractures) at 1 through 4 Hz. We found that the shift in myofilament calcium sensitivity observed in control animals was nearly abolished in animals with right ventricular hypertrophy. This blunting of myofilament desensitization was accompanied by elevated diastolic force compared to controls, possibly reflecting some diastolic dysfunction in the hypertrophied tissue. In conclusion, myofilament calcium desensitization in response to elevated heart rate is a regulated, kinase specific effect that may be necessary to prevent insufficient diastolic filling at times of high heart rates.
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)
161 p.
Health
Cardiac; Heart Failure; Hypertrophy; Force Frequency Relationship; Myofilament Calcium Sensitivity

Recommended Citations

Citations

  • Varian, K. D. (2008). Cardiac Myofilament Calcium Sensitivity in Health and Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211898886

    APA Style (7th edition)

  • Varian, Kenneth. Cardiac Myofilament Calcium Sensitivity in Health and Disease. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1211898886.

    MLA Style (8th edition)

  • Varian, Kenneth. "Cardiac Myofilament Calcium Sensitivity in Health and Disease." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211898886

    Chicago Manual of Style (17th edition)

osu1211898886
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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.