Document Type


Degree Name



Oregon Health & Science University


Sympathetic nerve regeneration is common after peripheral injuries. A well documented example of this is sympathetic sprouting and reinnervation after chronic cardiac ischemia. Surprisingly though, following a more common cardiac injury, ischemia-reperfusion (I-R), the resulting infarcted myocardium remains denervated. The degree of sympathetic denervation after I-R has been identified as a sensitive predictor of secondary cardiac pathologies, including sudden cardiac death and arrhythmias. Given the prevalence of I-R and incidence of secondary cardiac pathologies following this type of injury, sympathetic denervation resulting from I-R has proven to be a considerable clinical issue. In order to understand why sympathetic regeneration fails following I-R, we examined the infarct for potential inhibitory components in the extracellular matrix. We found that chondroitin sulfate proteoglycans (CSPGs) were present in the infarct after I-R and that CSPGs caused inhibition of sympathetic axon outgrowth in vitro. Furthermore, in the absence of protein tyrosine phosphatase sigma (PTPσ), a receptor for CSPGs, sympathetic innervation was restored to the infarct in vivo. Due to the importance of sympathetic denervation in determining arrhythmia susceptibility, we wanted to examine the electrophysiological consequences of sympathetic reinnervation after I-R. We found that both the absence of PTPσ using transgenic animals and pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) restored sympathetic innervation to the scar and markedly reduced arrhythmia susceptibility. Using optical mapping, we observed increased dispersion of action potential duration, super-sensitivity to β-adrenergic receptor stimulation, 2 and Ca2+ mishandling following MI. However, sympathetic reinnervation prevented these changes and rendered hearts remarkably resistant to induced arrhythmias. This work is the first to show that sympathetic reinnervation is protective against electrophysiological remodeling and ventricular arrhythmias even in the presence of a scar. It also establishes Ca2+ mishandling as an important underlying mechanism to elevated arrhythmia susceptibility after I-R injury. More broadly, this works establishes PTPσ as a potential clinical target following a heart attack to protect the heart against arrhythmias and sudden cardiac death.




Neuroscience Graduate Program


School of Medicine



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