Diastolic Dysfunction and Arrhythmia Incidence are Exacerbated by Central Chemoreflex Activation in HFpEF

Abstract

Heart failure with preserved ejection fraction (HFpEF) is characterized by decreased ventricular compliance and autonomic imbalance. Tonic and episodic chemoreflex activation contributes to autonomic imbalance in heart failure and is associated with poor prognosis. We sought to determine if the sensitivity of central chemoreceptors (CC) is enhanced in an animal model of HFpEF, and whether acute activation of CC exacerbates cardiac dysfunction. Volume overload (a‐v anastomosis) was used to induce HFpEF in adult male Sprague‐Dawley rats. Ventilatory responses to acute hypercapnia (FiCO2‐7% in O2) were measured by plethysmography to assess CC sensitivity, and a conductance catheter was used to measure pressure‐volume relationships as a measure of cardiac function. Neuronal activation was assessed by measuring FosB expression in brainstem micropunches from pre‐sympathetic regions of the rostral ventrolateral medulla (RVLM). Ejection fraction did not differ between HFpEF and sham rats(51±3 vs. 50±7 %, HFpEF vs. sham). HFpEF rats compared to sham rats exhibited cardiac hypertrophy (heart/body weight, 6.1±0.3 vs. 4.0±0.5 mg/g, HFpEF vs. sham), pulmonary congestion (lung wet/dry weight, 4.4±0.1 vs. 3.8±0.1 g/g, HFpEF vs. sham), increased arrhythmia incidence (104±34 vs. 11±2 events/h, HFpEF vs. sham), greater ventricular stiffness (β, 7.4±1.4 vs. 4.3±0.7 mmHg/ml, HFpEF vs. sham), and decreased ventricular active relaxation (τ, 9±2 vs. 15±2 ms, HFpEF vs. sham). In HFpEF rats, CC sensitivity was increased (165.3±9.1 vs. 127.3±10.3 ml/min/100g, HFpEF vs. sham), and CC stimulation (normocapnia vs. hypercapnia) significantly increased (P<.05) arrhythmia incidence (104±34 vs. 1164±204 events/h,) and β (7.4±1.4 vs. 17.5±7.5 1/ml), but did not affect τ values (9±2 vs. 9±1 ms) or significantly compromise ventricular capacitance. RVLM activation (FosB expression) was increased in HFpEF rats compared to sham animals. Our results indicate that the CC is enhanced in in HFpEF, neuronal activation is increased in pre‐sympathetic regions of the brainstem, and acute CC activation further exacerbates diastolic dysfunction and arrhythmia incidence in HFpEF.Support or Funding InformationSupported by Fondecyt 1140275.