Maintenance of sufficient cardiac output to provide the body and the heart itself with nutrients and oxygen is a must to sustain life. To accomplish increase output, heart rate goes up significantly, and the specific force generated by the myocardium increases as well, boosting stroke volume. The latter phenomenon is known as the force-frequency relationship (FFR). In recent studies we observed that in rabbits, which display a similar FFR behavior as humans, not only is calcium handling involved in the FFR but post-translational modification of myofilament proteins occurs too, resulting in a frequency-dependent decrease in myofilament calcium sensitivity. This latter finding can at least partially explain the increased contractile kinetics, and explains how the heart can maintain a low diastolic tension despite significantly elevated intracellular calcium levels that prevail at high pacing rates, and may also play a prominent role in the FFR. In heart failure, the positive FFR is severely blunted or even becomes negative, and relaxation is impaired, these are classic hallmarks of this disease. A further understanding of frequency-dependent myofilament processes and modification is therefore paramount in understanding cardiac pathophysiology. Several central questions remain to be resolved in this emerging field. What is the relative contribution of the calcium transient and myofilament properties on frequency-dependent force and kinetics? What are the kinases involved, and what are the myofilament targets of these kinases regarding the FFR? To what extent are the myofilament-based contributions different in hypertrophy and heart failure? What is the sequence of events that leads to the disease's phenotype? Based on our previous work and current preliminary experiments, we have formulated the hypothesis that myofilament-based frequency-dependent regulation is mediated via kinase-mediated phosphorylation, and that this process is deranged in hypertrophy and heart failure. We will address our hypothesis in two rabbit model that exhibits FFR behavior very close to human in both aspects of calcium handling and myofilament composition and properties, as well as in non-failing and failing human tissue via 4 specific aims: 1) Dissect the temporal resolution of the force-frequency relationship, 2) Mechanistically dissect the myofilament-based protein targets and kinase-dependent process that are involved in the FFR. 3) Assess alterations in frequency- dependent activation in human heart failure tissue, and in a rabbit model of hypertrophy, and 4) Correlate and dissect functional and molecular changes in the FFR during the transition from healthy to failing myocardium in a novel muscle culture system. Combined, the outcome of this study will provide critical new information on a central deficit in function in patients with heart failure, and will allow us to strategize future treatment options.
In a healthy human being when the heart rate increases during activity, the heart does not only beat faster, it also bets stronger and faster. This response is significantly impaired in patients with heart failure;their heart has lost the abilityto beat significantly stronger and faster, and this loss is a hallmark of the disease. In this study, e aim to unravel the molecular processes involved in the regulation of heart-rate-dependent strength and speed. In both rabbits that have a very similar rate-dependent regulation of contraction and relaxation, as well as in muscle tissue obtained from end-stage failing human hearts, we will investigate the contribution of myofilament protein phosphorylation on rate-dependent processes. The completion of this study will go a long way in understanding rate-dependent activation in health and disease, and will provide critical new information that can be used to strategize future treatment options.
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