Obstructive sleep apnoea (OSA) is a strong independent risk factor for atrial fibrillation (AF). Emerging clinical data cite adverse effects of OSA on AF induction, maintenance, disease severity, and responsiveness to treatment. Prevention using continuous positive airway pressure (CPAP) is effective in some groups but is limited by its poor compliance. Thus, an improved understanding of the underlying arrhythmogenic mechanisms will facilitate the development of novel therapies and/or better selection of those currently available to complement CPAP in alleviating the burden of AF in OSA. Arrhythmogenesis in OSA is a multifactorial process characterised by a combination of acute atrial stimulation on a background of chronic electrical, structural, and autonomic remodelling. Chronic intermittent hypoxia (CIH), a key feature of OSA, is associated with long-term adaptive changes in myocyte ion channel currents, sensitising the atria to episodic bursts of autonomic reflex activity. CIH is also a potent driver of inflammatory and hypoxic stress, leading to fibrosis, connexin downregulation, and conduction slowing. Atrial stretch is brought about by negative thoracic pressure (NTP) swings during apnoea, promoting further chronic structural remodelling, as well as acutely dysregulating calcium handling and electrical function. Here, we provide an up-to-date review of these topical mechanistic insights and their roles in arrhythmia.

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood and oxygen delivery to the brain and vital organs. However, in certain conditions, including obstructive sleep apnea, heart failure and essential/spontaneous hypertension, the CB becomes hyperactive, promoting neurogenic hypertension and arrhythmia. G-protein-coupled receptors (GPCRs) are very highly expressed in the CB and have key roles in mediating baseline CB activity and hypoxic sensitivity. Here, we provide a brief overview of the numerous GPCRs that are expressed in the CB, their mechanism of action and downstream effects. Furthermore, we will address how these GPCRs and signaling pathways may contribute to CB hyperactivity and cardiovascular and respiratory disease. GPCRs are a major target for drug discovery development. This information highlights specific GPCRs that could be targeted by novel or existing drugs to enable more personalized treatment of CB-mediated cardiovascular and respiratory disease.

Chronic hypoxia (CH) is a key feature of chronic obstructive pulmonary disease (COPD), and carotid body hyperactivity is a major contributor to the cardiovascular pathology seen in these patients. CD73, an ecto‐5′‐nucleotidase that converts AMP to adenosine, is functionally important in the healthy carotid body. However it is unknown if CD73 contributes to carotid body hyperactivity associated with CH. The current work investigated whether selective targeting of CD73 could attenuate carotid body hyperactivity and ameliorate cardiovascular function in CH animals. CH rats (F _i O ₂ of 12% for 10 days) exhibited basal carotid body chemoafferent hyperactivity, augmented hypoxic sensitivity and increased minute ventilation. Immunohistochemical analysis demonstrated that CH increased the number of tyrosine hydroxylase positive (TH ⁺ ) type I cells containing CD73 (CD73 ⁺ TH ⁺ ) within the carotid body. Pharmacological inhibition of CD73 using α, β‐methylene ADP (AOPCP) abolished CH‐induced basal chemoafferent hyperactivity and normalised the heightened hypoxic sensitivity ex vivo . These effects were largely mimicked by the transmembrane adenylyl cyclase (tmAC) inhibitor SQ22536. In vivo administration of AOPCP to CH animals caused a dose‐dependent decrease in arterial blood pressure, an effect that was attenuated following carotid sinus nerve section (CSNX). Therefore this research identifies CD73 and tmAC as important determinants of carotid body hyperactivity associated with CH. Effective targeting of CD73 alleviates carotid body hyperactivity, leading to a decrease in blood pressure, without abolishing reflex responses to hypoxia. These findings should be a first step towards the development of selective CD73/tmAC targeted therapies in the carotid body to safely improve cardiovascular outcomes in CH patients. image Key points: Chronic hypoxia (CH), a key feature of chronic obstructive pulmonary disease, causes carotid body hyperactivity and cardiovascular pathology. The current work evaluated whether ecto‐5′‐nucleotidase (CD73) is important in promoting carotid body hyperactivity in CH animals. CH increases the proportion of type I cells containing CD73 (CD73 ⁺ TH ⁺ ) in the carotid body. Pharmacological targeting of CD73 and transmembrane adenylyl cyclases (tmAC) abolishes basal carotid body chemoafferent hyperactivity in CH and normalises the exaggerated responses to acute hypoxia ex vivo . In vivo inhibition of CD73 induces a dose‐dependent decrease in arterial blood pressure in normoxia, which is attenuated following carotid sinus nerve section. However AOPCP does not abolish cardiovascular‐respiratory responses to severe hypoxia. CD73 and tmAC are important in promoting carotid body hyperactivity in CH. Selective targeting of CD73 and cAMP signalling may safely reduce carotid body hyperactivity and thus improve cardiovascular outcomes in chronically hypoxic patients.