Catecholaminergic RVLM C1 neurons mediates heart failure decompensation and mortality during salt loading.

Heart failure (HF) is a complex clinical syndrome affecting over 37 million people worldwide. Although advances in medical therapy have significantly improve HF condition, morbidity and mortality rate are still high and global prevalence is continuously rising. Common clinical features of HF include cardiac sympathoexcitation and disordered breathing, which are strongly associated with poor survival of HF patients. Importantly, we have previously shown that brainstem pre-sympathetic neurons (C1) from the rostral ventrolateral medulla (RVLM), play a key role in sympathetic regulation in HF. However, the role played by RVLM-C1 neurons during heart failure decompensation is totally unknown. Accordingly, we aimed to determine the contribution of RVLM-C1 neurons on survival during HF decompensation. Adult male Sprague-Dawley rats underwent volume overload induce non-ischemic HF. After two weeks, anti-dopamine β-hydroxylase-saporin toxin (DβH-SAP: 2.5ng/150nl; or saline) was bilaterally injected into RVLM to ablate C1 neurons. Animals were then expose to high salt diet (3% Na in food and 2% Na in water) for 3 weeks to induce transition from compensated to decompensated HF state. At 6 weeks post-HF induction, echocardiography, cardiac autonomic function, breathing function, blood pressure, and mortality were assessed. Compared to normal chow fed HF animals, HF+Na rats displayed an increased cardiac index (15.1 ± 0.6 vs. 18.5 ± 1.3 ml/min/100cm , HF vs. HF+Na , respectively) and cardiac sympathetic tone (∆HR to propranolol: 8.7 ± 3.1 vs. 23.4 ± 2.5 bpm, HF vs. HF+Na , respectively). Furthermore, HF+Na animals showed a further increase in the incidence of breathing disorders compared to HF (apnea-hypopnea index: 8.1 ± 0.6 vs. 12.5 ± 2.1 events/hr, HF vs. HF+Na , respectively). Lastly, salt loading results in marked decompensation in HF rats being the outcome a significant increase in mortality risk (survival: 100% vs. 10% HF vs. HF+Na , respectively). We found that partial ablation of RVLM C1 neurons in HF+Na prevented further deterioration in cardiac autonomic function and breathing disorders and markedly improved survival in HF rats that underwent salt loading (survival: 10% vs. 75% HF+Na vs. HF+DβH-SAP+Na , respectively). Our results strongly support the role for RVLM C1 neurons in HF decompensation during salt loading and suggest that RVLM C1 may act as a key nodal point mediating salt induced cardiorespiratory distress, decompensation and mortality in HF.