Exercise training intolerance in heart failure with preserved ejection fraction is associated with altered chemoreflex gain and sympathoexcitation in rats
Authors: Andrade David C , Arce‐Alvarez Alexis , Toledo Camilo , Diaz Hugo , Lucero Claudia , Faundez Marcelo , Iturriaga Rodrigo , Del Rio Rodrigo 
Published: November 2023

Heart failure with preserved ejection fraction (HFpEF) is characterized by cardiac dysfunction and autonomic imbalance. In HF, sympathoexcitation is strongly associated to altered chemoreflex drive. Exercise training (EX) has been demonstrated that normalizes autonomic control and chemoreflex function in HF with reduced ejection fraction (HFrEF). Indeed, in HFrEF patients EX improve survival. Importantly, this effect appears to be related to EX tolerance (EX‐T). In contrast to what is known in HFrEF, much less is known about the effects of EX in HFpEF and the mechanisms underpinning the EX‐T. Then, we determine i) EX tolerance/intolerance in experimental HFpEF and ii) whether EX intolerance is associated with heightened chemoreflex drive in HFpEF. HFpEF was induced by volume overload in male Sprague‐Dawley rats (250±20g). EX (60 min/day, 25 m/min, 10% inclination) was performed for 6 weeks. EX intolerance (CHF+EX‐inT) was defined as the incapacity to complete daily training session (<50% total training time). Rats that accomplished total training sessions were defined as EX tolerant (CHF+EX‐T). Degree of HF was estimated by echocardiography and intraventricular pressure‐volume loops. Arrhythmia index was scored. Sympathetic drive was assessed by ΔHR following 1mg/kg propranolol i.v. infusion. Peripheral and central chemoreflex drive were study using hypoxic (HVR) and hypercapnic ventilatory response (HCVR), respectively. EX intolerance in CHF was ~40% and was independent of the degree of cardiac failure. Compared to sedentary HF rats (CHF‐sed), CHF+EX‐T rats showed a 1.5‐fold improvement in cardiac systolic function without changes in diastolic function. In addition, a significant decrease in the number of arrhythmias (43±33 vs. 196±85, events/hr, CHF+EX‐T vs. CHF‐sed, respectively) and sympathetic drive (−61.3±10.1 vs. −90.0±13.1 bpm, ΔHR, CHF+EX‐T vs. CHF‐Sed, respectively) were found in CHF+EX‐T rats. In contrast, EX severely compromises diastolic dysfunction in CHF+EX‐inT rats (289.5±21.3 vs. 237.8±6.5 μl V0, CHF+EX‐inT vs. CHF‐Sed, respectively). No effects of EX on systolic function, cardiac arrhythmias and sympathetic drive were found in CHF+EX‐inT. In addition, we found that EX normalized the HVR only in CHF+EX‐T rats but not in CHF+EX‐inT rats. Indeed, we found that EX induced a 1.5‐fold increase in HVR in CHF+EX‐inT animals compared to CHF‐Sed animals (respiratory frequency: 232.3±19.8 vs. 152.5±5.2 %bas, CHF+EX‐inT vs. CHF‐Sed, respectively). No effects of EX on HCVR was found in CHF+EX‐T and CHF+EX‐inT vs. CHF+Sed. Importantly, we found that acute hypoxic exposure (FiO2 10%) induced severe lethal cardiac arrhythmias in CHF+EX‐inT rats (~60% survival) but not in CHF+EX‐T rats. CHF‐sed nor CHF+EX‐T groups exhibited mortality events during hypoxia. Our results showed that EX in CHF+EX‐T rats improves cardiac function, arrhythmia incidence and sympathetic drive. In contrast, EX in CHF+EX‐inT rats results in a further deterioration of cardiac function and an increased peripheral chemoreflex drive. Importantly, life‐threating cardiac arrhythmic events triggered by hypoxic exposure lead to sudden death in CHF+EX‐inT rats.Support or Funding InformationFONDECYT 1140275 and 1150040