Aging is associated with more than a ten-fold increase in the incidence of sudden cardiac death (SCD). This multi-PI proposal brings together two investigators with very different but complementary areas of expertise to investigate the role of fibroblast senescence in the increased fibrosis and abnormal electrical activity found in SCD. The Koren laboratory has developed a minimally invasive myocardial infarction (MI) model in aged rabbits that exhibits increased incidence of SCD and closely recapitulates human pathophysiology. The Sedivy laboratory has developed biomarkers and genetically manipulated mice to study cellular senescence in vitro and in vivo. We propose that the interplay between aging cardiomyocytes (CMs) that have a lower threshold for arrhythmogenic activity, and the increased fibrosis in the infarct border zone (IBZ) that slows the conduction of electrical impulses, are the two main elements that promote the initiation of triggered activity and its spread to the rest of the heart, leading to SCD. We hypothesize that cellular senescence of cardiac fibroblasts (CFs) plays a key role in post-myocardial infarction (MI) wound healing processes. We postulate that aging results in changes that modify the senescence response of CFs, leading to excess fibrosis after MI.
In Aim 1 the Koren laboratory will create MI by implanting a coil in the circumflex coronary artery and monitor the rabbits for spontaneous and inducible arrhythmias. The hearts will be optically mapped ex vivo to study action potential dispersion, conduction velocities and blocks in the IBZ, triggered activity, and heterogeneities in electrical and mechanical restitution at the IBZ and remote zones (RZ). CMs cultured from the IBZ and RZ will be studied for changes in action potential durations (APDs), depolarizing and repolarizing currents, calcium dynamics and triggered activity.
In Aim 2 the Sedivy laboratory will use mouse models to specifically focus on fibrosis, and its regulation by the senescence of CFs. CFs will be cultured from the IBZ and RZ after MI and investigated in vitro for a variety of senescence markers, regulation of the senescence response, and phenotypes elicited in senescent cells. Corresponding tissue specimens will be investigated for evidence of these processes in vivo. Young and old animals of both species will be studied. Senescence will be manipulated in vivo using genetic (transgenic mice) and pharmacological (drugs that promote senescence) approaches. Recent work on liver, cutaneous and post-MI wound healing suggests that senescence normally limits fibrosis. Hence, we postulate that accelerating senescence will reduce fibrosis, which should have a beneficial effect by alleviating SCD. In summary, we envision that by understanding and controlling the cellular senescence mechanisms we will be able to reduce the aging fibrotic response and alleviate the propensity for arrhythmogenesis.
Sudden cardiac death (SCD) causes 20% of deaths in industrialized countries, and aging is associated with a greater than ten-fold increase in the incidence of SCD. This proposal will investigate the innovative hypothesis that cellular senescence of cardiac fibroblasts is causally involved in the excessive fibrosis of the aging heart, predisposing it to arrhythmogenesis which can lead to SCD. We envision that pharmacological manipulation of cellular senescence could lead to better management of heart fibrosis and hence alleviate subsequent progression to SCD.
