The cardiac sympathetic nervous system (SNS) exerts profound influence on
ventricular myocardial excitability. Disturbances in excitability result in ventricular arrhythmias (VAs). Remodeling of cardiac SNS is associated with risk of VAs, however the mechanistic underpinnings of this relationship remain poorly understood.
To characterize structural intra-cardiac (ventricular) SNS remodeling (ICNR),
ventricular myocardium from humans and porcine with ischemic or non-ischemic cardiomyopathy (ICM and NICM respectively), and normal controls (CON) of both species were subjected to detailed histologic and immuno-histochemical (IHC) analyses. Similarly, structural characterization of extra-cardiac neural remodeling (ECNR) within left and right stellate ganglia (LSG and RSG respectively) were performed using histologic and IHC methods to determine neuronal characteristics in normal vs. ICM and NICM. Lastly, the functional consequences of ICNR and ECNR were studied in porcine with myocardial infarcts (MI), and compared to CON.
In myocardium, structural sympathetic nerve remodeling consists of increased
sympathetic nerve density at border-zones of scar and normal myocardium. In stellate ganglia of humans with ICM and NICM (and porcine with MI), neuronal size was significantly increased. LSG and RSG from porcine with MI, also showed a decrease in the percentage of non-adrenergic neurons, compared to CON, indicating that ECNR also consisted of a shift from non-adrenergic to adrenergic phenotypes. Functional mapping of myocardial activation recovery intervals (ARIs), an accepted surrogate for action potential duration (APD) in normal porcine hearts showed that RSG innervation predominated on the anterior wall, while LSG innervation predominated on the posterior wall. After MI, ICNR and ECNR resulted in loss of innervation patterns seen in normal. Further, dispersion of repolarization (DOR) was increased in the infarct and border zone
regions of infarcted porcine compared to other cardiac regions, but this was not the case in CON. In addition, global DOR (including or excluding the infarct zones) was greater in the hearts of infarcted animals compared to normal controls.
In conclusion, following MI significant remodeling of stellate ganglion neurons,
and nerve terminals within the heart occurs. This results in significant functional alteration of innervation patterns, and worsening of repolarization heterogeneity. These mechanisms partly explain the association between SNS remodeling and arrhythmogenesis.