TY - JOUR
T1 - Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy
AU - Dajani, Al Hassan J.
AU - Liu, Michael B.
AU - Olaopa, Michael A.
AU - Cao, Lucian
AU - Valenzuela-Ripoll, Carla
AU - Davis, Timothy J.
AU - Poston, Megan D.
AU - Smith, Elizabeth H.
AU - Contreras, Jaime
AU - Pennino, Marissa
AU - Waldmann, Christopher M.
AU - Hoover, Donald B.
AU - Lee, Jason T.
AU - Jay, Patrick
AU - Javaheri, Ali
AU - Slavik, Roger
AU - Qu, Zhilin
AU - Ajijola, Olujimi A.
N1 - Publisher Copyright:
© 2023, Dajani et al.
PY - 2023
Y1 - 2023
N2 - 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 [11C]meta-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.
AB - 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 [11C]meta-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.
UR - http://www.scopus.com/inward/record.url?scp=85178369874&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.157956
DO - 10.1172/jci.insight.157956
M3 - Article
C2 - 37815863
AN - SCOPUS:85178369874
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 22
M1 - e157956
ER -