Hypertension-induced heart failure disrupts cardiac sympathetic innervation

About 26 million people worldwide live with heart failure (HF), and hypertension is the primary cause in 25% of these cases. Autonomic dysfunction and sympathetic hyperactivity accompany cardiovascular diseases, including HF. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in hypertension-induced HF. Male and female C57BL6/J mice were infused with angiotensin II (ANG II) for 4 wk to generate hypertension leading to HF; controls were infused with saline. ANG II-treated mice displayed HF phenotype, including reduced cardiac function, hypertrophy, and fibrosis. ANG II-treated mice also had significantly reduced sympathetic nerve density in the left ventricle, intraventricular septum, and right ventricle. In the left ventricle, the subepicardium remained normally innervated, whereas the subendocardium was almost devoid of sympathetic nerves. Loss of sympathetic fibers led to loss of norepinephrine content in the left ventricle. Several potential triggers for axon degeneration were tested and ruled out. ANG II-treated mice had increased premature ventricular contractions after isoproterenol and caffeine injection. Although HF can induce a cholinergic phenotype and neuronal hypertrophy in stellate ganglia, ANG II treatment did not induce a cholinergic phenotype or activation of trophic factors in this study. Cardiac neurons in the left stellate ganglion were significantly smaller in ANG II-treated mice, whereas neurons in the right stellate were unchanged. Our findings show that ANG II-induced HF disrupts sympathetic innervation, particularly in the left ventricle. Further investigations are imperative to unveil the mechanisms of denervation in HF and to develop neuromodulatory therapies for patients with autonomic imbalance.NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension leads to a heart failure phenotype and cardiac sympathetic denervation with the endocardial region of the left ventricle being the most affected. Denervation is accompanied by loss of norepinephrine content in the left ventricle and increased premature ventricular contractions (PVCs) after isoproterenol and caffeine injection. ANG II treatment also causes morphological changes in cardiac-projecting left stellate ganglion neurons.