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On the Role of Heart Rate Variability and Pyruvate on Cardiac Contractility

Torres, Carlos Alexandre Andrade
http://rave.ohiolink.edu/etdc/view?acc_num=osu1398688195

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Biophysics.
There is a scarcity of inotropic therapies for the long term treatment of congestive heart failure. We examine the effect of beat-to-beat variability on contractility and investigate the inotropic mechanism of pyruvate on myocardial contractility. The specific hypothesis behind the research performed is that heart rate variability (HRV) plays an important role in maintaining normal cardiac contractility and that HRV can modulate contractility. We developed a model utilizing trabeculae at physiologic temperatures to investigate the frequency-dependence of HRV independent of previous loading conditions and define the load dependence of contractility during heart rate variability. First, we detected a slight positive increase in force indicating an effect of HRV in parts of the force frequency relationships (FFR) that are more concave or convex (i.e. non-linear). We also observed a positive tight correlation between inter-beat duration and strength of the following beat suggesting that HRV influences beat-to-beat contractile strength, independent of loading conditions. The variation in beat-to-beat duration correlated with variations in calcium transients. We then researched if these findings would translate to larger species closer to human myocardium. Cardiac trabeculae were isolated from the right ventricle of rabbits and dogs and a similar pacing protocol was imposed. We observed no change in force in dog and a nonsignificant decrease of force in rabbit. By applying a precisely timed stretch (preload) during the inter-beat period the correlation between pre beat duration and force was enhanced and the negative effect was reversed except for at the extreme stretch and frequency range for rabbit. We propose that these species differences are due to the distinct handling of EC coupling and calcium regulation and to different myosin heavy chain isoform compositions. Pyruvate has cardioprotective and antioxidant properties that are ideal for many settings where traditional inotropes are fraught with undesirable effects. . We hypothesized that the majority of the inotropic effect of pyruvate was due to an increase in myofilament calcium sensitivity. By utilizing ultra-thin rabbit heart trabeculae and iontophoretic fluorescent methods we were able to characterize the effects of pyruvate on calcium transients and developed force and isolate them from those induced by pH changes. With sarcoplasmic reticulum (SR) block there was little change in systolic calcium (or calcium transient development) compared to the large change in force development (up to 200%) seen with infusion of pyruvate. Changes in [pH]i did not correlate with force and calcium changes. Pyruvate’s effect on myofilament calcium sensitivity was studied both by K+ contractures in intact trabeculae and by skinned fiber experiments. Pyruvate induced a leftward shift in the myofilament sensitivity curve in the intact trabeculae not reproduced in the skinned fiber experiments. Finally, we investigated the effects of pyruvate in pulmonary artery banded rabbits with right ventricular hypertrophy. We found a similar increase in force development and shift in myofilament calcium sensitivity. In conclusion, we demonstrate that a leftward shift in myofilament calcium sensitivity is an important mediator of the inotropic effect of pyruvate.
Paul Janssen, PhD (Advisor)
Mark Angelos, MD (Committee Member)
Jonathan Davis, PhD (Committee Member)
Peter Reiser, PhD (Committee Member)
128 p.
Biophysics; Medicine; Physiology
Heart Contractility; Pyruvate; Heart Rate Variability; Inotrope

Recommended Citations

Citations

  • Torres, C. A. A. (2014). On the Role of Heart Rate Variability and Pyruvate on Cardiac Contractility [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1398688195

    APA Style (7th edition)

  • Torres, Carlos. On the Role of Heart Rate Variability and Pyruvate on Cardiac Contractility. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1398688195.

    MLA Style (8th edition)

  • Torres, Carlos. "On the Role of Heart Rate Variability and Pyruvate on Cardiac Contractility." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1398688195

    Chicago Manual of Style (17th edition)

osu1398688195
269
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.