Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure

Abstract

Activation of the sympathetic nervous system is a hallmark of heart failure (HF) and is positively correlated with disease progression. Catecholaminergic (C1) neurons located in the rostral ventrolateral medulla (RVLM) are known to modulate sympathetic outflow and are hyperactivated in volume overload HF. However, there is no conclusive evidence showing a contribution of RVLM-C1 neurons to the development of cardiac dysfunction in the setting of HF. Therefore, the aim of this study was to determine the role of RVLM-C1 neurons in cardiac autonomic control and deterioration of cardiac function in HF rats. A surgical arteriovenous shunt was created in adult male Sprague-Dawley rats to induce HF. RVLM-C1 neurons were selectively ablated using cell-specific immunotoxin (dopamine-β hydroxylase saporin [DβH-SAP]) and measures of cardiac autonomic tone, function, and arrhythmia incidence were evaluated. Cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction were present in HF rats and improved after DβH-SAP toxin treatment. Most importantly, the progressive decline in fractional shortening observed in HF rats was reduced by DβH-SAP toxin. Our results unveil a pivotal role played by RVLM-C1 neurons in cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction in volume overload-induced HF.

Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats

“…, b ; Andrade et al . ). Control rats (vehicle) were injected with sterile saline solution (0.9% of NaCl/100 nl) (Taxini et al .…”

“…; Andrade et al . , ). The EF and fractional shortening (FS) were calculated from left ventricle volumes and diameters, respectively (Lang, ; Toledo et al .…”

“…HF was induced by the surgical creation of an arteriovenous (A-V) fistula as previously described (Brodsky et al 1998;Toledo et al 2017;Del Rio et al 2017;Andrade et al 2017;Andrade et al 2019). Briefly, under anaesthesia (isoflurane: 5% for induction, 1.5% for maintenance, balanced with O 2 ), the inferior vena cava and the abdominal aorta were exposed using a midline incision.…”

“…; Andrade et al . ). The RVLM‐C1 neurones are a subpopulation of catecholaminergic neurones that reside in the ventral lateral aspect of the brainstem and play an important role in regulating cardiac autonomic function (Schreihofer et al .…”

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

“…This group has shown that HF is associated with increases in basal sympathetic tone (Andrade et al . ). The reason for this increase, also shown by this group, is that chemoreceptor activation caused by hypercapnic stimulation leads to RVLM‐C1 neuron activation.…”