Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats

Abstract

Key pointsr Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho-vagal imbalance.r Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood.r We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre-sympathetic regions of the brainstem.r Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho-vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF.Abstract Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho-vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague-Dawley rats (n = 32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho-vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean ± SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2 ± 4.0 vs. 9.7 ± 2.6 events h −1 ), autonomic imbalance [0.6 ± 0.2 vs. 0.2 ± 0.1 low/high frequency heart rate variability (LF/HF HRV )] and cardiac arrhythmias (196.0 ± 239.9 vs. 19.8 ± 21.7 events h −1 ). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6 ± 43.2% vs. 296.0 ± 43.9% LF/HF HRV , normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0 ± 239.9 vs. 576.7 ± 472.9 events h −1 ) and diastolic dysfunction (0.008 ± 0.004 vs. 0.027 ± 0.027 mmHg μl −1 ). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since * These authors contributed equally to this work. these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF.

Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

“…These comorbidities are frequent in patients with HFpEF or HFmrEF, thus suggesting the presence of chemoreflex dysfunction in these patients. In fact, Toledo and colleagues recently reported that the central chemoreflex is enhanced in HFpEF (Toledo et al, 2017). These authors observed that the activation of the central chemoreflex pathway by hypercapnia exacerbates sympatho-vagal imbalance in HFpEF rats, and that sympathetic blockade with propranolol attenuates the response of cardiac sympathetic modulation.…”

“…These authors observed that the activation of the central chemoreflex pathway by hypercapnia exacerbates sympatho-vagal imbalance in HFpEF rats, and that sympathetic blockade with propranolol attenuates the response of cardiac sympathetic modulation. In addition, these authors showed that neuronal activation in the RVLM was increased in HFpEF rats compared with sham rats (Toledo et al, 2017). However, further studies are needed to better understand the mechanistic intricacies of these new findings.…”

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

“…; Toledo et al . ). V T oscillations were analysed by the calculation of the coefficient of variation of the magnitude of each V T cycle in the same respiratory segments.…”

“…The end‐systolic volume (ESV) and EDV were calculated using the Teicholz method ([ESV = 7 × ESD3/(2.4 + ESD)] and [EDV = 7 × EDD3/(2.4 + EDD)], respectively) (Lang, ; Toledo et al . ; Del Rio et al . ; Andrade et al .…”

Heart Failure With Preserved Ejection Fraction: A Perioperative Review

“…The proinflammatory state is attributed to increased central autonomic tone via a central chemoreflex pathway that is responsible for causing diastolic dysfunction and imbalance between the sympathetic and parasympathetic setpoint. 14 Pressure-volume loops show an upward or leftward shift of the LV end-systolic pressure volume relationship, reflecting increased end-systolic myocardial stiffness. Patients with HFpEF typically have normal LV chamber size and greater wall thickness (concentric remodeling), resulting in lower brain natriuretic peptide (BNP) levels.…”