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Background Activation of the oxytocin network has shown benefits in animal models of Obstructive Sleep Apnea (OSA) as well as other cardiorespiratory diseases. We sought to determine if nocturnal intranasal oxytocin administration could have beneficial effects in reducing the duration and/or frequency of obstructive events in obstructive sleep apnea subjects. Methods Two sequential standard “in-lab” polysomnogram (PSG) sleep studies were performed in patients diagnosed with OSA that were randomly assigned to initially receive either placebo or oxytocin (40 i.u.) administered intranasally in this double blinded randomized placebo controlled study. Changes in cardiorespiratory events during sleep, including apnea and hypopnea durations and frequency, risk of event-associated bradycardias, arterial oxygen desaturation and respiratory rate were assessed in 2 h epochs following sleep onset. Oxytocin significantly decreased the duration of obstructive events, as well as the oxygen desaturations and incidence of bradycardia that were associated with these events. Notably, oxytocin increased respiratory rate during non-obstructive periods. There were no significant changes in sleep architecture and no adverse effects were reported. Conclusions Oxytocin administration can benefit OSA subjects by reducing the duration and adverse consequences of obstructive events. Oxytocin could also be beneficial in situations involving respiratory depression as oxytocin increased respiratory rate. Additional studies are needed to further understand the mechanisms by which oxytocin promotes these changes in cardiorespiratory function. The long-term efficacy and optimal dose of intranasal oxytocin treatment should also be determined in OSA subjects. ClinicalTrials.gov NCT03148899.

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/β-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/β-catenin signaling pathway. The mechanisms involved in the alterations of Wnt/β-catenin signaling in HF and its contribution to the development/maintenance of CI deserves future investigations.

During an apnea, changes in PaO2activate 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 (VE), 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.

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 chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses and exercise tolerance were assessed at the end of a 6 weeks exercise training program. Exercise tolerant HF rats (HF+EX-T) completed all training sessions and benefit 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 chemoreflex contributes to EX-inT in HF.

Background and objective Chronic intermittent hypoxia (CIH), one of the main features of obstructive sleep apnea (OSA), enhances carotid body-mediated chemoreflex and induces hypertension and breathing disorders. The carbamylated form of erythropoietin (cEpo) may have beneficial effects as it retains its antioxidant/anti-inflammatory and neuroprotective profile without increasing red blood cells number. However, no studies have evaluated the potential therapeutic effect of cEpo on CIH-related cardiorespiratory disorders. We aimed to determine whether cEpo normalized the CIH-enhanced carotid body ventilatory chemoreflex, the hypertension and ventilatory disorders in rats. Methods Male Sprague-Dawley rats (250 g) were exposed to CIH (5% O2, 12/h, 8 h/day) for 28 days. cEPO (20 μg/kg, i.p) was administrated from day 21 every other day for one more week. Cardiovascular and respiratory function were assessed in freely moving animals. Results Twenty-one days of CIH increased carotid body-mediated chemoreflex responses as evidenced by a significant increase in the hypoxic ventilatory response (FiO2 10%) and triggered irregular eupneic breathing, active expiration, and produced hypertension. cEpo treatment significantly reduced the carotid body--chemoreflex responses, normalizes breathing patterns and the hypertension in CIH. In addition, cEpo treatment effectively normalized carotid body chemosensory responses evoked by acute hypoxic stimulation in CIH rats. Conclusion Present results strongly support beneficial cardiorespiratory therapeutic effects of cEpo during CIH exposure.

Background: Breathing disorders (BD) are highly prevalent in chronic heart failure (CHF) and are associated with altered central respiratory control. Ample evidence identifies the retrotrapezoid nucleus (RTN) as an important chemosensitivity region for ventilatory control and generation of BD in CHF, however little is known about the cellular mechanisms underlying the RTN/BD relationship. Within the RTN, astrocyte‐mediated purinergic signalling modulates respiration, but the potential contribution of RTN astrocytes to BD in CHF has not been explored. Methods: Selective neuron and/or astrocyte-targeted interventions using either optogenetic and chemogenetic manipulations in the RTN of CHF rats were used to unveil the contribution of the RTN on the development/maintenance of BD, the role played by astrocytes in BD and the molecular mechanism underpinning these alterations. Findings: We showed that episodic photo-stimulation of RTN neurons triggered BD in healthy rats, and that RTN neurons ablation in CHF animals eliminates BD. Also, we found a reduction in astrocytes activity and ATP bioavailability within the RTN of CHF rats, and that chemogenetic restoration of normal RTN astrocyte activity and ATP levels improved breathing regularity in CHF. Importantly, P2X7 receptor (P2X7r) expression was reduced in RTN astrocytes from CHF rats and viral vector-mediated delivery of human P2X7r into astrocytes increases ATP bioavailability and abolished BD. Interpretation: Our results support that RTN astrocytes play a pivotal role on BD generation and maintenance in the setting CHF by a mechanism encompassing P2X7r signalling. Funding: This study was funded in part by the National Research and Development Agency of Chile and the Basal Centre of Excellence in Aging and Regeneration Declaration of Interest: None to declare. Ethical Approval: All experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication eighth edition, update 2011). All experimental protocols were approved by the IACUC from the Pontificia Universidad Catolica de Chile (protocol ID #170710022).

Recent evidence shows that chronic activation of catecholaminergic neurons of the rostral ventrolateral medulla is crucial in promoting autonomic imbalance and cardiorespiratory dysfunction in high output heart failure (HF). Brainstem endoplasmic reticulum stress (ERS) is known to promote cardiovascular dysfunction; however, no studies have addressed the potential role of brainstem ERS in cardiorespiratory dysfunction in high output HF. In this study, we assessed the presence of brainstem ERS and its potential role in cardiorespiratory dysfunction in an experimental model of HF induced by volume overload. High output HF was surgically induced via creation of an arterio-venous fistula in adult male Sprague-Dawley rats. Tauroursodeoxycholic acid (TUDCA), an inhibitor of ERS, or vehicle was administered intracerebroventricularly for 4 weeks post-HF induction. Compared with vehicle treatment, TUDCA improved cardiac autonomic balance (LF HRV /HF HRV ratio, 3.02±0.29 versus 1.14±0.24), reduced cardiac arrhythmia incidence (141.5±26.7 versus 35.67±12.5 events/h), and reduced abnormal respiratory patterns (Apneas: 11.83±2.26 versus 4.33±1.80 events/h). TUDCA administration (HF+Veh versus HF+TUDCA, P

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.

Nickel nanopillar arrays were electrodeposited onto silicon substrates using porous alumina membranes as a template. The characterization of the samples was done by scanning electron microscopy, X-ray diffraction, and alternating force gradient magnetometry. Ni nanostructures were directly grown on Si by galvanostatic and potentiostatic electrodeposition techniques in three remarkable charge transfer configurations. Differences in the growth mechanisms of the nanopillars were observed, depending on the deposition method. A high correlation between the height of the nanopillars and the charge synthesis was observed irrespective of the electrochemical technique. The magnetization measurements demonstrated a main dependence with the height of the nanopillars. The synthesis of Ni nanosystems with a controllable aspect ratio provides an effective way to produce well-ordered networks for wide scientific applications.

In December 2019, a novel coronavirus-related disease (Covid-19) emerged in Wuhan, China, caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). This outbreak rapidly spread throughout the world, being declared a pandemic by the world health organization on March 11, 2020. Covid-19 and other coronavirus diseases such as SARS and MERS cause serious morbidity and mortality through initiation of severe viral pneumonia often progressing to acute respiratory distress syndrome (ARDS) and multiple organ system dysfunction (MODS) (Paules et al., 2020). Non-respiratory co-morbidities such as cardiac dysfunction, renal failure, and neurological abnormalities are reported in the literature; however it is still unclear whether these are a direct result of SARS-Cov-2 invading and destroying these tissues or are more broadly related to hypoxemia, inflammation, and/or thrombosis associated with ARDS/MODS in Covid-19 patients. Currently, there are no approved antiviral therapies or vaccines available to combat Covid-19, however major efforts are ongoing worldwide to rapidly address this urgent need. Biomedical research has become fundamental in the understanding of the mechanism(s) by which SARS-CoV-2 infects its host and leads to deterioration of human health. So far, genetic analysis has revealed several similarities between SARS-CoV-2 and the virus that caused the SARS epidemic in 2002, including the molecular targets that SARS coronaviruses use to bind to their host cells (Hoffmann et al., 2020). Specifically, the SARS-CoV-2 “spike” protein binds to the type 2 angiotensin converting enzyme (ACE2) at the surface of the host cell (Hoffmann et al., 2020). ACE2 is widely expressed in the human body (found in lung, bowel, kidney, brain, blood vessels) and participates in the regulation of angiotensin II (ANGII), a potent vasoactive peptide hormone. Synthesis of ANGII depends on the catalytic activity of the type 1 angiotensin converting enzyme (ACE) and ANGII levels are modulated by the catalytic activity of ACE2 which hydrolyzes ANGII to angiotensin 1-7 (Diaz et al., 2020; Guan et al., 2020; Hoffmann et al., 2020; Huang et al., 2020; Paules et al., 2020; South et al., 2020; Yang et al., 2020), a by-product of ANGII cleavage. Thus, ACE2 activity serves to limit ANGII production and protect from the potentially damaging consequences of high levels of systemic ANGII (South et al., 2020). ACE2 is also associated with processes that attenuate inflammation, making this enzyme an interesting pharmacological target for disease processes that result in over-activation of inflammatory pathways (South et al., 2020). In early March 2020, the first epidemiological and clinical characteristics of Covid-19 patients (191 patients) were published (Huang et al., 2020). Of the total number of patients confirmed with Covid-19, 48% of total hospitalized patients in this study had significant comorbidities including hypertension (30%), diabetes (19%), and heart disease (8%). A second study with 1,099 Covid-19 patients reported that the most severe outcomes were observed in patients with hypertension, diabetes mellitus, coronary heart disease, and cerebrovascular disease (Guan et al., 2020). In a third study, out of 140 patients positive for Covid-19, 30% had hypertension and 12% had diabetes. Finally, a study by Yang et al. (2020) found that in a cohort of patients who succumbed to Covid-19, the most prevalent comorbidities were diabetes and cardiovascular disease. Of note, most of the comorbidities reported in these studies are treated with ACE inhibitors (ACEi), as increased ANGII levels are a common pathophysiological feature. Recent opinion pieces have noted that in pre-clinical studies ACEi cause up-regulation of ACE2 and theorize that this could increase susceptibility of patients currently being treated with ACEi to infection by SARS-CoV-2. This observation has led some to hypothesize that withdrawing ACEi treatment in patients with hypertension or other cardio-metabolic conditions characterized by upregulation of the renin-angiotensin system (RAS) may decrease the risk of developing severe Covid-19. While this hypothesis is worthy of further study, to our knowledge there is no evidence at this time to support removal of ACEi or other RAS-related drugs in patients for whom they are indicated. In fact, we wish to advance the hypothesis that doing so could be directly detrimental to Covid-19 related morbidity in the cohort of patients who are statistically most likely to suffer the worst outcomes. There are well-established relationships between RAS activation and autonomic dysfunction in cardio-metabolic diseases such as hypertension, heart failure, and diabetes (Diaz et al., 2020). In these conditions often a positive feedback loop exists between RAS activation and tonic increases in efferent sympathetic nerve activity, wherein increases in sympathetic activity can stimulate activation of RAS which in turn can further upregulate sympathetic activity (Diaz et al., 2020). Removal of drugs which attenuate this positive feedback loop could in fact exacerbate autonomic dysfunction and inflammation associated with these diseases, and potentially contribute to morbidity associated with Covid-19.

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.

Alterations in connexins and specifically in 43 isoform (Cx43) in the heart have been associated with a high incidence of arrhythmogenesis and sudden death in several cardiac diseases. We propose to determine salutary effect of Cx43 mimetic peptide Gap27 in the progression of heart failure. High-output heart failure was induced by volume overload using the arterio-venous fistula model (AV-Shunt) in adult male rats. Four weeks after AV-Shunt surgery, the Cx43 mimetic peptide Gap27 or scrambled peptide, were administered via osmotic minipumps (AV-ShuntGap27 or AV-ShuntScr) for 4 weeks. Cardiac volumes, arrhythmias, function and remodeling were determined at 8 weeks after AV-Shunt surgeries. At 8th week, AV-ShuntGap27 showed a marked decrease in the progression of cardiac deterioration and showed a significant improvement in cardiac functions measured by intraventricular pressure-volume loops. Furthermore, AV-ShuntGap27 showed less cardiac arrhythmogenesis and cardiac hypertrophy index compared to AV-ShuntScr. Gap27 treatment results in no change Cx43 expression in the heart of AV-Shunt rats. Our results strongly suggest that Cx43 play a pivotal role in the progression of cardiac dysfunction and arrhythmogenesis in high-output heart failure; furthermore, support the use of Cx43 mimetic peptide Gap27 as an effective therapeutic tool to reduce the progression of cardiac dysfunction in high-output heart failure.

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.

Activation of oxytocin receptors has shown benefits in animal models of obstructive sleep apnea (OSA). We tested if nocturnal oxytocin administration could have beneficial effects in OSA patients. Eight patients diagnosed with OSA were administered intranasal oxytocin (40 IU). Changes in cardiorespiratory events during sleep, including apnea and hypopnea durations and frequency, risk of event-associated arousals, and heart rate variability, were assessed. Oxytocin significantly increased indexes of parasympathetic activity, including heart rate variability, total sleep time, and the postpolysommogram sleep assessment score, an index of self-reported sleep satisfaction. Although the apnea-hypopnea index was not significantly changed with oxytocin administration, when apnea and hypopnea events were compared independently, the frequency of hypopneas, but not apneas, was significantly ( P ≤ 0.005) decreased with oxytocin treatment. Both apneas and hypopneas were significantly shortened in duration with oxytocin treatment. Oxytocin treatment significantly decreased the percent of apnea and hypopnea events that were accompanied with an arousal. Oxytocin administration has the potential to restore cardiorespiratory homeostasis and reduce some clinically important (objective and patient-reported) adverse events that occur with OSA. Additional studies are needed to further understand the mechanisms by which oxytocin promotes these changes in cardiorespiratory and autonomic function in OSA patients.

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. Kruppel-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, Kruppel-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

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.

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.

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.

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. This work was supported by Vicerrectoría de Investigación from Universidad Mayor (PEP I-2019050). Del Rio R., is supported by Fondecyt grant 1180172 and the Basal Center of Excellence in Aging and Regeneration (AFB 170005) and the special grant 'Lithium in Health and Disease' from the Sociedad Química y Minera de Chile (SQM).

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 ([Formula: see text]) 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.

Heart failure (HF) is a complex clinical syndrome affecting roughly 26 million people worldwide. Increased sympathetic drive is a hallmark of HF and is associated with disease progression and higher mortality risk. Several mechanisms contribute to enhanced sympathetic activity in HF, but these pathways are still incompletely understood. Previous work suggests that inflammation and activation of the renin-angiotensin system (RAS) increases sympathetic drive. Importantly, chronic inflammation in several brain regions is commonly observed in aged populations, and a growing body of evidence suggests neuroinflammation plays a crucial role in HF. In animal models of HF, central inhibition of RAS and pro-inflammatory cytokines normalizes sympathetic drive and improves cardiac function. The precise molecular and cellular mechanisms that lead to neuroinflammation and its effect on HF progression remain undetermined. This review summarizes the most recent advances in the field of neuroinflammation and autonomic control in HF. In addition, it focuses on cellular and molecular mediators of neuroinflammation in HF and in particular on brain regions involved in sympathetic control. Finally, we will comment on what is known about neuroinflammation in the context of preserved vs. reduced ejection fraction HF.

Ventilation is peripherally controlled by afferent activity arising from the peripheral chemoreceptors. In the rat, chemosensory activity is conveyed to the central nervous system through axons of neurons located in the nodose-petrosal-jugular-complex. These neurons have distinct electrophysiological properties, including a persistent Na+ current. Acute blockade of this current with phenytoin and other anti-epileptic drugs reduces normoxic chemosensory activity and responses to acute hypoxia. However, because anti-epileptic therapy is prolonged and there is no information on the effects of chronic phenytoin treatment on peripheral chemosensory activity, we studied the effects of long-lasting phenytoin treatment (~25 days) on afferent chemosensory activity, on a wide range of oxygen inspiratory fractions. Osmotic pumps containing dissolved phenytoin (166mg/mL) or vehicle (daily flow: 60µL) were implanted subcutaneously in male adult Sprague Dawley rats. At the end of the treatment, the animals were anesthetized and carotid sinus nerve activity was recorded in vivo. Afferent chemosensory activity in normoxia was not significantly different between control (71.2±2.2Hz) and phenytoin treated (95.4±2.1Hz) rats. In contrast, carotid body chemosensory responses to acute hypoxic challenges were markedly reduced in phenytoin treated rats, specifically in the lowest part of the hypoxic range (control 133.5±18.0Hz vs phenytoin treated 50.2±29.4, at 5% FIO2). Chronic phenytoin treatment severely impaired the chemosensory responses to acute hypoxia, suggesting that long-term phenytoin treatment in patients may result in a reduced peripheral respiratory drive together with a reduction in the respiratory responses to hypoxic challenges.

Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) chemosensory responses to hypoxia and produces autonomic dysfunction, cardiac arrhythmias, and hypertension. We tested whether autonomic alterations, arrhythmogenesis, and the progression of hypertension induced by CIH depend on the enhanced CB chemosensory drive, by ablation of the CB chemoreceptors. Male Sprague–Dawley rats were exposed to control (Sham) conditions for 7 days and then to CIH (5% O 2 , 12/h 8 h/d) for a total of 28 days. At 21 days of CIH exposure, rats underwent bilateral CB ablation and then exposed to CIH for 7 additional days. Arterial blood pressure and ventilatory chemoreflex response to hypoxia were measured in conscious rats. In addition, cardiac autonomic imbalance, cardiac baroreflex gain, and arrhythmia score were assessed during the length of the experiments. In separate experimental series, we measured extracellular matrix remodeling content in cardiac atrial tissue and systemic oxidative stress. CIH induced hypertension, enhanced ventilatory response to hypoxia, induced autonomic imbalance toward sympathetic preponderance, reduced baroreflex gain, and increased arrhythmias and atrial fibrosis. CB ablation normalized blood pressure, reduced ventilatory response to hypoxia, and restored cardiac autonomic and baroreflex function. In addition, CB ablation reduced the number of arrhythmias, but not extracellular matrix remodeling or systemic oxidative stress, suggesting that reductions in arrhythmia incidence during CIH were related to normalization of cardiac autonomic balance. Present results show that autonomic alterations induced by CIH are critically dependent on the CB and support a main role for the CB in the CIH-induced hypertension.

Chronic heart failure (CHF) is a major public health problem. Tonic hyper-activation of sympathetic neural outflow is commonly observed in patients with CHF. Importantly, sympatho-excitation in CHF exacerbates its progression and is strongly related to poor prognosis and high mortality risk. Increases in both peripheral and central chemoreflex drive are considered markers of the severity of CHF. The principal peripheral chemoreceptors are the carotid bodies (CBs) and alteration in their function has been described in CHF. Mainly, during CHF the CB chemosensitivity is enhanced leading to increases in ventilation and sympathetic outflow. In addition to peripheral control of breathing, central chemoreceptors (CCs) are considered a dominant mechanism in ventilatory regulation. Potentiation of the ventilatory and sympathetic drive in response to CC activation has been shown in patients with CHF as well as in animal models. Therefore, improving understanding of the contribution of the peripheral and central chemoreflexes to augmented sympathetic discharge in CHF could help in developing new therapeutic approaches intended to attenuate the progression of CHF. Accordingly, the main focus of this review is to discuss recent evidence that peripheral and central chemoreflex function are altered in CHF and that they contribute to autonomic imbalance and progression of CHF.

Changes in the polarization state of light due to its interaction (reflection and transmission) with samples of CuSCN nanorod and ZnO nanowire arrays are analyzed and compared following a recently proposed technique (Valente et al., 2019). The determination of the degree of polarization and measurements of diffusive light are used to investigate the influence of the morphology of nanorods and nanowires on the optical properties. It is shown that the CuSCN nanorods are better than ZnO nanowires to preserve polarization, although the degree of polarization decreases with the lengths for both materials. It is shown that the degree of polarization correlate with the diffusive light, which allow an estimation of the large scale uniformity of the samples. However, it is also shown that the loss of polarization quality can be present even in absence of diffusion, which indicates that the interferometric effect on the nanoscale should be an important cause of the depolarizing effect.

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 β-hydroxylase-saporin toxin (DβH-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+DβH-SAP; P 0.5 between breathing and cardiovascular signals) and was attenuated by DβH-SAP treatment (coherence: 0.74 ± 0.12 vs. 0.54 ± 0.10, HF+Veh vs. HF+DβH-SAP rats; P

Background: chronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it's impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation. Results: exposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R-R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R-R spectrograms and produced a prominent component in the low-frequency component (0.2-0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits. Conclusions: These results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.

Plyometric training performed at sea level enhance explosive and endurance performance at sea level. However, its effects on explosive and endurance performance at high altitude had not been studied. Therefore, the aim of this study was to determine the effects of a sea level short-term (i.e., 4-week) plyometric training program on explosive and endurance performance at sea level and at high altitude (i.e., 3,270 m above sea level). Participants were randomly assigned to a control group (n = 12) and a plyometric training group (n = 11). Neuromuscular (reactive strength index – RSI) and endurance (2-km time-trial; running economy [RE]; maximal oxygen uptake - VO2max) measurements were performed at sea level before, at sea level after intervention (SL +4 week), and at high altitude 24-h post SL +4 week. The ANOVA revealed that at SL +4 week the VO2max was not significantly changed in any group, although RE, RSI and 2-km time trial were significantly (p < 0.05) improved in the plyometric training group. After training, when both groups were exposed to high altitude, participants from the plyometric training group showed a greater RSI (p < 0.05) and were able to maintain their 2-km time trial (11.3 ± 0.5 min vs. 10.7 ± 0.6 min) compared to their pre-training sea level performance. In contrast, the control group showed no improvement in RSI, with a worse 2-km time trial performance (10.3 ± 0.8 min vs. 9.02 ± 0.64 min; p < 0.05; ES = 0.13). Moreover, after training, both at sea level and at high altitude the plyometric training group demonstrated a greater (p < 0.05) RSI and 2-km time trial performance compared to the control group. The oxygen saturation was significantly decreased after acute exposure to high altitude in the two groups (p < 0.05). These results confirm the beneficial effects of sea level short-term plyometric training on explosive and endurance performance at sea level. Moreover, current results indicates that plyometric training may also be of value for endurance athletes performing after an acute exposure to high altitude.

Obstructive sleep apnea (OSA) is the most common form of sleep disordered breathing and is associated with wide array of cardiovascular morbidities. It has been proposed that during OSA, the respiratory control center (RCC) is affected by exaggerated afferent signals coming from peripheral/central chemoreceptors which leads to ventilatory instability and may perpetuate apnea generation. Treatments focused on decreasing hyperactivity of peripheral/central chemoreceptors may be useful to improving ventilatory instability in OSA patients. Previous studies indicate that oxidative stress and inflammation are key players in the increased peripheral/central chemoreflex drive associated with OSA. Recent data suggest that erythropoietin (Epo) could also be involved in modulating chemoreflex activity as functional Epo receptors are constitutively expressed in peripheral and central chemoreceptors cells. Additionally, there is some evidence that Epo has anti-oxidant/anti-inflammatory effects. Accordingly, we propose that Epo treatment during OSA may reduce enhanced peripheral/central chemoreflex drive and normalize the activity of the RCC which in turn may help to abrogate ventilatory instability. In this perspective article we discuss the potential beneficial effects of Epo administration on ventilatory regulation in the setting of OSA.

Erythropoietin (EPO) has protective effects in several tissues and could be used for therapeutic purposes. However, EPO-induced erythropoiesis could be detrimental in treated patients. Carbamylation of erythropoietin maintains the tissue-protective effects of EPO but without erythropoietic effects. Here, we assume that carbamylated erythropoietin (cEPO) prevents the cardiorespiratory deleterious effects induced by chronic intermittent hypoxia. Indeed, Obstructive Sleep Apnoea (OSA) is characterised by Chronic Intermittent Hypoxia (CIH) that leads to an increase in oxidative stress, responsible for cardiorespiratory disorders. To test our hypothesis, Sprague-Dawley male rats (around 300g) were exposed to CIH for 1 month (8 h/days; 12 cycles per hour; FiO2 nadir: 5% O2). cEpo was administrated during the last week of CIH exposure and cardiorespiratory variables as well as chemoreflex function were evaluated in control conditions (Sham), after 3 weeks of CIH and then 1 week after and cEPO treatment (CIH-Epo). As expected, cEPO had no effect on haematocrit. CIH increased mean arterial pressure, frequency of apnea/hypopnea and hypoxic and hypercapnic ventilatory responses. cEPO treatment prevented CIH-induced hypertension, reduced the Apnea-Hypopnea index and improved the stability of breathing pattern after CIH exposure. Furthermore, cEpo reduced the increase in chemoreflex function observed during exposure to CIH. In conclusion, cEpo prevented cardiorespiratory disorders induced by CIH. These results suggest that cEpo could be considered as a treatment for patients with OSA-induced cardio-respiratory disorders.

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). 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. 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. 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.

Recent advances have drawn interest in the potential for carotid body (CB) ablation or desensitization as an effective strategy for clinical treatment and management of cardio-respiratory diseases including hypertension, heart failure, diabetes mellitus, metabolic syndrome, and renal failure. These disease states have in common sympathetic overactivity, which plays an important role in the development and progression of the disease and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. Evidence from both chronic heart failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic activity and the development of periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a tonic increase in afferent activity from CB glomus cells is likely to be a main driving force. This report will focus on our understanding of mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.

Chronic heart failure (CHF) is a leading medical problem worldwide. Common hallmarks of CHF include autonomic imbalance and breathing disorders, both of which are closely related to the progression of the disease and strongly predict mortality in CHF patients. The role played by the carotid body (CB) chemoreceptors on the progression of CHF has received attention since enhanced carotid chemoreflex drive is thought to contribute to autonomic dysfunction, abnormal breathing patterns, and increased mortality in CHF. Therefore, therapeutic tools intended to normalize CB-mediated chemoreflex drive could have the potential to better improve life quality and decrease mortality of CHF patients. In experimental CHF it has been shown an enhancement of the CB chemoreflex drive, elevated sympathetic outflow, increased resting breathing variability and apnoea incidence, and desensitization of the baroreflex. Notably, selective elimination of the CB reduced central presympathetic neuronal activation, normalized sympathetic outflow and baroreflex sensitivity, and stabilized breathing function in CHF. More remarkably, CB ablation has been shown to be a valuable therapeutic tool that significantly reduced aberrant cardiac remodeling and improved left ventricle ejection fraction and reduced cardiac arrhythmogenesis. Most importantly, CHF animals that underwent CB ablation showed a marked improvement in survival rate. Interestingly, a case report from a heart failure patient in which unilateral CB ablation was performed showed promising results with significant improvement in autonomic balance and breathing variability. Together, CHF data from experimental animals as well as humans unveil a major role for the carotid body chemoreceptors in the progression of heart failure and support the notion that CB ablation could represent a novel therapeutic strategy to reduce cardiorespiratory dysfunction and improve survival during heart failure.

Chronic heart failure (CHF) is a global health problem affecting millions of people. Autonomic dysfunction and disordered breathing patterns are commonly observed in patients with CHF, and both are strongly related to poor prognosis and high mortality risk. Tonic activation of carotid body (CB) chemoreceptors contributes to sympathoexcitation and disordered breathing patterns in experimental models of CHF. Recent studies show that ablation of the CB chemoreceptors improves autonomic function and breathing control in CHF and improves survival. These exciting findings indicate that alterations in CB function are critical to the progression of CHF. Therefore, better understanding of the physiology of the CB chemoreflex in CHF could lead to improvements in current treatments and clinical management of patients with CHF characterized by high chemosensitivity. Accordingly, the main focus of this brief review is to summarize current knowledge of CB chemoreflex function in different experimental models of CHF and to comment on their potential translation to treatment of human CHF.

Cheyne–Stokes respiration and cardiac arrhythmias are associated with increased morbidity and mortality in patients with chronic heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body (CB) nitric oxide and nitric oxide synthase (NOS) levels play an important role in the enhanced CBC. In other disease models, Simvastatin (statin) treatment increases endothelial NOS, in part, by increasing Krüppel-like Factor 2 expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index, in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and CB chemoreceptor afferent responses to hypoxia were assessed in rats with CHF induced by coronary ligation. CHF was associated with enhanced ventilatory and CB afferent responses to hypoxia as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in respiratory variability, apnea/hypopnea index, and arrhythmia index. Krüppel-like Factor 2 and endothelial NOS protein were decreased in the CB and nucleus tractus solitarii of CHF animals, and statin treatment increased the expression of these proteins. Our findings demonstrate that the increased CBC sensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by statin treatment and suggest that statins may be an effective treatment for Cheyne–Stokes respiration and arrhythmias in patient populations with high chemoreflex sensitivity.

In congestive heart failure (CHF), carotid body (CB) chemoreceptor activity is enhanced and is associated with oscillatory (Cheyne–Stokes) breathing patterns, increased sympathetic nerve activity (SNA) and increased arrhythmia incidence. We hypothesized that denervation of the CB (CBD) chemoreceptors would reduce SNA, reduce apnoea and arrhythmia incidence and improve ventricular function in pacing-induced CHF rabbits. Resting breathing, renal SNA (RSNA) and arrhythmia incidence were measured in three groups of animals: (1) sham CHF/sham–CBD (sham–sham); (2) CHF/sham–CBD (CHF–sham); and (3) CHF/CBD (CHF–CBD). Chemoreflex sensitivity was measured as the RSNA and minute ventilatory () responses to hypoxia and hypercapnia. Respiratory pattern was measured by plethysmography and quantified by an apnoea–hypopnoea index, respiratory rate variability index and the coefficient of variation of tidal volume. Sympatho-respiratory coupling (SRC) was assessed using power spectral analysis and the magnitude of the peak coherence function between tidal volume and RSNA frequency spectra. Arrhythmia incidence and low frequency/high frequency ratio of heart rate variability were assessed using ECG and blood pressure waveforms, respectively. RSNA and responses to hypoxia were augmented in CHF–sham and abolished in CHF–CBD animals. Resting RSNA was greater in CHF–sham compared to sham–sham animals (43 ± 5% max vs. 23 ± 2% max, P

Objectives This study sought to investigate whether selective ablation of the carotid body (CB) chemoreceptors improves cardiorespiratory control and survival during heart failure. Background Chronic heart failure (CHF) is a recognized health problem worldwide, and novel treatments are needed to better improve life quality and decrease mortality. Enhanced carotid chemoreflex drive from the CB is thought to contribute significantly to autonomic dysfunction, abnormal breathing patterns, and increased mortality in heart failure. Methods Chronic heart failure was induced by coronary ligation in rats. Selective CB denervation was performed to remove carotid chemoreflex drive in the CHF state (16 weeks post-myocardial infarction). Indexes of autonomic and respiratory function were assessed in CB intact and CB denervated animals. CB denervation at 2 weeks post-myocardial infarction was performed to evaluate whether early targeted CB ablation decreases the progression of left ventricular dysfunction, cardiac remodeling, and arrhythmic episodes and improves survival. Results The CHF rats developed increased CB chemoreflex drive and chronic central pre-sympathetic neuronal activation, increased indexes of elevated sympathetic outflow, increased breathing variability and apnea incidence, and desensitization of the baroreflex. Selective CB ablation reduced the central pre-sympathetic neuronal activation by 40%, normalized indexes of sympathetic outflow and baroreflex sensitivity, and reduced the incidence of apneas in CHF animals from 16.8 ± 1.8 events/h to 8.0 ± 1.4 events/h. Remarkably, when CB ablation was performed early, cardiac remodeling, deterioration of left ventricle ejection fraction, and cardiac arrhythmias were reduced. Most importantly, the rats that underwent early CB ablation exhibited an 85% survival rate compared with 45% survival in CHF rats without the intervention. Conclusions Carotid chemoreceptors play a seminal role in the pathogenesis of heart failure, and their targeted ablation might be of therapeutic value to reduce cardiorespiratory dysfunction and improve survival during CHF.

Important recent advances implicate a role of the carotid body (CB) chemoreflex in sympathetic and breathing dysregulation in several cardio-respiratory diseases, drawing renewed interest in its potential implications for clinical treatment. Evidence from both chronic heart failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF, and contributes to the tonic elevation in sympathetic nerve activity (SNA) and periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a change in afferent function of the CB is likely to be a main driving force. This review will focus on recent advances in our understanding of the pathophysiological mechanisms that alter CB function in CHF and their potential translational impact on treatment of chronic heart failure (CHF).

Thin amorphous nanostructured CdS films were photochemically obtained via direct UV radiation (λ=254 nm) of complex Cd[(CH3)2CHCH2CH2OCS2]2 on Si(1 0 0) and ITO-covered glass substrate by spin coating. Thin cadmium xanthate complex films’ UV photolysis results in loss of all ligands from the coordination sphere. X-ray photoelectron spectra for as-deposited CdS thin films show the most representative signals of Cd 3d5/2 located at 405 eV, Cd 3d3/2 located at 412 eV and a small signal S 2p located at 162 eV. The surface morphology of the films was examined via atomic force microscopy. This can be described as a fibrous-type surface without structural order, which is characteristic of an amorphous deposit. The optical band gap value was 2.85 and 3.15±0.1 eV.

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO−scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2(266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO−formation.

The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.