October 10, 2023Open Access

Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy

Q: What is the clinical evidence from this study?

Study design: Other. Population: Dilated cardiomyopathy (n=116). Intervention: Dilated cardiomyopathy vs. Healthy controls. Primary outcome: Transmural sympathetic innervation gradients and ventricular arrhythmogenesis.

ADAl-Hassan DajaniUniversity of California, Los Angeles MLMichael B. LiuMayo Clinic in Arizona MOMichael A. OlaopaUCLA Health

Key Result

Dilated cardiomyopathy induces heterogeneous transmural sympathetic innervation gradients that synergistically promote ventricular arrhythmogenesis.

PICO

Population

105 mice aged 6-12 weeks and 11 human postmortem samples were analyzed to evaluate the impact of sympathetic innervation gradients on arrhythmogenesis in dilated cardiomyopathy.

Exposure / Comparator

Dilated cardiomyopathy vs Healthy controls

Primary Outcome

Transmural sympathetic innervation gradients and ventricular arrhythmogenesis

Limitations

Murine pathophysiology and electrophysiology might incompletely translate to humans.
The study demonstrates an association and not a causal link between myocardial sympathetic innervation gradients and arrhythmogenesis.
Only one geometry of anatomical ventricle was simulated in the computer models.
The adrenergic surge was modeled by ramping up ICaL without any other effects.
Arrhythmia provocation studies relied on norepinephrine injections, reflecting adrenergic receptor sensitivity rather than direct nerve alteration.

Abstract

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog 11Cmeta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Ask AI

Helpful

Bookmark

View Full Paper