Hypoxic peripheral chemoreflex stimulation-dependent cardiorespiratory coupling is decreased in swimmer athletes.

Swimmer athletes showed a decreased ventilatory response and reduced sympathetic activation during peripheral hypoxic chemoreflex stimulation. Based on these observations, we hypothesized that swimmers develop a diminished cardiorespiratory coupling due to their decreased hypoxic peripheral response. To resolve this hypothesis, we conducted a study using coherence time-varying analysis to assess the cardiorespiratory coupling in swimmer athletes. We recruited 12 trained swimmers and 12 control subjects for our research. We employed wavelet time-varying spectral coherence analysis to examine the relationship between the respiratory frequency (Rf ) and the heart rate (HR) time series during normoxia and acute chemoreflex activation induced by five consecutive inhalations of 100% N2 . Comparing swimmers to control subjects, we observed a significant reduction in the hypoxic ventilatory responses to N2 in swimmers (0.012 ± 0.001 vs. 0.015 ± 0.001 ΔVE /ΔVO2 , and 0.365 ± 0.266 vs. 1.430 ± 0.961 ΔVE /ΔVCO2 /ΔSpO2 , both p < 0.001, swimmers vs. control, respectively). Furthermore, the coherence at the LF cutoff during hypoxia was significantly lower in swimmers compared to control subjects (20.118 ± 3.502 vs. 24.935 ± 3.832 area under curve [AUC], p < 0.012, respectively). Our findings strongly indicate that due to their diminished chemoreflex control, swimmers exhibited a substantial decrease in cardiorespiratory coupling during hypoxic stimulation.

Cardiorespiratory optimal point as a submaximal evaluation tool in endurance athletes: An exploratory study.

Introduction: The cardiorespiratory optimal point (COP) represents the lowest minute ventilation to oxygen consumption ratio (VE/VO2) and can be estimated during a CPET at submaximal intensity when an exercise test until volitional fatigue is not always advisable (i.e., a conflict zone where you cannot be confident of the security because near-competition, off-season, among other). COP's physiological components have not been wholly described yet. Therefore, this study seeks to identify the determinants of COP in highly trained athletes and its influence on maximum and sub-maximum variables during CPET through principal c omponent analysis (PCA) (explains the dataset's variance). Methods: Female (n = 9; age, 17.4 ± 3.1 y; maximal VO2 [VO2max]), 46.2 ± 5.9 mL/kg/min) and male (n = 24; age, 19.7 ± 4.0 y; VO2max, 56.1 ± 7.6 mL/kg/min) athletes performed a CPET to determine the COP, ventilatory threshold 1 (VT1) and 2 (VT2), and VO2max. The PCA was used to determine the relationship between variables and COP, explaining their variance. Results: Our data revealed that females and males displayed different COP values. Indeed, males showed a significant diminished COP compared to the female group (22.6 ± 2.9 vs. 27.2 ±3.4 VE/VO2, respectively); nevertheless, COP was allocated before VT1 in both groups. Discussion: PC analysis revealed that the COP variance was mainly explained (75.6%) by PC1 (expired CO2 at VO2max) and PC2 (VE at VT2), possibly influencing cardiorespiratory efficiency at VO2max and VT2. Our data suggest that COP could be used as a submaximal index to monitor and assess cardiorespiratory system efficiency in endurance athletes. The COP could be particularly useful during the offseason and competitive periods and the return to the sports continuum.

Intrahospital supervised exercise training improves survival rate among hypertensive patients with COVID-19.

Among the people most affected by coronavirus disease 2019 (COVID-19) are those suffering from hypertension (HTN). However, pharmacological therapies for HTN are ineffective against COVID-19 progression and severity. It has been proposed that exercise training (EX) could be used as post-COVID treatment, which does not rule out the possible effects during hospitalization for COVID-19. Therefore, we aimed to determine the impact of supervised EX on HTN patients with COVID-19 during hospitalization. Among a total of 1,508 hospitalized patients with COVID-19 (confirmed by PCR), 439 subjects were classified as having HTN and were divided into two groups: EX (n = 201) and control (n = 238) groups. EX (3-4 times/wk during all hospitalizations) consisted of aerobic exercises (15-45 min; i.e., walking); breathing exercises (10-15 min) (i.e., diaphragmatic breathing, pursed-lip breathing, active abdominal contraction); and musculoskeletal exercises (8-10 sets of 12-15 repetitions/wk; lifting dumbbells, standing up and sitting, lumbar stabilization). Our data revealed that the EX (clinician: patient, 1:1 ratio) intervention was able to improve survival rates among controlled HTN patients with COVID-19 during their hospitalization when compared with the control group (chi-squared: 4.83; hazard ratio: 1.8; 95% CI: 1.117 to 2.899; P = 0.027). Multivariate logistic regression analysis revealed that EX was a prognostic marker (odds ratio: 0.449; 95% CI: 0.230-0.874; P = 0.018) along with sex and invasive and noninvasive mechanical ventilation. Our data showed that an intrahospital supervised EX program reduced the mortality rate among patients with HTN suffering from COVID-19 during their hospitalization.NEW & NOTEWORTHY In the present study, we found that exercise training improves the survival rate in hypertensive patients with COVID-19 during their hospitalization period. Our results provide strong evidence for the therapeutic efficacy of exercise training as a feasible approach to improving the outcomes of patients with COVID-19 who suffer from hypertension during their hospitalization.

Dynamic circadian fluctuations of glycemia in patients with type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) has glucose variability that is of such relevance that the appearance of vascular complications in patients with DM has been attributed to hyperglycemic and dysglycemic events. It is known that T1D patients mainly have glycemic variability with a specific oscillatory pattern with specific circadian characteristics for each patient. However, it has not yet been determined whether an oscillation pattern represents the variability of glycemic in T2D. This is why our objective is to determine the characteristics of glycemic oscillations in T2D and generate a robust predictive model. RESULTS: Showed that glycosylated hemoglobin, glycemia, and body mass index were all higher in patients with T2D than in controls (all p < 0.05). In addition, time in hyperglycemia and euglycemia was markedly higher and lower in the T2D group (p < 0.05), without significant differences for time in hypoglycemia. Standard deviation, coefficient of variation, and total power of glycemia were significantly higher in the T2D group than Control group (all p < 0.05). The oscillatory patterns were significantly different between groups (p = 0.032): the control group was mainly distributed at 2-3 and 6 days, whereas the T2D group showed a more homogeneous distribution across 2-3-to-6 days. CONCLUSIONS: The predictive model of glycemia showed that it is possible to accurately predict hyper- and hypoglycemia events. Thus, T2D patients exhibit specific oscillatory patterns of glycemic control, which are possible to predict. These findings may help to improve the treatment of DM by considering the individual oscillatory patterns of patients.

Chemoreflex Control as the Cornerstone in Immersion Water Sports: Possible Role on Breath-Hold.

Immersion water sports involve long-term apneas; therefore, athletes must physiologically adapt to maintain muscle oxygenation, despite not performing pulmonary ventilation. Breath-holding (i.e., apnea) is common in water sports, and it involves a decrease and increases PaO2 and PaCO2, respectively, as the primary signals that trigger the end of apnea. The principal physiological O2 sensors are the carotid bodies, which are able to detect arterial gases and metabolic alterations before reaching the brain, which aids in adjusting the cardiorespiratory system. Moreover, the principal H+/CO2 sensor is the retrotrapezoid nucleus, which is located at the brainstem level; this mechanism contributes to detecting respiratory and metabolic acidosis. Although these sensors have been characterized in pathophysiological states, current evidence shows a possible role for these mechanisms as physiological sensors during voluntary apnea. Divers and swimmer athletes have been found to displayed longer apnea times than land sports athletes, as well as decreased peripheral O2 and central CO2 chemoreflex control. However, although chemosensitivity at rest could be decreased, we recently found marked sympathoexcitation during maximum voluntary apnea in young swimmers, which could activate the spleen (which is a reservoir organ for oxygenated blood). Therefore, it is possible that the chemoreflex, autonomic function, and storage/delivery oxygen organ(s) are linked to apnea in immersion water sports. In this review, we summarized the available evidence related to chemoreflex control in immersion water sports. Subsequently, we propose a possible physiological mechanistic model that could contribute to providing new avenues for understanding the respiratory physiology of water sports.

Dynamic circadian fluctuations of glycemia in patients with type 2 diabetes mellitus

BACKGROUND: Diabetes mellitus (DM) has glucose variability that is of such relevance that the appearance of vascular complications in patients with DM has been attributed to hyperglycemic and dysglycemic events. It is known that T1D patients mainly have glycemic variability with a specific oscillatory pattern with specific circadian characteristics for each patient. However, it has not yet been determined whether an oscillation pattern represents the variability of glycemic in T2D. This is why our objective is to determine the characteristics of glycemic oscillations in T2D and generate a robust predictive model. RESULTS: Showed that glycosylated hemoglobin, glycemia, and body mass index were all higher in patients with T2D than in controls (all p < 0.05). In addition, time in hyperglycemia and euglycemia was markedly higher and lower in the T2D group (p < 0.05), without significant differences for time in hypoglycemia. Standard deviation, coefficient of variation, and total power of glycemia were significantly higher in the T2D group than Control group (all p < 0.05). The oscillatory patterns were significantly different between groups (p = 0.032): the control group was mainly distributed at 2-3 and 6 days, whereas the T2D group showed a more homogeneous distribution across 2-3-to-6 days. CONCLUSIONS: The predictive model of glycemia showed that it is possible to accurately predict hyper- and hypo-glycemia events. Thus, T2D patients exhibit specific oscillatory patterns of glycemic control, which are possible to predict. These findings may help to improve the treatment of DM by considering the individual oscillatory patterns of patients.

Oscillatory pattern of glycemic control in patients with diabetes mellitus.

Daily glucose variability is higher in diabetic mellitus (DM) patients which has been related to the severity of the disease. However, it is unclear whether glycemic variability displays a specific pattern oscillation or if it is completely random. Thus, to determine glycemic variability pattern, we measured and analyzed continuous glucose monitoring (CGM) data, in control subjects and patients with DM type-1 (T1D). CGM data was assessed for 6 days (day: 08:00-20:00-h; and night: 20:00-08:00-h). Participants (n = 172; age = 18-80 years) were assigned to T1D (n = 144, females = 65) and Control (i.e., healthy; n = 28, females = 22) groups. Anthropometry, pharmacologic treatments, glycosylated hemoglobin (HbA1c) and years of evolution were determined. T1D females displayed a higher glycemia at 10:00-14:00-h vs. T1D males and Control females. DM patients displays mainly stationary oscillations (deterministic), with circadian rhythm characteristics. The glycemia oscillated between 2 and 6 days. The predictive model of glycemia showed that it is possible to predict hyper and hypoglycemia (R2 = 0.94 and 0.98, respectively) in DM patients independent of their etiology. Our data showed that glycemic variability had a specific oscillation pattern with circadian characteristics, with episodes of hypoglycemia and hyperglycemia at day phases, which could help therapeutic action for this population.

Hypoxic Respiratory Chemoreflex Control in Young Trained Swimmers.

During an apnea, changes in PaO2 activate peripheral chemoreceptors to increase respiratory drive. Athletes with continuous apnea, such as breath-hold divers, have shown a decrease in hypoxic ventilatory response (HVR), which could explain the long apnea times; however, this has not been studied in swimmers. We hypothesize that the long periods of voluntary apnea in swimmers is related to a decreased HVR. Therefore, we sought to determine the HVR and cardiovascular adjustments during a maximum voluntary apnea in young-trained swimmers. In fifteen trained swimmers and twenty-seven controls we studied minute ventilation (V E ), arterial saturation (SpO2), heart rate (HR), and autonomic response [through heart rate variability (HRV) analysis], during acute chemoreflex activation (five inhalations of pure N2) and maximum voluntary apnea test. In apnea tests, the maximum voluntary apnea time and the end-apnea HR were higher in swimmers than in controls (p < 0.05), as well as a higher low frequency component of HRV (p < 0.05), than controls. Swimmers showed lower HVR than controls (p < 0.01) without differences in cardiac hypoxic response (CHR). We conclude that swimmers had a reduced HVR response and greater maximal voluntary apnea duration, probably due to decreased HVR.

Baroreflex Modulation During Acute High-Altitude Exposure in Rats.

Baroreflex (BR) control is critically dependent of sympathetic and parasympathetic modulation. It has been documented that during acute hypobaric hypoxia there is a BR control impairment, however, the effect of a natural hypoxic environment on BR function is limited and controversial. Therefore, the aim of this study was to determine the effect of acute High-Altitude exposure on sympathetic/parasympathetic modulation of BR control in normal rats. Male Sprague Dawley rats were randomly allocated into Sea-Level (n = 7) and High-Altitude (n = 5) (3,270 m above sea level) groups. The BR control was studied using phenylephrine (Phe) and sodium nitroprusside (SNP) through sigmoidal analysis. The autonomic control of the heart was estimated using heart rate variability (HRV) analysis in frequency domain. Additionally, to determine the maximum sympathetic and parasympathetic activation of BR, spectral non-stationary method analysis, during Phe (0.05 µg/mL) and SNP administration (0.10 µg/mL) were used. Compared to Sea-Level condition, the High-Altitude group displayed parasympathetic withdrawal (high frequency, 0.6-2.4 Hz) and sympathoexcitation (low frequency, 0.04-0.6 Hz). Regarding to BR modulation, rats showed a significant decrease (p < 0.05) of curvature and parasympathetic bradycardic responses to Phe, without significant differences in sympathetic tachycardic responses to SNP after High-Altitude exposure. In addition, the non-stationary analysis of HRV showed a reduction of parasympathetic activation (Phe) in the High-Altitude group. Our results suggest that acute exposure to High-Altitude produces an autonomic and BR control impairment, characterized by parasympathetic withdrawal after 24 h of high-altitude exposure.

Acute effects of high-intensity interval training session and endurance exercise on pulmonary function and cardiorespiratory coupling.

The aim of this study was to determine the acute effects of high-intensity interval training (HIIT) exercise and endurance exercise (EE) on pulmonary function, sympathetic/parasympathetic balance, and cardiorespiratory coupling (CRC) in healthy participants. Using a crossover repeated-measurements design, four females and four males were exposed to EE (20 min at 80% maximal heart rate [HR]), HIIT (1 min of exercise at 90% maximal HR per 1 min of rest, 10 times), or control condition (resting). Pulmonary function, HR, CRC, and heart rate variability (HRV) were assessed before and after the interventions. Results revealed no significant effects of EE or HIIT on pulmonary function. The EE, but not HIIT, significantly increased CRC. In contrast, HRV was markedly changed by HIIT, not by EE. Indeed, both the low-frequency (LFHRV ) and high-frequency (HFHRV ) components of HRV were increased and decreased, respectively, after HIIT. The increase in LFHRV was greater after HIIT than after EE. Therefore, a single bout of HIIT or EE has no effects on pulmonary function. Moreover, CRC and cardiac autonomic regulation are targeted differently by the two exercise modalities.

Episodic stimulation of central chemoreceptor neurons elicits disordered breathing and autonomic dysfunction in volume overload heart failure.

Enhanced central chemoreflex (CC) gain is observed in volume overload heart failure (HF) and is correlated with autonomic dysfunction and breathing disorders. The aim of this study was to determine the role of the CC in the development of respiratory and autonomic dysfunction in HF. Volume overload was surgically created to induce HF in male Sprague-Dawley rats. Radiotelemetry transmitters were implanted for continuous monitoring of blood pressure and heart rate. After recovering from surgery, conscious unrestrained rats were exposed to episodic hypercapnic stimulation [EHS; 10 cycles/5 min, inspiratory fraction of carbon dioxide (FICO2) 7%] in a whole body plethysmograph for recording of cardiorespiratory function. To determine the contribution of CC to cardiorespiratory variables, selective ablation of chemoreceptor neurons within the retrotrapezoid nucleus (RTN) was performed via injection of saporin toxin conjugated to substance P (SSP-SAP). Vehicle-treated rats (HF+Veh and Sham+Veh) were used as controls for SSP-SAP experiments. Sixty minutes post-EHS, minute ventilation was depressed in sham animals relative to HF animals (ΔV̇e: -5.55 ± 2.10 vs. 1.24 ± 1.35 mL/min 100 g, P < 0.05; Sham+Veh vs. HF+Veh). Furthermore, EHS resulted in autonomic imbalance, cardiorespiratory entrainment, and ventilatory disturbances in HF+Veh but not Sham+Veh rats, and these effects were significantly attenuated by SSP-SAP treatment. Also, the apnea-hypopnea index (AHI) was significantly lower in HF+SSP-SAP rats compared with HF+Veh rats (AHI: 5.5 ± 0.8 vs. 14.4 ± 1.3 events/h, HF+SSP-SAP vs. HF+Veh, respectively, P < 0.05). Finally, EHS-induced respiratory-cardiovascular coupling in HF rats depends on RTN chemoreceptor neurons because it was reduced by SSP-SAP treatment. Overall, EHS triggers ventilatory plasticity and elicits cardiorespiratory abnormalities in HF that are largely dependent on RTN chemoreceptor neurons.

Cognitive impairment in heart failure is associated with altered Wnt signaling in the hippocampus.

Age represents the highest risk factor for death due to cardiovascular disease. Heart failure (HF) is the most common cardiovascular disease in elder population and it is associated with cognitive impairment (CI), diminishing learning and memory process affecting life quality and mortality in these patients. In HF, CI has been associated with inadequate O2 supply to the brain; however, an important subset of HF patients displays CI with almost no alteration in cerebral blood flow. Importantly, nothing is known about the pathophysiological mechanisms underpinning CI in HF with no change in brain tissue perfusion. Here, we aimed to study memory performance and learning function in a rodent model of HF that shows no change in blood flow going to the brain. We found that HF rats presented learning impairments and memory loss. In addition, HF rats displayed a decreased level of Wnt/ß-catenin signaling downstream elements in the hippocampus, one pathway implicated largely in aging diseases. Taken together, our results suggest that in HF rats CI is associated with dysfunction of the Wnt/ß-catenin signaling pathway. The mechanisms involved in the alterations of Wnt/ß-catenin signaling in HF and its contribution to the development/maintenance of CI deserves future investigations.

Heart rate variability alterations in infants with spontaneous hypertonia.

BACKGROUND: Hypertonia is characterized by increased resting muscle tone. Previous studies have shown that adult patients with hypertonia displayed autonomic imbalance. However, cardiac sympatho-vagal control in infants with hypertonia have not been explored. The main aim was to estimate cardiac autonomic control in infants with hypertonia using heart rate variability (HRV). METHODS: Thirty infants (0-2 years old) were studied. Heart rate (HR) and R-R interval time series were obtained in 15 Control and 15 Hypertonia infants. HRV was analyzed in time and frequency domains. Additionally, non-linear analysis and entropy measurements were performed. RESULTS: Infants with hypertonia showed cardiac autonomic imbalance as evidenced by alterations in HRV, characterized by an increased power spectral density of low frequency (LF) over high frequency (HF) components of HRV. Indeed, a ∼7% increase in LF, and ∼30% reduction in HF, were found in infants with hypertonia vs. control infants. In addition, time domain and non-linear HRV analysis (Root-mean-square of successive normal sinus R-R interval difference, entropy, and R-R interval variability) were all significantly decreased in hypertonia vs. control subjects. CONCLUSIONS: Our results showed that hypertonia infants displayed HRV disturbances, which suggest an alteration in overall autonomic cardiac modulation in infants with hypertonia compared with healthy condition.

Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure.

Activation of the sympathetic nervous system is a hallmark of heart failure (HF) and is positively correlated with disease progression. Catecholaminergic (C1) neurons located in the rostral ventrolateral medulla (RVLM) are known to modulate sympathetic outflow and are hyperactivated in volume overload HF. However, there is no conclusive evidence showing a contribution of RVLM-C1 neurons to the development of cardiac dysfunction in the setting of HF. Therefore, the aim of this study was to determine the role of RVLM-C1 neurons in cardiac autonomic control and deterioration of cardiac function in HF rats. A surgical arteriovenous shunt was created in adult male Sprague-Dawley rats to induce HF. RVLM-C1 neurons were selectively ablated using cell-specific immunotoxin (dopamine-ß hydroxylase saporin [DßH-SAP]) and measures of cardiac autonomic tone, function, and arrhythmia incidence were evaluated. Cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction were present in HF rats and improved after DßH-SAP toxin treatment. Most importantly, the progressive decline in fractional shortening observed in HF rats was reduced by DßH-SAP toxin. Our results unveil a pivotal role played by RVLM-C1 neurons in cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction in volume overload-induced HF.

Topical Application of Connexin43 Hemichannel Blocker Reduces Carotid Body-Mediated Chemoreflex Drive in Rats.

The carotid body (CB) is the main arterial chemoreceptor involved in oxygen sensing. Upon hypoxic stimulation, CB chemoreceptor cells release neurotransmitters, which increase the frequency of action potentials in sensory nerve fibers of the carotid sinus nerve. The identity of the molecular entity responsible for oxygen sensing is still a matter of debate; however several ion channels have been shown to be involved in this process. Connexin-based ion channels are expressed in the CB; however a definitive role for these channels in mediating CB oxygen sensitivity has not been established. To address the role of these channels, we studied the effect of blockers of connexin-based ion channels on oxygen sensitivity of the CB. A connexin43 (Cx43) hemichannel blocking agent (CHBa) was applied topically to the CB and the CB-mediated hypoxic ventilatory response (FiO2 21, 15, 10 and 5%) was measured in adult male Sprague-Dawley rats (~250 g). In normoxic conditions, CHBa had no effect on tidal volume or respiratory rate, however Cx43 hemichannels inhibition by CHBa significantly impaired the CB-mediated chemoreflex response to hypoxia. CHBa reduced both the gain of the hypoxic ventilatory response (HVR) and the maximum HVR by ~25% and ~50%, respectively. Our results suggest that connexin43 hemichannels contribute to the CB chemoreflex response to hypoxia in rats. Our results suggest that CB connexin43 hemichannels may be pharmacological targets in disease conditions characterized by CB hyperactivity.

Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter?

Heart failure (HF) is a global public health problem that, independent of its etiology [reduced (HFrEF) or preserved ejection fraction (HFpEF)], is characterized by functional impairments of cardiac function, chemoreflex hypersensitivity, baroreflex sensitivity (BRS) impairment, and abnormal autonomic regulation, all of which contribute to increased morbidity and mortality. Exercise training (ExT) has been identified as a nonpharmacological therapy capable of restoring normal autonomic function and improving survival in patients with HFrEF. Improvements in autonomic function after ExT are correlated with restoration of normal peripheral chemoreflex sensitivity and BRS in HFrEF. To date, few studies have addressed the effects of ExT on chemoreflex control, BRS, and cardiac autonomic control in HFpEF; however, there are some studies that have suggested that ExT has a beneficial effect on cardiac autonomic control. The beneficial effects of ExT on cardiac function and autonomic control in HF may have important implications for functional capacity in addition to their obvious importance to survival. Recent studies have suggested that the peripheral chemoreflex may also play an important role in attenuating exercise intolerance in HFrEF patients. The role of the central/peripheral chemoreflex, if any, in mediating exercise intolerance in HFpEF has not been investigated. The present review focuses on recent studies that address primary pathophysiological mechanisms of HF (HFrEF and HFpEF) and the potential avenues by which ExT exerts its beneficial effects.

Carotid Body-Mediated Chemoreflex Drive in The Setting of low and High Output Heart Failure.

Enhanced carotid body (CB) chemoreflex function is strongly related to cardiorespiratory disorders and disease progression in heart failure (HF). The mechanisms underlying CB sensitization during HF are not fully understood, however previous work indicates blood flow per se can affect CB function. Then, we hypothesized that the CB-mediated chemoreflex drive will be enhanced only in low output HF but not in high output HF. Myocardial infarcted rats and aorto-caval fistulated rats were used as a low output HF model (MI-CHF) and as a high output HF model (AV-CHF), respectively. Blood flow supply to the CB region was decreased only in MI-CHF rats compared to Sham and AV-CHF rats. MI-CHF rats exhibited a significantly enhanced hypoxic ventilatory response compared to AV-CHF rats. However, apnea/hypopnea incidence was similarly increased in both MI-CHF and AV-CHF rats compared to control. Kruppel-like factor 2 expression, a flow sensitive transcription factor, was reduced in the CBs of MI-CHF rats but not in AV-CHF rats. Our results indicate that in the setting of HF, potentiation of the CB chemoreflex is strongly associated with a reduction in cardiac output and may not be related to other pathophysiological consequences of HF.

Exercise training improves cardiac autonomic control, cardiac function, and arrhythmogenesis in rats with preserved-ejection fraction heart failure.

Chronic heart failure is characterized by autonomic imbalance, cardiac dysfunction, and arrhythmogenesis. It has been shown that exercise training (ExT) improves central nervous system oxidative stress, autonomic control, and cardiac function in heart failure with reduced ejection fraction; however, to date no comprehensive studies have addressed the effects of ExT, if any, on oxidative stress in brain stem cardiovascular areas, cardiac autonomic balance, arrhythmogenesis, and cardiac function in heart failure with preserved ejection fraction (HFpEF). We hypothesize that ExT reduces brain stem oxidative stress, improves cardiac autonomic control and cardiac function, and reduces arrhythmogenesis in HFpEF rats. Rats underwent sham treatment or volume overload to induce HFpEF. ExT (60 min/day, 25 m/min, 10% inclination) was performed for 6 wk starting at the second week after HFpEF induction. Rats were randomly allocated into Sham+sedentary (Sed) (n = 8), Sham+ExT (n = 6), HFpEF+Sed (n = 8), and HFpEF+ExT (n = 8) groups. Compared with the HFpEF+Sed condition, HFpEF+ExT rats displayed reduced NAD(P)H oxidase activity and oxidative stress in the rostral ventrolateral medulla (RVLM), improved cardiac autonomic balance, and reduced arrhythmogenesis. Furthermore, a threefold improvement in cardiac function was observed in HFpEF+ExT rats. These novel findings suggest that moderate-intensity ExT is an effective means to attenuate the progression of HFpEF through improvement in RVLM redox state, cardiac autonomic control, and cardiac function.NEW & NOTEWORTHY In the present study, we found that exercise reduced oxidative stress in key brain stem areas related to autonomic control, improved sympathovagal control of the heart, reduced cardiac arrhythmias, and delayed deterioration of cardiac function in rats with heart failure with preserved ejection fraction (HFpEF). Our results provide strong evidence for the therapeutic efficacy of exercise training in HFpEF.

Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats.

KEY POINTS: Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho-vagal imbalance. Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood. We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre-sympathetic regions of the brainstem. Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho-vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF. ABSTRACT: Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho-vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague-Dawley rats (n = 32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho-vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean ± SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2 ± 4.0 vs. 9.7 ± 2.6 events h-1 ), autonomic imbalance [0.6 ± 0.2 vs. 0.2 ± 0.1 low/high frequency heart rate variability (LF/HFHRV )] and cardiac arrhythmias (196.0 ± 239.9 vs. 19.8 ± 21.7 events h-1 ). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6 ± 43.2% vs. 296.0 ± 43.9% LF/HFHRV , normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0 ± 239.9 vs. 576.7 ± 472.9 events h-1 ) and diastolic dysfunction (0.008 ± 0.004 vs. 0.027 ± 0.027 mmHg µl-1 ). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF.