In human heart failure, patient-to-patient variability is extremely well known, but extremely understudied. Relaxation disorders and aberrant force-frequency relationship (FFR) are both primary hallmarks of heart failure, and thus it is critical we understand the actual individual's dysfunction of these two parameters. It is imperative that we understand the actual molecular events in an affected individual, and not the purported molecular events that are based on group averages, that are known to be incorrect. Since clinical assessment and treatment is done on the single individual level, in this cycle of the grant we will work from the governing hypothesis that understanding of patient-specific protein expression and post-translational modification will allow us to understand the patient-specific relaxation dysfunction and aberrant FFR in failing human myocardium. To correlate a patient-specific profile with relaxation and FFR dysfunction, we propose to complete the following aims; 1) Continue procurement of failing and non- failing human myocardium, and assess relaxation behavior and the force-frequency relationship, 2) To assess individual protein levels and PTMs involved in the tri-modal regulation of relaxation and frequency-dependent contractile activation in human myocardium. We will assess levels and post-translational modifications in calcium- handling proteins, proteins involved in myofilament calcium sensitivity, and proteins involved in cross-bridge cycling kinetics, and 3) To assess the level of correlation between protein expression patterns and myocardial relaxation and force-frequency behavior in non-failing and failing human myocardium. Direct linking patient-specific molecular events to the pathophysiological situation in that patient will allow to better focus and target treatment of this debilitating disease.
In patients with end-stage heart failure, relaxation disorders and the inability to pump stronger and faster with exercise are both primary hallmarks of this disease. It is imperative that we better understand the actual molecular events in an affected individual, and in this project we will correlate the patients' protein expression of the heart with the dysfunction in the same patient. We will obtain healthy and diseased human hearts, and will analyze relaxation function and exercise tolerance in the laboratory setting.
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