Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

Figures

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  Figure 1. Prevalence of exercise tolerant (T) and intolerant (inT) heart failure (HF) rats and echocardiographic parameters after 6 weeks of exercise training (EX). (A) Timeline of experiments. HF surgery was performed at week 0. After 2 weeks, echocardiography and chemoreflex test were performed and then exercise training was started. Exercise tolerance (EX-T) and intolerance (EX-inT) classification was performed 2 weeks after the initiation of the exercise program. In a separate experiment, carotid bodies were ablated (CBA) bilaterally in HF + EX-T rats. Finally, at 8 weeks post-HF induction, we performed terminal physiological cardiorespiratory measurements. (B) Total training times. During the first 2 weeks of training, daily training times are reported. After the second week of training up to the end of the experiment (8 weeks post-HF induction) data is reported on a weekly basis. Note that total training time was 70% lower in HF + EX-inT rats. (C) Prevalence of tolerant vs intolerant HF rats. (D) representative recordings of echocardiography in M-mode from one sedentary HF rat (HF + Sed), one HF + EX-T rat and one HF + EX-inT rat. (E–J) Summary data of left ventricular (LV) end…

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  Figure 2. Heart failure rats with exercise training intolerance (HF + EX-inT) displayed similar sympathetic tone and spontaneous arrhythmia incidence compared to sedentary heart failure rats (HF + Sed). (A) Representative recordings of heart rate response to propranolol (1 mg/kg i.p.) from one HF + Sed rat, one HF + EX-T rat, and one HF + EX-inT rat. Note that EX did not improve cardiac autonomic control in HF + EX-inT rats. (B) summary of the effects of EX on heart rate responses to propranolol. (C) representative tachograms from one HF + Sed rat, one HF + EX-T rat, and one HF + EX-inT rat. No beneficial effects of EX on incidence of spontaneous cardiac arrhythmias were found in HF + EX-inT rats. (D) Summary of the effects of EX on arrhythmia incidence. *p < 0.05 vs. HF + Sed; +p < 0.05 vs. HF + EX-inT. HF + Sed, n = 6; HF + EX-T, n = 7; HF + EX-inT, n = 5 rats.

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  Figure 3. Diastolic function, but not systolic function is worse in heart failure rats with exercise training intolerance (HF + EX-inT). (A) (Left) end-diastolic pressure–volume relationship (EDPVR) by single beat analysis and (right) end-systolic pressure–volume relationship (ESPVR) by single beat analysis. (B) Summary of the effects of EX on the volume at pressure 0 (EDPVR single beat). Note that HF + EX-inT rats showed a significant increase of volume at pressure 0. (C) Summary of the effects of EX on LVEDP. Note that HF + EX-T improves diastolic function. (D) Summary of the effects of EX on ESPVR. Importantly, HF + EX-T rats displayed a significant improvement of systolic function. (E) isovolumetric pressure (PISO) was not different between all groups. *p < 0.05 vs. HF + Sed; +p < 0.05 vs. HF + EX-T condition. HF + Sed, n = 6; HF + EX-T, n = 7; HF + EX-inT, n = 5 rats.

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  Figure 4. Moderate hypoxia but not hypercapnia increases mortality in exercise intolerant heart failure rats. (A) Representative recordings of respiratory frequency (Rf), intraventricular pressure, and the electrocardiogram (ECG) from one HF + Sed, one HF + EX-T, and one HF + EX-inT rat during acute hypercapnic exposure (FiCO2 7%) (arrow, hypercapnia ON). Note that hypercapnic exposure lead to cardiac arrhythmias only in HF + EX-inT. (B) Kaplan–Meier survival curves showing no mortality during hypercapnia. (C) Representative recording of Rf, intraventricular pressure, and ECG from one HF + Sed, one HF + EX-T, and one HF + EX-inT rat during acute hypoxic exposure (FiO2 10%) (arrow, hypoxia ON). Note that hypoxic exposure lead to cardiac arrhythmias only in HF rats with exercise intolerance (HF + EX-inT); (D) Kaplan–Meier survival curves showing that 40% of HF + EX-inT rats died during hypoxia. *p < 0.05 vs. HF + EX-T condition.

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  Figure 5. Peripheral chemoreflex gain is lower in exercise intolerant heart failure rats (HF + EX-inT). (A) Representative traces of whole-body plethysmography from one HF + Sed rat, one HF + EX-T rat, and one HF + EX-inT rat during normoxia (FiO2 21%), hypercapnia (FiCO2 7%), and hypoxia (FiO2 10%). (B) Summary data of hypercapnic ventilatory response HCVR. (C) Summary effects of EX on HVR. Note that HF + EX-inT showed a lower hypoxic ventilatory response (HVR) compared to the HF + Sed rats and HF + EX-T rats. *p < 0.05 vs. HF + Sed; +p < 0.05 vs. HF + EX-T. HF + Sed, n = 6; HF + EX-T, n = 6; HF + EX-inT, n = 6.

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  Figure 6. Carotid body ablation (CBA) in HF-EX-T rats induces a phenotypic switch from exercise tolerant to exercise intolerant. (A) Summary data showing training time before and after CBA in HF-EX-T rats. Note that CBA was associated with significantly lower training time in rats that were previously tolerant of EX. (B) Representative traces of HVR from one HF + EX-T rat before and 2 weeks post-CBA. (C) Summary data of minute ventilation during normoxia and hypoxia. Note that ventilatory response to hypoxia was significantly reduced after CBA. *p < 0.05 vs. HF + EX-T during hypoxia. HF + EX-T, n = 4; HF + EX-T + CBA, n = 4.

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  Figure 7. Schematic representation of used animals in the present study. From 40 heart failure (HF) animals, n = 12 were assigned to sedentary (Sed) condition and n = 28 were assigned to exercise training (EX). From Sed animals, n = 6 were allocated to anesthetized experiments and n = 6 to non-anesthetized preparation. From HF + EX animals, n = 17 were classified as HF tolerant (HF + EX-T) animals and n = 11 were classified as HF intolerant (HF + EX-inT) rats. From total HF + EX-T animals, n = 7 were allocated to anesthetized experiments and n = 10 to non-anesthetized preparation (n = 4 to carotid body ablation and n = 6 to chemoreflex test at 8th weeks). From HF + EX-inT rats, n = 5 were allocated to anesthetized experiments and n = 6 to non-anesthetized preparation.