The superior cervical ganglion is involved in chronic chemoreflex sensitization during recovery from acute lung injury.

Introduction: Acute lung injury (ALI) initiates an inflammatory cascade that impairs gas exchange, induces hypoxemia, and causes an increase in respiratory rate (fR). This stimulates the carotid body (CB) chemoreflex, a fundamental protective reflex that maintains oxygen homeostasis. Our previous study indicated that the chemoreflex is sensitized during the recovery from ALI. The superior cervical ganglion (SCG) is known to innervate the CB, and its electrical stimulation has been shown to significantly sensitize the chemoreflex in hypertensive and normotensive rats. We hypothesized that the SCG is involved in the chemoreflex sensitization post-ALI. Methods: We performed a bilateral SCG ganglionectomy (SCGx) or sham-SCGx (Sx) in male Sprague Dawley rats 2 weeks before inducing ALI (Week -2 i.e., W-2). ALI was induced using a single intra-tracheal instillation of bleomycin (bleo) (day 1). Resting-fR, Vt (Tidal Volume), and V̇ E (Minute Ventilation) were measured. The chemoreflex response to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before surgery on W (-3), before bleo administration on W0 and on W4 post-bleo using whole-body plethysmography (WBP). Results: SCGx did not affect resting fR, Vt and V̇E as well as the chemoreflex responses to hypoxia and normoxic hypercapnia in either group prior to bleo. There was no significant difference in ALI-induced increase in resting fR between Sx and SCGx rats at W1 post-bleo. At W4 post-bleo, there were no significant differences in resting fR, Vt, and V̇E between Sx and SCGx rats. Consistent with our previous study, we observed a sensitized chemoreflex (delta fR) in response to hypoxia and normoxic hypercapnia in Sx rats at W4 post-bleo. However, at the same time, compared to Sx rats, the chemoreflex sensitivity was significantly less in SCGx rats in response to either hypoxia or normoxic hypercapnia. Discussion: These data suggest that SCG is involved in the chemoreflex sensitization during ALI recovery. Further understanding of the underlying mechanism will provide important information for the long-term goal of developing novel targeted therapeutic approaches to pulmonary diseases to improve clinical outcomes.

Time-dependent alteration in the chemoreflex post-acute lung injury.

Acute lung injury (ALI) induces inflammation that disrupts the normal alveolar-capillary endothelial barrier which impairs gas exchange to induce hypoxemia that reflexively increases respiration. The neural mechanisms underlying the respiratory dysfunction during ALI are not fully understood. The purpose of this study was to investigate the role of the chemoreflex in mediating abnormal ventilation during acute (early) and recovery (late) stages of ALI. We hypothesized that the increase in respiratory rate (fR) during post-ALI is mediated by a sensitized chemoreflex. ALI was induced in male Sprague-Dawley rats using a single intra-tracheal injection of bleomycin (Bleo: low-dose = 1.25 mg/Kg or high-dose = 2.5 mg/Kg) (day 1) and respiratory variables- fR, Vt (Tidal Volume), and VE (Minute Ventilation) in response to 10% hypoxia (10% O2, 0% CO2) and 5% hypercapnia/21% normoxia (21% O2, 5% CO2) were measured weekly from W0-W4 using whole-body plethysmography (WBP). Our data indicate sensitization (∆fR = 93 ± 31 bpm, p < 0.0001) of the chemoreflex at W1 post-ALI in response to hypoxic/hypercapnic gas challenge in the low-dose bleo (moderate ALI) group and a blunted chemoreflex (∆fR = -0.97 ± 42 bpm, p < 0.0001) at W1 post-ALI in the high-dose bleo (severe ALI) group. During recovery from ALI, at W3-W4, both low-dose and high-dose groups exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia. We then hypothesized that the blunted chemoreflex at W1 post-ALI in the high-dose bleo group could be due to near maximal tonic activation of chemoreceptors, called the "ceiling effect". To test this possibility, 90% hyperoxia (90% O2, 0% CO2) was given to bleo treated rats to inhibit the chemoreflex. Our results showed no changes in fR, suggesting absence of the tonic chemoreflex activation in response to hypoxia at W1 post-ALI. These data suggest that during the acute stage of moderate (low-dose bleo) and severe (high-dose bleo) ALI, chemoreflex activity trends to be slightly sensitized and blunted, respectively while it becomes significantly sensitized during the recovery stage. Future studies are required to examine the molecular/cellular mechanisms underlying the time-course changes in chemoreflex sensitivity post-ALI.

Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle.

KEY POINTS: Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle-specific transgenic mouse models with unbiased-omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two-way model to understand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and other stresses. ABSTRACT: Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2-deficient or overexpressed skeletal muscle tissues will provide a broader spectrum of Nrf2 targets and downstream pathways than are currently known. To this end, we created two transgenic mouse models; the iMS-Nrf2flox/flox and iMS-Keap1flox/flox , employing which we demonstrated that selective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle function. Mass spectrometry revealed that Nrf2-KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 proteins in common between the groups. Gene ontology analysis suggested that Nrf2 KO-changed proteins are involved in metabolism of oxidoreduction coenzymes, purine ribonucleoside triphosphate, ATP and propanoate, which are considered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detoxification, NADP metabolism, glutathione metabolism and the electron transport chain, which belong to the induced effect of Nrf2. Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did not. Ingenuity pathway analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and functions. Finally, we validated the proteomic and bioinformatics data by analysing glutathione metabolism and mitochondrial function. In conclusion, we found that Nrf2-targeted proteins are assigned to two groups: one mediates the tonic effects evoked by a low level of Nrf2 at basal condition; the other is responsible for the inducible effects evoked by a surge of Nrf2 that is dependent on a Keap1 mechanism.

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.

Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats.

KEY POINTS: A strong association between disordered breathing patterns, elevated sympathetic activity, and enhanced central chemoreflex drive has been shown in experimental and human heart failure (HF). The aim of this study was to determine the contribution of catecholaminergic rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) to both haemodynamic and respiratory alterations in HF. Apnoea/hypopnoea incidence (AHI), breathing variability, respiratory-cardiovascular coupling, cardiac autonomic control and cardiac function were analysed in HF rats with or without selective ablation of RVLM-C1 neurones. Partial lesion (∼65%) of RVLM-C1 neurones reduces AHI, respiratory variability, and respiratory-cardiovascular coupling in HF rats. In addition, the deleterious effects of central chemoreflex activation on cardiac autonomic balance and cardiac function in HF rats was abolished by ablation of RVLM-C1 neurones. Our findings suggest that RVLM-C1 neurones play a pivotal role in breathing irregularities in volume overload HF, and mediate the sympathetic responses induced by acute central chemoreflex activation. ABSTRACT: Rostral ventrolateral medulla catecholaminergic neurones (RVLM-C1) modulate sympathetic outflow and breathing under normal conditions. Heart failure (HF) is characterized by chronic RVLM-C1 activation, increased sympathetic activity and irregular breathing patterns. Despite studies showing a relationship between RVLM-C1 and sympathetic activity in HF, no studies have addressed a potential contribution of RVLM-C1 neurones to irregular breathing in this context. Thus, the aim of this study was to determine the contribution of RVLM-C1 neurones to irregular breathing patterns in HF. Sprague-Dawley rats underwent surgery to induce volume overload HF. Anti-dopamine ß-hydroxylase-saporin toxin (DßH-SAP) was used to selectively lesion RVLM-C1 neurones. At 8 weeks post-HF induction, breathing pattern, blood pressures (BP), respiratory-cardiovascular coupling (RCC), central chemoreflex function, cardiac autonomic control and cardiac function were studied. Reduction (∼65%) of RVLM-C1 neurones resulted in attenuation of irregular breathing, decreased apnoea-hypopnoea incidence (11.1 ± 2.9 vs. 6.5 ± 2.5 events h-1 ; HF+Veh vs. HF+DßH-SAP; P < 0.05) and improved cardiac autonomic control in HF rats. Pathological RCC was observed in HF rats (peak coherence >0.5 between breathing and cardiovascular signals) and was attenuated by DßH-SAP treatment (coherence: 0.74 ± 0.12 vs. 0.54 ± 0.10, HF+Veh vs. HF+DßH-SAP rats; P < 0.05). Central chemoreflex activation had deleterious effects on cardiac function and cardiac autonomic control in HF rats that were abolished by lesion of RVLM-C1 neurones. Our findings reveal that RVLM-C1 neurones play a major role in irregular breathing patterns observed in volume overload HF and highlight their contribution to cardiac dysautonomia and deterioration of cardiac function during chemoreflex activation.

Sympathoexcitation in response to cardiac and pulmonary afferent stimulation of TRPA1 channels is attenuated in rats with chronic heart failure.

Excessive sympathoexcitation characterizes the chronic heart failure (CHF) state. An exaggerated cardiac sympathetic afferent reflex (CSAR) contributes to this sympathoexcitation. Prior studies have demonstrated that the CSAR to capsaicin [transient receptor potential (TRP) vanilloid 1 agonist] is exaggerated in CHF animal models. We recently discovered that capsaicin application to the lung visceral pleura in anesthetized, vagotomized, open-chested rats increases mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). We named this response the pulmonary spinal afferent reflex (PSAR). Due to the similarities between TRP vanilloid 1 and TRP ankyrin 1 (TRPA1) channels as well as the excessive sympathoexcitation of CHF, we hypothesized that stimulation of the CSAR and PSAR with a specific TRPA1 agonist would result in an augmented response in CHF rats (coronary ligation model) compared with sham control rats. In response to a TRPA1 agonist, both CSAR and PSAR in sham rats resulted in biphasic changes in MAP and increases in HR and RSNA 10-12 wk postmyocardial infarction (post-MI). These effects were blunted in CHF rats. Assessment of TRPA1 expression levels in cardiopulmonary spinal afferents by immunofluorescence, quantitative RT-PCR, and Western blot analysis 10-12 wk post-MI all indicates reduced expression in CHF rats but no reduction at earlier time points. TRPA1 protein was reduced in a dorsal root ganglia cell culture model of inflammation and simulated tissue ischemia, raising the possibility that the in vivo reduction of TRPA1 expression was, in part, caused by CHF-related tissue ischemia and inflammation. These data provide evidence that reflex responses to cardiopulmonary spinal afferent TRPA1 stimulation may be attenuated in CHF rather than enhanced. NEW & NOTEWORTHY Excessive sympathoexcitation characterizes chronic heart failure (CHF). The contribution of transient receptor potential ankyrin 1 (TRPA1) channel-mediated reflexes to this sympathoexcitation is unknown. We found that application of TRPA1 agonist to the heart and lung surface resulted in increased heart rate and sympathetic output and a biphasic change in mean arterial pressure in control rats. These effects were attenuated in CHF rats, decreasing the likelihood that TRPA1 channels contribute to cardiopulmonary afferent sensitization in CHF.

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.

Curcumin improves exercise performance of mice with coronary artery ligation-induced HFrEF: Nrf2 and antioxidant mechanisms in skeletal muscle.

A hallmark of chronic heart failure (HF) with low ejection fraction (HFrEF) is exercise intolerance. We hypothesized that reduced expression of nuclear factor E2-related factor 2 (Nrf2) in skeletal muscle contributes to impaired exercise performance. We further hypothesized that curcumin, a Nrf2 activator, would preserve or increase exercise capacity in HF. Experiments were carried out in mice with coronary artery ligation-induced HFrEF. Curcumin was deliveried by a subcutaneous osmotic minipump at a dose of 50 mg·kg-1·day-1 for 8 weeks. In vivo, in situ, and in vitro experiments were employed to evaluate exercise capacity, muscle function, and molecular mechanisms. We found that: 1) the maximal speed, running distance to exhaustion, and limb grip force were significantly lower in HFrEF mice compared with sham. Curcumin-treated HF mice displayed enhanced exercise performance compared with vehicle-treated HF mice; 2) both soleus (Sol) and extensor digitorum longus (EDL) muscles of HFrEF mice exhibited reduced force and rapid fatigue, which were ameliorated by curcumin; and 3) protein expression of Nrf2, hemeoxygenase-1, SOD2, myogenin, and MyoD were significantly lower, but total ubiquitinated proteins, MURF1, and atrogen-1 were higher in Sol and EDL of HFrEF compared with sham mice, whereas these alterations in Nrf2 signaling and antioxidant defenses in HFrEF were attenuated by curcumin, which had no effect on cardiac function per se in mice with severe HFrEF. These data suggest that impaired Nrf2 signaling intrinsic to skeletal muscle contributes to exercise intolerance in HFrEF. Skeletal muscle Nrf2 should be considered as a novel therapeutic target in severe HF. NEW & NOTEWORTHY These studies suggest that impaired nuclear factor E2-related factor 2 (Nrf2) signaling is a critical mechanism underlying the enhanced oxidative stress in skeletal muscle in heart failure with low ejection fraction (HFrEF). Curcumin prevents the decline in running performance in HFrEF mice by upregulating antioxidant defenses in skeletal muscle, likely mediated by activating Nrf2 signaling. These findings suggest a novel therapeutic target for the improvement of exercise capacity and quality of life in HFrEF patients.

Chronic Heart Failure Abolishes Circadian Rhythms in Resting and Chemoreflex Breathing.

Physiological systems often display 24 h rhythms that vary with the light/dark cycle. Disruption of circadian physiological rhythms have been linked to the progression of various cardiovascular diseases, and advances in the understanding of these rhythms have led to novel interventions and improved clinical outcomes. Although respiratory function has been known to vary between the light and dark periods, circadian rhythms in breathing have been understudied in clinical conditions. In the current study, we have begun to assess light/dark variations in respiration in chronic heart failure (CHF), a condition associated with abnormal resting and chemoreflex breathing as well as exercise intolerance. CHF was induced using coronary artery ligation and verified using echocardiography. Sham animals underwent a thoracotomy without coronary artery ligation. Tidal volume, respiratory frequency, and minute ventilation were all determined by whole body plethysmography under resting conditions and in response to chemoreflex challenges during the light and dark periods. Light/dark differences in voluntary exercise were assessed using a running wheel. The sham control group showed light/dark differences in resting and chemoreflex breathing, as well as arterial pressure, and these effects were eliminated in the CHF group. Both groups completed more rotations on the running wheel during the dark period compared to during the light period. The data suggest that CHF disrupts cardiovascular and respiratory circadian rhythms.

Sympatho-excitatory response to pulmonary chemosensitive spinal afferent activation in anesthetized, vagotomized rats.

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1-sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague-Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1-expressing afferent soma at the level of T1-T4 dorsal root ganglia pleura. This treatment abolished all sympatho-excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9-10 weeks post-RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli.

KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure.

KEY POINTS: Enhanced carotid body chemoreflex activity contributes to development of disordered breathing patterns, autonomic dysregulation and increases in incidence of arrhythmia in animal models of reduced ejection fraction heart failure. Chronic reductions in carotid artery blood flow are associated with increased carotid body chemoreceptor activity. Krüppel-like Factor 2 (KLF2) is a shear stress-sensitive transcription factor that regulates the expression of enzymes which have previously been shown to play a role in increased chemoreflex sensitivity. We investigated the impact of restoring carotid body KLF2 expression on chemoreflex control of ventilation, sympathetic nerve activity, cardiac sympatho-vagal balance and arrhythmia incidence in an animal model of heart failure. The results indicate that restoring carotid body KLF2 in chronic heart failure reduces sympathetic nerve activity and arrhythmia incidence, and improves cardiac sympatho-vagal balance and breathing stability. Therapeutic approaches that increase KLF2 in the carotid bodies may be efficacious in the treatment of respiratory and autonomic dysfunction in heart failure. ABSTRACT: Oscillatory breathing and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid body chemoreflex (CBC) sensitivity plays a role in this process and can be precipitated by chronic blood flow reduction. We hypothesized that downregulation of a shear stress-sensitive transcription factor, Krüppel-like Factor 2 (KLF2), mediates increased CBC sensitivity in CHF and contributes to associated autonomic, respiratory and cardiac sequelae. Ventilation (Ve), renal SNA (RSNA) and ECG were measured at rest and during CBC activation in sham and CHF rabbits. Oscillatory breathing was quantified as the apnoea-hypopnoea index (AHI) and respiratory rate variability index (RRVI). AHI (control 6 ± 1/h, CHF 25 ± 1/h), RRVI (control 9 ± 3/h, CHF 29 ± 3/h), RSNA (control 22 ± 2% max, CHF 43 ± 5% max) and arrhythmia incidence (control 50 ± 10/h, CHF 300 ± 100/h) were increased in CHF at rest ( FIO2 21%), as were CBC responses (Ve, RSNA) to 10% FIO2 (all P < 0.05 vs. control). In vivo adenoviral transfection of KLF2 to the carotid bodies in CHF rabbits restored KLF2 expression, and reduced AHI (7 ± 2/h), RSNA (18 ± 2% max) and arrhythmia incidence (46 ± 13/h) as well as CBC responses to hypoxia (all P < 0.05 vs. CHF empty virus). Conversely, lentiviral KLF2 siRNA in the carotid body decreased KLF2 expression, increased chemoreflex sensitivity, and increased AHI (6 ± 2/h vs. 14 ± 3/h), RRVI (5 ± 3/h vs. 20 ± 3/h) and RSNA (24 ± 4% max vs. 34 ± 5% max) relative to scrambled-siRNA rabbits. In conclusion, down-regulation of KLF2 in the carotid body increases CBC sensitivity, oscillatory breathing, RSNA and arrhythmia incidence during CHF.

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.

The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?

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.