Claudia Lucero

Carotid Body Ablation Abrogates Hypertension and Autonomic Alterations Induced by Intermittent Hypoxia in Rats

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% O2, 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.

Relevance of the Carotid Body Chemoreflex in the Progression of 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.

Contribution of peripheral and central chemoreceptors to sympatho‐excitation in heart failure

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.

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

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.

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.

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.

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

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