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Functional Remodeling Following Myofilament Calcium Sensitization in Rats with Volume Overload Heart Failure

Lewis, Kristin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058520

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Hemodynamic volume overload (VO) is characterized by left ventricular (LV) dilation, progressive LV dysfunction, and heart failure (HF). In the aortocaval fistula (ACF) model of VO HF, LV dysfunction is accompanied by a variety of changes at the myocyte level including myofilament proteins including decreased a-to-ß-myosin heavy chain (MHC) expression, decreased myofilament Ca2+ sensitivity and altered regulation of intercalated disc proteins involved in electromechanical coupling. While pharmacologic therapy alone cannot resolve the hemodynamic overload in human patients or in animal models, pre-operative pharmacologic therapy may delay time to surgical intervention, and post-operative pharmacologic therapy may accelerate functional recovery. Current therapies that target neurohormonal pathway activation provide some relief but do not reverse the decreased cardiac contractility, the central feature of systolic HF. Targeting neurohormonal pathway activation can result in increased myocardial oxygen consumption and myocardial Ca2+ overload, and therefore it is necessary to investigate drugs that have alternative mechanisms of action. Levosimendan (Levo) stabilizes Ca2+-saturated troponin C (cTnC) prolonging its interaction with cardiac troponin I (cTnI), which promotes contractile force without increasing the intracellular Ca2+ transient amplitude or myocardial oxygen consumption. Given these overall factors, my hypothesis is that therapeutic strategies such as Levo that target myofilament Ca2+ sensitization will preserve/improve LV function in VO HF. To test this hypothesis, three specific aims were proposed: 1) determine if short-term Levo treatment would preserve/improve LV function in rats with ACF-induced pre-HF or reversed pre-HF (Chapter 2), 2) determine if Levo could improve the detrimental effects of delayed reversal (Chapter 3), and 3) determine if chronic Levo treatment would preserve LV function when initiated in rats with ACF-induced pre-HF or established HF (Chapter 4). Sham and ACF surgery were performed at Week 0 following by Levo treatment with and without hemodynamic load reduction surgery (reversal) at various timepoints. Continued Levo improved systolic and diastolic function regardless of the treatment starting point and hemodynamic load. Improved LV function variably correlated with increased myofilament Ca2+ sensitivity, cMyBP-C/cTnI phosphorylation and normalization of a-to-ß-MHC. Finally, speckle-tracking echocardiographic analysis suggests that Levo improves short-axis, but not long-axis function at end-stage HF. Because of the improved LV function with Levo, with and without hemodynamic load reduction, Levo offers a new therapeutic option in patients with VO HF. More broadly, therapeutic strategies targeting myofilament Ca2+ sensitization may provide a new therapeutic target for patients with volume overload heart failure.
Pamela Lucchesi, PhD (Advisor)
Christopher Breuer, MD (Committee Member)
Christopher Premanandan, DVM, PhD (Committee Member)
Lynette Rogers, PhD (Committee Member)
172 p.
Pharmacology; Physiology
Levosimendan; myosin heavy chain; myosin binding protein C; troponin I

Recommended Citations

Citations

  • Lewis, K. (2014). Functional Remodeling Following Myofilament Calcium Sensitization in Rats with Volume Overload Heart Failure [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058520

    APA Style (7th edition)

  • Lewis, Kristin. Functional Remodeling Following Myofilament Calcium Sensitization in Rats with Volume Overload Heart Failure. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058520.

    MLA Style (8th edition)

  • Lewis, Kristin. "Functional Remodeling Following Myofilament Calcium Sensitization in Rats with Volume Overload Heart Failure." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058520

    Chicago Manual of Style (17th edition)

osu1397058520
513
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.