Abstract 487: Cardiac Sympathetic Afferent Denervation Improves Cardiac Inflammation and Ameliorates Cardiac Remodeling in Post-MI Rats

Abstract

A recent study from our laboratory demonstrated that chronic and selective cardiac sympathetic afferent denervation at the time of myocardial infarction (MI) by epicardial application of resiniferatoxin (RTX), a neuronal toxin capable of inducing rapid degeneration of transient receptor potential vanilloid 1 (TRPV1)-expressing afferent neurons and fibers, largely prevented the deleterious cardiac remodeling process 9-11 weeks post-MI. This included reduced cardiac hypertrophy, fibrosis and apoptosis. Here, we further investigated the effect of epicardial application of RTX during MI on cardiac extracellular matrix (ECM) remodeling at 10 weeks post-MI. Echocardiographic and morphologic data demonstrated that, compared to MI+vehicle, MI+RTX exhibited a significantly slower LV chamber dilation (6-week echocardiographic data: left ventricular end-diastolic diameter, 10.7 ± 0.2 vs. 9.6 ± 0.3 mm; left ventricular end-systolic diameter: 8.8 ± 0.2 vs. 7.8 ± 0.3 mm; MI+vehicle vs. MI+RTX, n=18, P<0.05). To further explore its molecular mechanism, we used zymography to evaluate the effect of RTX application on the matrix metalloproteinase (MMP) activity, which is responsible for degrading ECM and cardiac dilation after MI. Our preliminary data show that MMP9 activity was increased by 3.9 times in the peri-infarct myocardium post-MI compared to sham. This was largely abolished by RTX application (peri-infarct area: 3.9 ± 0.5 vs. 1.7 ± 0.4, MI+vehicle vs. MI+RTX, n=3, p=0.03). We further investigated the effect of RTX application on MI-induced cardiac inflammation, which has been reported as an upstream mechanism triggering MMP activation post-MI. Our data show that cardiac TNF alpha levels are markedly increased in the peri-infarct or remote myocardium of post-MI rats, which was largely abolished by RTX application during MI (TNF alpha levels in peri-infarct area: 214.2 ± 13.1 vs. 647.5 ± 45.1 vs. 357.3 ± 25.4 pg/mg protein, sham+vehicle vs. MI+vehicle vs. MI+RTX, n=5/each, p<0.05). These data suggest that cardiac sympathetic afferent denervation during MI exerts a local anti-inflammatory effect and reduces the ECM remodeling by preventing excessive MMP activation in post-MI rats.