Chronic intermittent hypoxia-induced cardiovascular and renal dysfunction: from adaptation to maladaptation

Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH-induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro-inflammatory and pro-oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho-vagal imbalance, oxidative stress, inflammation, dysregulated HIF-1 alpha transcriptional responses and resultant pro-apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH-induced morphological damage of the kidney is dependent on TLR4/NF-kappa B/NLRP3/caspase-1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut-kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes.image Abstract figure legend Chronic intermittent hypoxia (CIH) refers to a pathological pattern of oxygen dysregulation, characterised by brief (seconds-to-minutes), recurrent cycling between normal physiological and low levels of O2 (multiple events per hour), that is prolonged (days-to-years). CIH induces molecular and functional responses in the heart, vessels and kidneys that initially might be protective and adaptive but become deleterious according to the severity and chronicity of the exposure. In rodents, there is some consensus that exposure to 10% O2, 15 cycles/h, 12 h/day, less than 14 days is a mild/short-term CIH paradigm while exposure to 2-5% O2, 48 cycles/h, 6 h/day, for 30 days is severe/long-term and causes detrimental effects. The molecular pattern caused by CIH has many similarities among the heart, vessels and kidney and is compatible with sympathetic and renin-angiotensin-aldosterone system activation, HIF activation, oxidative stress and inflammation. The translation of the molecular signatures found in rodent models to humans is a challenge to be addressed in the future to allow a better patient stratification and to predict responses to drug and mainstay treatments such as continuous positive airway pressure (CPAP). CHOP, C/EBP homologous protein (endoplasmic reticulum stress-induced apoptosis pathway); EPO, erythropoietin; ET-1, endothelin-1; HIF, hypoxia inducible factor; iNOS, inducible nitric oxide synthase; VEGF, vascular endothelial growth factor.image