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Derangements in cardiac efferent control post-myocardial infarction

      Background: Myocardial infarction (MI) increases the risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. We have used transgenic mice to investigate the mechanisms triggering axon degeneration and preventing axon regeneration following ischemia-reperfusion (I-R). Previous studies showed that the loss of peri-infarct nerves after cardiac I-R is triggered by activation of the p75 neurotrophin receptor (P75NTR). Results: Our new data indicate that peri-infarct axon degeneration occurs via P75NTR induction of TACE (TNF α converting enzyme/ADAM 17) and can be blocked by inhibiting TACE cleavage of p75NTR. In contrast to the p75NTR-dependent loss of peri-infarct axons after I-R, sustained denervation of the infarct and borderzone is due to the presence of chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. CSPGs prevent sympathetic axon growth by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Removing PTPσ promotes sympathetic reinnervation of the infarct and borderzone and markedly reduces arrhythmia susceptibility. Using optical mapping we observed increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation, and Ca2+ mishandling following MI. Sympathetic reinnervation prevented these changes and rendered hearts remarkably resistant to induced arrhythmias. Conclusion: Sympathetic denervation increases arrhythmia susceptibility after MI by disrupting calcium handling in cardiac myocytes and increasing sensitivity to beta receptor stimulation.
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