Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias

Abstract

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca2+ mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

The nervous heart

“…It is thought that increases in nerve growth factor (NGF) are primarily responsible for hyperinnervation (Cao et al, 2000a) and blocking NGF prevents nerve sprouting following MI (Hasan et al, 2006). Conversely, sympathetic denervation is also associated with ventricular arrhythmia (Boogers et al, 2010; Fallavollita et al, 2014) and occurs in MI, diabetic neuropathy, and heart failure (Gardner and Habecker, 2013; Gardner et al, 2015; Jacobson et al, 2010; Kimura et al, 2010). Interestingly, whereas NGF stimulates axon growth, its precursor, proNGF, triggers axon degeneration (Nykjaer et al, 2004) and may be involved in post-MI denervation (Siao et al, 2012).…”

“…This increase in circulating catecholamines coupled with localized β-AR supersensitivity may be particularly arrhythmogenic. For example, Gardner et al (2015) recently showed in a murine model that reperfused infarcts remain denervated and display β-AR supersensitivity, Ca2+ mishandling, and triggered arrhythmia in response to circulating β-AR agonists. Therefore, in much the same way that regional hyperinnervation and nerve sprouting lead to localized β-AR stimulation and triggered activity, denervation also leads to localized β-AR stimulation and triggered activity through localized supersensitivity.…”

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death

“…30 Denervation of myocardium increases beta adrenergic sensitivity, calcium mishandling, and APD dispersion. 50,51 …”

“…61 When this paired binding is prevented with intracellular sigma peptide, sympathetic innervation is restored and arrhythmia susceptibility is reduced. 51 In summary, pathologic patterns of denervation predispose to sudden death by creating proarrhythmic substrate. Understanding this pathophysiology has led to a few promising therapeutic molecular targets that focus on modulating re-innervation at the level of myocardium.…”

“…64 Restoring appropriate re-innervation of the scar has been shown to decrease arrhythmias in a mouse model of myocardial infarction. 51 Therefore, agents that promote homogeneous reinnervation may serve as an important cornerstone in autonomic clinical therapeutics.…”