Exercise Intolerance in Volume Overload Heart Failure Is Associated With Low Carotid Body Chemosensitivity

Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands during exercise and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in HF patients. We sought to determine if abnormal ventilatory chemoreex 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 weeks exercise training program. Exercise tolerant HF rats (HF+EX-T) completed all training sessions and benet from exercise as evidenced by improvements in cardiac systolic function and reductions in HCVR, sympathetic tone and arrhythmias. Contrarily, HF rats that failed to complete training sessions (HF+EX-inT) showed no improvements in cardiac systolic function nor in HCVR, sympathetic tone, or arrhythmias but displayed a further compromise in cardiac diastolic function when compared to HF-sedentary rats. In addition, HF+EX-inT rats showed impaired HVR which was associated with increased arrhythmias susceptibility and mortality during hypoxic challenges (~60% survival). Finally, exercise tolerance was closely dependent on carotid body (CB) function since their selective ablation impaired exercise capacity in HF. Our results indicate that: i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and ii) reduced CB chemoreex contributes to EX-inT in HF.

Exercise intolerance (EX-inT) is de ned as impairment of the ability to perform physical activity and is characterized by decreased exercise and functional capacities 21 . It is one of several important indicators in the diagnosis of patients with HF 22 . The precise mechanisms underlying EX-inT in HF are not fully understood; however, it has been proposed that EX-inT may be linked to reductions in perfusion of working muscles and consequent decreases in oxygen supply. Theoretically, 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 . Most of the experimental support for this hypothesis comes from studies examining reduced ejection fraction HF, which is indeed, characterized by reductions in blood ow to muscle secondary to heart damage 24 . However, it is worth noting that patients with preserved ejection fraction HF, who often do not have hemodynamic compromise at rest also experience EX-inT.
In order to meet the metabolic demands of exercise, increases in ventilation are required in addition to increases in and re-distribution of cardiac output. Peripheral chemore exes is one of several important homeostatic mechanisms that contribute to increases in pulmonary ventilation during exercise. Early evidence of this, came from studies in patients who had undergone bilateral denervation of the peripheral chemoreceptors (i.e. carotid bodies) for treatment of bronchial asthma. In these people, carotid body resection resulted in a signi cant reduction in exercise hyperpnea 25 . Previous studies have shown that aberrant chemore ex function contributes to autonomic dysfunction, abnormal breathing patterns, and cardiac dysfunction in HF 1,2,[4][5][6][7][8] . However, to date no studies have addressed the role of chemore ex function in EX-inT in HF. Reductions in chemore ex gain could potentially have an adverse impact on exercise tolerance due to inadequate pulmonary ventilation. In the present study, we aimed to determine the prevalence of EX-inT in a volume-overload HF model (which lacks the confounding effect of reduced blood ow) 5,26 and the extent to which aberrant chemore ex function contributes to EX-inT in this model.

Ethical approval and animals
Forty male Sprague-Dawley rats (250 ± 20g) were used in these experiments. All experiments were performed 8-weeks following induction of HF. In accordance the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Guía para el Cuidado y Uso de los Animales de Laboratorio from CONICYT, all animals were kept at controlled room temperature under a 12 hours light/dark cycle with ad libitum access to food and water. All experimental protocols were approved by the Ethics Committee for Animal Experiments of the Ponti cia Universidad Católica de Chile (#170710022) and were performed according to the ARRIVE Guidelines. All experiments were performed in the Laboratory of Cardiorespiratory Control at Physiology Department of the Ponti cia Universidad Católica de Chile. At the end of the appropriate experiments, all animals were humanely euthanized via anesthetic overdose (sodium pentobarbital 100 mg/kg i.p.).
Two-weeks after HF induction surgery, rats were randomly allocated to endurance exercise training (EX; n=28) or sedentary (Sed; n=12) conditions. Sedentary animals were assigned to plethysmography experiments (n=6) and echocardiography and cardiac function experiments (n=6). Rats that trained less than 50% of the total EX session were classi ed as intolerant to EX (HF+EX-inT), similar to has been previously described 38 . Then, based on training times rats were assigned to one of the following groups: HF+EX-T (n=17) and HF+EX-inT, (n=11). From inT animals, n=6 rats were assigned to plethysmography experiments and n=5 rats, were allocated to anesthetized preparation at 8 th weeks. From tolerant animals, n=7 rats were allocated to anesthetized experiments, n=6 rats were assigned to plethysmography experiments. Finally, n=4 rats from HF+EX-T rats were used to CBA (Fig. 7). Volume overload HF model. Volume overload was used to induced HF as described previously 1,3,8,[39][40][41] . Brie y, under anesthesia (2% iso urane/ 98% O 2 ) after laparotomy, an anastomosis was created between abdominal aorta and inferior vena cava vessels using 1.20 x 40 mm needle (BD Precision Glide). The opening in the aorta was closed using tissue adhesive (Histoacryl, Braun). The abdomen was then closed in layers. Post-operative management consisted of administration of 5 mg enro oxacin (s.c.), 1 mg ketoprofen (s.c.), 5 ml saline solution (i.p.) and 2% lidocaine hydrochloride jelly (topical).

Exercise training protocol
The EX-training protocol was similar to previous studies 1 . Brie y, rats ran on a motor-driven treadmill (PanLab, Harvard Apparatus, USA) at low speed (10 m/min), low % grade (0%), and for a short duration (10 min/day) during the rst 2 weeks of the training program. Then, intensity and duration were gradually increased to 25 m/min at 10% grade for 60 min/day until they completed 6 weeks of training. Regardless of whether HF rats were classi ed as EX-T or EX-inT, all rats exercised to their capacity for 6 weeks.
Nevertheless, the inT animals were removed from the treadmill whether exhausted-rat must remained 3 times for longer than 5 seconds in the platform with electric shock (3-5 mA). Soleus to body weight ratio was calculated in each animal to estimate effectiveness of EX as previously described 1 .

Echocardiography
To assess cardiac function, echocardiography was performed two weeks after HF surgery as previously

Invasive cardiac hemodynamics
Rats were anesthetized with α-chloralose (40 mg/kg) and urethane (800 mg/kg), and then were intubated (16-g cannula). After this a 2F pressure-volume (PV) conductance catheter (Millar, SPR-869) was placed into the right carotid artery and advanced into the left ventricle 8,[44][45][46] . In addition, another catheter was inserted in the jugular vein for bolus calibration 44 . Before LV placement of the PV catheter, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), pulse pressure (PP) and heart rate (HR) were determined. Systolic and diastolic cardiac function were determined by single beat analysis [47][48][49] . After an equilibration period (25-min), baseline PV loops were recorded, and LV hemodynamic parameters were calculated using 10-15 successive PV loops. Baseline PV loop parameters were left ventricular end-systolic pressure (LVESP) and left ventricular end-diastolic pressure (LVEDP). Load-dependent cardiac function parameters were determined by means of the calculation of dp/dt max and dp/dt min . Load-independent systolic cardiac function was determined by calculating the slope of end-systolic pressure-volume relationship (ESPVR) from one cardiac cycle. Diastolic cardiac function was determined by volume at pressure 0, from one cardiac cycle. In addition, during PV-loop preparation cardiovascular response to hypoxia (F i O 2 10% O 2 /balance N 2 ) and hypercapnia (F i CO 2 7% CO 2 /93% O 2 ) were evaluated. Volumes were calibrated using arterial blood by the cuvette calibration method and NaCl 30% i.v. bolus for determination of parallel conductance 8,40 . Data analysis was performed using the PV loop module of LabChart 8.0 software.

Cardiac sympathetic tone
We determined cardiac sympathetic tone by measuring the maximum bradycardic response to propranolol as previously described 3,8 . Brie y, during PV-loop recording a bolus of propranolol was injected (1mg/kg i.v.) and the maximal chronotropic response was quanti ed. Sympathetic tone was quanti ed as the change in heart rate (ΔHR) in response to propranolol.

Central and peripheral chemore ex function
Central and peripheral chemore ex sensitivity was assessed by allowing the rats to breathe a mixture of hypercapnic or hypoxic gas, respectively 4,8 . Brie y, unrestrained whole-body plethysmography was used to measure or calculate the following: tidal volume V T , respiratory frequency R f , minute ventilation (V E ), inspiratory time (T i ), expiratory time (T e ), total respiratory time (T tot ), peak inspiratory ow (PiF) and peak expiratory ow (PeF). These were measured during stimulation of central chemoreceptors with hyperoxic hypercapnia (7% CO 2 /93% O 2 , for 10 min) and during stimulation of peripheral chemoreceptors with poikilocapnic hypoxia (10% O 2 /balance N 2 , for 10 min). The hypercapnic ventilatory response (HCVR) was obtained by calculating the slope of the linear regression adjustment of the V E response following F i CO 2 0.03% and 7%, as previously described 8 . The hypoxic ventilatory response (HVR) was obtained by calculating the slope of the linear regression adjustment of the V E response following F i O 2 21% and 10% challenges, as previously described 8 . All recordings were made at an ambient temperature of 25 ± 2 °C.
Carotid body ablation (CBA) After six weeks of exercise training the carotid bodies (CBs) were ablated as previously described 4 . Brie y, rats were anesthetized with 2% iso urane in O 2 . Under sterile surgical conditions, the CBs were exposed via a ventral incision on the neck, visually identi ed, and cryogenically destroy 4 . The effectiveness of this maneuver was con rmed by the lack of hypoxic ventilatory responses immediately after recovery from surgery 4 . Post-operative management consisted of administration of 5 mg enro oxacin (s.c.), 1 mg ketoprofen (s.c.), 5 ml saline solution (i.p.) and 2% lidocaine hydrochloride jelly (topical).

Statistical analysis
Data were expressed as mean ± standard error of the mean (SEM). All data were subjected to Shapiro-Wilk normality test. Differences among groups were assessed using one-way ANOVA, followed by Holm-Sidak´ s post hoc comparisons. An alpha of p < 0.05 was considered statistically signi cant. All analysis was performed with Prism version 8.4.0 (GraphPad Software, USA)

Results
Tolerance/intolerance to exercise training in HF animals.
HF+EX-inT rats showed a signi cant increase of cardiac hypertrophy compared to HF+EX-T animals ( Table 1). HF+EX-T showed an increase in the soleus muscle-to-body weight (soleus/BW) ratio compared to HF+Sed animals (p<0.05) ( Table 1). HF-EX-inT rats showed a slight but not signi cant increase in soleus/BW compared to HF+Sed animals (Table 1). EX did not change cardiac hypertrophy in HF+EX-T and HF+EX-inT animals compared to HF+Sed rats (Table 1).
Resting respiratory parameters (in normoxia) are shown in Table 2. No signi cant changes were found in V T amplitude or R f . Accordingly, no changes in respiratory cycle duration or peak ows were found between groups (Table 2).

Cardiac responses to chemore ex activation
Our previous work showed that chemore ex activation increased cardiac arrhythmias and promoted deterioration in cardiac function in volume-overloaded HF rats 8 . Accordingly, we tested the effects of EX on arrhythmia incidence during stimulation of central and peripheral chemore exes. Central chemore ex activation with acute hypercapnia elicits cardiac arrhythmias in HF+Sed and HF+EX-inT rats to a similar extent (14.4 ± 5.5 vs 17.0 ± 3.8 evens/10 min, respectively). Notably, the chemore ex-induced cardiac arrhythmogenesis was blunted in HF+EX-T rats. HF+EX-T animals showed a ~3-fold reduction in arrhythmia incidence compared to HF+Sed animals (5.6 ± 2.1 vs. 14.4 ± 5.5 evens/10 min, HF+EX-T vs. HF+Sed, respectively) ( Fig. 4A and B).
Peripheral chemore ex activation with acute hypoxia did not trigger an increase in cardiac arrhythmias in HF+Sed rats nor in HF+EX-T rats (9.8 ± 4.7 events/10 min, HF+EX-T rats) (Fig. 4C). Indeed, during the hypoxic challenge both HF+Sed and HF+EX-T animals displayed an increase R f without changes in intraventricular pressure and/or EKG integrity (Fig. 4C, left panel). In contrast, peripheral chemore ex activation induced a marked increase in cardiac arrhythmias and related mortality in HF+EX-inT rats (Fig.  4C). Within a minute of hypoxic stimulation, arrhythmic events begin to appear and were accompanied by decreases in intraventricular pressures (Fig. 4C, right panel). Peripheral chemore ex activation led to mortality in 40% of HF+EX-inT, but did not have a similar effect in the other experimental groups (Fig. 4D).
Peripheral and central chemore ex gain.
Peripheral chemore ex gain in HF+EX-T not showed signi cant differences compared to HF+Sed rats ( Fig. 5A and C). While, HF+EX-inT rats evidenced a signi cantly lower HVR than HF+EX-T and HF+Sed animals (2.9 ± 0.7 vs. 5.6 ± 0.2 and 4.8 ± 0.2 ΔV E /ΔF i O 2 %, HF+EX-inT vs. HF+EX-T and HF+Sed) ( Fig. 5A and C). In addition, HF+EX-inT animals showed signi cant differences in R f , V e , T e , T tot , PiF and PeF responses to hypoxia compared to HF+EX-T and HF+Sed animals ( Fig. 5 and Table 2). V T was signi cantly reduced in HF+EX-inT rats compared to the HF+EX-T animals ( Table 2). In addition, Ti was signi cantly higher in HF+EX-inT rats compared to HF+Sed animals ( Table 2).
Carotid body ablation (CBA) and EX tolerance in HF rats.
The effects of CBA on training times are displayed in Fig. 6. Total training time was reduced by ~50% in HF+EX-T rats after CBA compared to previous EX times obtained before ablation of carotid body chemoreceptors (Fig. 6A). Accordingly, CBA results in a signi cant reduction in the ventilatory response to hypoxia in HF+EX-T (50.3 ± 1.4 vs. 33.1 ± 3.7 ml/min/100g, before vs. after CBA in HF+EX-T; Fig. 6B and C).

Discussion
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 central/peripheral chemore ex gain prior to the onset of EX in HF rats; iii) HF+EX-inT 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) EX results in a signi cant reduction in peripheral chemore ex gain in HF+EX-inT, which 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 su cient to induce a phenotype similar to EX-inT animals. Taken together, our data suggest that decreased peripheral chemore ex gain contributes to EX-inT in HF. Based on our ndings it is plausible that reductions in chemore ex gain in a subset of HF patients may lead to EX-inT, further abnormalities in cardiac function, and potentially predispose to severe arrhythmogenesis and increased mortality risk during moderate hypoxic exposure.
Intolerance to exercise is a well-recognized characteristic in the diagnosis of HF 22 . HF patients typically have reduced exercise and functional capacity and experience dyspnea during daily activities 21,27 . Interestingly, intolerance to physical exercise is observed in both types of HF (i.e. reduced and preserved ejection fraction) 27 . Current theories on exercise intolerance center on an inability to adequately increase cardiac output during exercise and reductions in muscle blood ow secondary to reduced EF and potentially abnormalities in muscle metabolism 20 . In addition to cardiac, vascular, and metabolic responses to exercise, respiratory adjustments to exercise are just as crucial to maintaining homeostasis and therefore exercise tolerance. Despite well-documented derangements in ventilatory control in HF 2 , no studies to date have addressed this as a potential mechanism contributing to exercise intolerance in HF with no reductions in EF.
In the present study, we used volume-overload HF model to study the contribution of chemore exes to exercise tolerance in the absence of reduced EF 5,26 . We showed that volume-overloaded HF rats display exercise intolerance independent of the initial degree of cardiac failure. With respect to respiratory control, we observed that these animals displayed decreased peripheral chemore ex gain after training despite the fact that peripheral chemore ex gain was similar between all groups prior to the onset of the EX program. Therefore, it is reasonable to hypothesize that exercise intolerance in volume-overload HF stems in part from a reduction in peripheral chemore ex gain. To test this assumption, we eliminated the peripheral chemore ex in HF rats that were previously proven to be exercise tolerant. These HF+EX-T rats underwent bilateral ablation of the carotid bodies after six weeks of EX. Notably, we found that HF+EX-T rats showed a signi cant loss in EX performance at 2 weeks post-ablation. Indeed, total training times in HF+EX-T rats that underwent ablation were not signi cantly different from the values obtained in HF+EX-inT rats. This result strongly supports a role for peripheral chemoreceptors in contributing to exercise tolerance in HF. Based on our ndings, the precise mechanisms by which peripheral chemoreceptors contribute to exercise tolerance in volume-overload HF, a model of HF with no reductions in EF warrants future investigation. Impairment of systolic and diastolic function has been observed in patients with HF and in animal models of HF 1,3,8,28 . Whether or not EX results in improvements in diastolic function in HF is still controversial. Indeed, a meta-analysis performed by Pandey et al. (2015) 29 showed that HF patients did not experience signi cant improvements in diastolic function following EX 29 . Our previous work showing that EX training did not improve diastolic dysfunction in high-output HF rats 1 is consistent with these ndings. The results of the present study in HF+EX-T rats agree with and extend our previous observations by illustrating the detrimental effects of EX in EX-inT HF rats. Indeed, we found that HF rats that do not tolerate EX had worse diastolic function after completing EX protocol. This result suggests that in some HF populations physical exercise may be detrimental. Interestingly, this concern has previously been discussed as an important factor in disease progression and decompensation in human Similar to what is known about the effects of EX on diastolic function in HF, evidence regarding the bene cial effects of EX on systolic function is limited and controversial 1,15,30,31 . It has been shown that endurance EX in HF patients results in minor improvements in systolic function 32 , however in these studies no effort was made to distinguish between EX tolerant vs. intolerant patients 32 . In contrast, we previously reported that EX improves systolic function in HF rats 1 . It is worth noting that in the present study we found similar bene cial effects of EX on cardiac contractility, but that this was restricted to EX tolerant HF animals. Indeed, no bene cial effects of EX on cardiac contractility were observed in HF+EX-inT rats. For future studies to accurately assess the bene cial effects of EX on cardiac function in HF it is important to identify and differentiate the proportion of the patient population that do not tolerate EX.
Autonomic dysfunction characterized by sympatho-vagal imbalance is a hallmark of HF in humans and is faithfully reproduced in animal models of HF 1,8,33 . Our previous work and that of others has shown that volume-overloaded HF rats exhibit autonomic imbalance characterized by heightened sympathetic activity 1, [3][4][5]8,34 . It has been proposed that autonomic imbalance, mainly sympathoexcitation, contributes to EX intolerance in HF by reducing muscle blood ow along with increases in peripheral vascular resistance 23 . Importantly, volume-overloaded HF with preserved ejection fraction is a particularly useful model for examining the effects of EX intolerance in the absence of overt reductions in cardiac output. We found that EX was an effective means to reduce cardiac sympathetic tone in HF rats that tolerate EX.
This is in agreement with our previous observations 1 ; however, this research extends our previous ndings by showing that EX has no salutary effect on sympathetic activity in HF rats with EX intolerance.
In this study, cardiac chronotropic responses to propranolol from HF+EX-inT rats were undistinguishable from those in in sedentary HF rats. Whether this lasting heightened sympathetic activity in HF+EX-inT group contributes to the EX intolerant phenotype in HF requires further study.
Cardiac arrhythmias are a major contributor to mortality in patients with HF 29 and are often associated with increased cardiac sympathetic tone 4,35 . In our previous studies we showed that volume-overloaded HF rats had a higher incidence of cardiac arrhythmias than shams and that EX training signi cantly reduced occurrence of these arrhythmias 1,8 . In this study we extend our previous ndings with the observation that EX training has no bene cial effect on cardiac arrhythmias in HF rats with EX intolerance. It is important to note that HF+EX-inT rats do not experience improvements in cardiac sympathetic tone as observed in HF rats that tolerate EX. Previously, we reported that cardiac arrhythmias in volume-overloaded HF rats are driven primarily by sympathetic activation 3 , therefore it is plausible that the lack of effects of EX on cardiac arrhythmias in HF+EX-inT rats was related, at least in part, to the inability of EX to reduce sympathoexcitation. However, we cannot rule out the possibility that cardiac cellular/molecular remodeling occurred following EX training in HF+EX-inT rats that contributed to the arrhythmic substrate.
It has been proposed that chemore ex-mediated sympathoexcitation is a major contributor to the progression of HF 4,6,35 . Previously we found that volume-overload HF is associated with enhanced central chemore ex gain and autonomic dysfunction, but that these animals did not exhibit changes in peripheral chemore ex gain 8 . In the present study we showed that EX in HF+EX-T rats signi cantly reduced central chemore ex gain without changing peripheral chemore ex gain. Therefore, it is possible that reductions in central chemore ex gain in HF+EX-T rats following EX contribute to the improvements we observed in autonomic and cardiac function. In contrast, EX in HF+EX-inT rats had no discernable effect on central chemore ex gain compared to HF sedentary rats. Surprisingly, we found that peripheral chemore ex gain was attenuated after EX in HF+EX-inT rats. This nding is of note in part because when exposed to moderate hypoxia, HF+EX-inT rats had increased incidence of cardiac arrhythmias and higher mortality compared to HF+Sed animals. It is plausible that a diminished hypoxic ventilatory response compromises cardiac oxygen supply during hypoxic challenge in HF+EX-inT animals triggering lethal cardiac arrhythmias.
Whether a decrease in peripheral chemore ex gain affects tolerance to EX in HF has not been previously addressed. It has been shown that CB ablation in humans results in a signi cant reduction of exercise hyperpnea 36 ; however, the extent to which this affects exercise tolerance is unclear. It has been proposed that carotid body chemoreceptors act not only to maintain arterial blood gas homeostasis, but that they also serve an important role as metabolic sensors. Recently, Chang et al. (2015) 36 , showed that carotid bodies respond to increases in extracellular lactate and can elicit a ventilatory response to physiologically relevant lactate concentrations. It is widely known that plasma lactate levels increase during acute exercise (of su cient intensity), therefore, it is possible that peripheral chemoreceptors modulate the ventilatory adjustments and tolerance to EX in HF. In the case of a decrease in peripheral chemore ex gain (as we observed) during higher intensity exercise, a loss in the sensitivity to metabolic by-products by peripheral chemoreceptors would adversely affect ventilatory responses to EX and contribute to EX intolerance. Since our HF+EX-inT animals displayed decreased peripheral chemore ex gain we decided to determine if reducing peripheral chemore ex gain (via ablation) would produce a phenotype switch in HF Page 13/21 animals that had previously demonstrated good tolerance for EX. Notably, ablation of the carotid bodies in HF+EX-T rats did indeed result in a phenotype switch, transforming the exercise tolerant animal into an intolerant one. Taken together, our observations suggest that reductions in peripheral chemore ex gain are an important mechanism underlying EX intolerance in volume-overload HF. Measuring ventilation during exercise in rodents is very di cult, however future studies that address the precise role of peripheral chemoreceptors in EX ventilation in HF would add important insight to our ndings.

Limitations
Limitations are inherent in any experimental model of human disease. Our HF model, as many others, does not fully recapitulate human HF. Indeed, HF models do not include any comorbidities (i.e. coronary artery disease, diabetes mellitus, atrial brillation and hypertension) that are typically associated with development or progression of HF 33,37 . However, it is worth noting that volume-overloaded HF model is a useful tool for separating the effects of neurohumoral activation on HF pathophysiology from the effects of reduced blood ow typically observed in reduced ejection fraction HF models. We acknowledge that our ndings cannot be extrapolated to all types of human HF. Finally, our experimental design did not allow for measurement of ventilation or other cardiovascular parameters during EX sessions. Additional studies which address cardiorespiratory responses during acute exercise will provide additional insights into EX intolerance in HF.

Conclusion
Exercise intolerant HF rats display a decreased peripheral chemore ex gain and a further deteriorated cardiac function. Interestingly, ablation of peripheral chemoreceptors in exercise tolerant HF rats resulted in transformation of exercise-tolerant animals to exercise-intolerant animals. Our data suggest that loss of chemore ex sensitivity contributes, at least in part, to exercise intolerance in HF rats.
Declarations undertaken in the laboratory of R.D.R. at the Ponti cia Universidad Católica de Chile. All authors approved the nal version of the manuscript.  Values are expressed as mean ± SEM. T: tolerant; inT: intolerant; HW: heart weight; HW/BW: heart weight/body weight; lung W/D: Lung Wet/Dry; SBP: systolic blood pressure; DPB: diastolic blood pressure; PP: pulse pressure; HR: heart rate. One-way ANOVA, Sidak post hoc analysis. * vs. HF+Sed, + vs.