THE ROLE OF CARDIOMYOCYTE AND CARDIOFIBROBLAST SENESCENCE IN THE AGING HEART

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DESCRIPTION (provided by applicant): Accounting for approximately 50% of deaths related to heart disease, sudden cardiac death (SCD) is a leading cause of death in the United States; thus, understanding the mechanisms that underlie deadly arrhythmias that cause SCD could lead to preventative pharmacological and therapeutic strategies that would increase life expectancy and quality of life among a growing susceptible population. It is known that aging is associated with an increase of the incidence of SCD. Yet, much remains unknown about the mechanisms that underlie the age- related, proarrhythmic changes in the mammalian heart at the cellular and molecular level and how they are related to arrhythmogenesis and increased incidence of SCD. Thus far, we have conducted preliminary in vivo EP studies and optical mapping experiments that reveal an aging- related slowing of conduction through the His-Purkinje system and the ventricles. We have also shown an age-related increase in ventricular fibrillation inducibility, and I have performed Gomori trichrome staining on paraffin embedded sections, which revealed increased fibrosis in old hearts at the subepicardial region and between the fibers of the heart in the same area that showed slow conduction. Based on our preliminary data, I hypothesize that aging is not only associated with overall reduced cardiac function but also with the accumulation of senescent- like cardiomyocytes (CMs) and senescent cardiofibroblasts (CFs) in the cardiac muscle. Moreover, I postulate that the progressive senescence of CMs and CFs is associated with alterations in gene expression that will directly lead to abnormal myocyte contractility and abnormal cell excitation, as well as accelerated fibrosis. These alterations would lead to impaired cardiac contractility, a slowing of the conduction velocity, and a decrease in the threshold for induction of ventricular fibrillation. To that end, I am pursuing a multi-leveled approach to identify novel mechanisms that underlie malignant arrhythmias in the aging heart using comparisons between young and old rabbit cohorts, as well as comparisons among non- senescent, chronologically aged, and senescent cardiac cell populations. With a combination of in vivo and in vitro techniques (including invasive hemodynamics, immuoblotting/qPCR, immunofluorescence, flow cytometry, and single-cell calcium recordings), I hope to provide both biochemical and functional evidence revealing that cellular senescence underlies electrical and structural triggers and substrates for arrhythmias in the aging heart. PUBLIC HEALTH RELEVANCE: In the US, sudden cardiac death (SCD) accounts about 50% of deaths related to heart disease, so understanding what causes arrhythmias that lead to sudden death would allow for new ways to increase life expectancy and quality of life. We know that aging increases one's risk for SCD, so this study seeks to reveal the age-related changes in the heart that are related to increased incidence of SCD.