Heart failure (HF) is defined as the condition where the heart is unable to pump enough blood to adequately perfuse the body, often due to (1) failure to contract properly and/or (2) failure to fill with enough blood. Symptoms include shortness of breath, fatigue, and fluid overload. Despite advancements in the field, novel therapeutics have yet to be successful. Although there have been numerous technological advances and knowledge gained over the past few decades, the mechanism underlying one of the earliest and most fundamental observations in nearly all patients, the inability of the heart to relax after an increase in physical activity also known as the impairment of the frequency-dependent acceleration of relaxation (FDAR), still eludes researchers. The long-term objective is to fill the critical gap in the current knowledge of the mechanistic underpinnings involving the impairment of FDAR in the failing heart to elucidate possible drug targets and to drive a more targeted drug discovery and development process. Our hypothesis is that impairment of FDAR in the failing human heart is primarily due to alterations in the phosphorylation status of proteins regulating myofilament calcium sensitivity and that this process involves protein phosphatase 2A (PP2A). We have built a physiological setup that allows for freezing of actively contracting human cardiac tissue. Using this setup and protein analysis techniques such as Western blotting and mass spectrometry, in specific aim 1, we will compare the effect of frequency modulation and beta-adrenergic stimulation on phosphoproteins involved in myofilament calcium sensitivity, focusing on the alterations found in end-stage human HF. In specific aim 2, we will determine whether PP2A is involved in this process. Successful completion of this project will begin to reveal the underlying mechanism involving impairment of FDAR, a basic pathophysiological feature of human HF.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 06/30/2022|