Brainstem C1 neurons mediate heart failure decompensation and mortality during acute salt loading

Abstract

Aims Heart failure (HF) is an emerging epidemic worldwide. Despite advances in treatment, the morbidity and mortality rate of HF remain high, and the global prevalence continues to rise. Common clinical features of HF include cardiac sympathoexcitation, disordered breathing, and kidney dysfunction; kidney dysfunction strongly contributes to sodium retention and fluid overload, leading to poor outcomes of HF patients. We have previously shown that brainstem pre-sympathetic neurons (C1) from the rostral ventrolateral medulla (RVLM) play a key role in sympathetic regulation in experimental models of HF. However, the role of RVLM-C1 neurons during salt-loading in the context of HF is unknown. This study tests whether RVLM C1 neurons drive cardiorespiratory decompensation, and ultimately lead to sudden death in HF rats. Methods and Results Adult male Sprague-Dawley rats underwent arterio-venous shunt to induce HF with preserved ejection fraction (HFpEF). Two-weeks after HFpEF induction, bilateral selective ablation of RVLM C1 neurons was performed using anti-dopamine β-hydroxylase-saporin toxin (DβH-SAP). Animals were then fed a high Na+ diet (3% Na+ in food and 2% Na+ in water) for 3 weeks to induce compensated-to-decompensated HF state transition. Echocardiography, cardiac autonomic function, breathing function, and survival were assessed during the progression of HF. Salt loading resulted in marked decompensation in HF rats, as evidenced by a significant increase in mortality risk (mortality: 100% vs. 10% HFpEF+Na+ vs. HFpEF). Furthermore, HFpEF+Na+ animals showed a further increase in cardiac sympathetic drive and more severe disordered breathing, including higher hypoxia-related epochs (i.e. apneas/hypopneas), compared to HF. Ablation of RVLM C1 neurons partly reduced the excessive cardiac sympathoexcitation during salt loading in HF, improved the exaggerated disordered breathing in HFpEF+Na+ rats, and reduced decompensation-linked mortality. We found that hypoxia, but not high sodium, was the major contributor to impaired calcium handling in isolated adult cardiomyocytes. Conclusion Our results strongly suggest that RVLM C1 neurons contribute to acute HF decompensation during salt loading by a mechanism encompassing further increases in sympathetic outflow and hypoxia-related breathing disorders. This mechanism may ultimately impact cardiac contractility through cardiomyocyte calcium mishandling, increasing morbidity and mortality.