Abstract
Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.
Highlights
Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients
Training times were significantly lower in HF + Exercise training (EX)-inT animals, compared to HF + EX-T rats (29.2 ± 10.1 vs. 100.0 ± 13.1% change, HF + EX-inT vs. HF + EX-T, respectively) (Fig. 1B)
In the present study we found that: (i) EX-inT was present in 39% of high-output HF rats; (ii) EX-inT was not related to the initial degree of cardiac failure nor to hypercapnic ventilatory response (HCVR)/hypoxic ventilatory response (HVR) prior to the onset of EX in HF rats; (iii) HF + EXinT rats had similar degrees of autonomic dysfunction, arrhythmia incidence, and cardiac systolic dysfunction compared to HF sedentary rats; (iv) EX-inT results in a greater degree of cardiac diastolic dysfunction in HF; (v) lower HVR in HF + EX-inT was associated with increased incidence of cardiac arrhythmias and higher mortality during hypoxic challenge; and (vi) ablation of peripheral chemoreceptors in HF + EX-T rats was sufficient to induce a phenotype similar to EX-inT animals
Summary
Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. Exercise training (EX) has been shown to be an effective non-pharmacological therapeutic adjunct in treatment of H F10–19, that results in improvements in cardiac function, quality of life, and survival These beneficial effects are frequently associated with improvement in cardiac autonomic imbalance and normalization of abnormal chemoreflex function[10,11,12,13,14,15,16,17,18,19], both of which are associated with lower survival rates in H F4,6. The precise mechanisms underlying EX-inT in HF are not fully understood; it has been proposed that EX-inT may be linked to reductions in perfusion of working muscles and consequent decreases in oxygen supply This is a result of impaired ability to increase cardiac output to working muscles which is compounded by persistent sympathoexcitation and reduced vasodilatory mechanisms in vascular beds regulating muscle perfusion[23]. We aimed to determine the prevalence of EX-inT in a volume-overload HF model (which lacks the confounding effect of reduced blood flow)[5,26] and the extent to which aberrant chemoreflex function contributes to EX-inT in this model
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