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

Abstract

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‐1α 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‐κB/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

Unraveling the Complexities of Oxidative Stress and Inflammation Biomarkers in Obstructive Sleep Apnea Syndrome: A Comprehensive Review

“…The work of Fadaei et al supports the potential utility of circulating miRNAs, specifically miR125a, miR126, and miR146a-5p, as biomarkers for endothelial dysfunction in OSA patients, which could serve as non-invasive diagnostic tools [65]. The transition from physiological adaptation to pathological maladaptation in response to chronic intermittent hypoxia, a hallmark of OSA, is discussed by Arnaud et al, providing insights into the systemic effects of the disorder [66]. Nguyen et al highlighted the role of peripheral inflammation due to sleep fragmentation, suggesting that inflammation biomarkers could be a key to understanding and treating OSA-related comorbidities [93].…”

“…Unfortunately, the specific mechanisms triggering the development of endothelial dysfunction in OSA remain unclear [62]. Exposure to harmful cellular risks, such as oxidative stress, may result in endothelial dysfunction [63][64][65], leading to a reduction in its ability to dilate blood vessels, an elevation in proinflammatory and prothrombotic reactions, and abnormal regulation of vascular growth [66]. OSAS induces intermittent hypoxia, triggering oxidative stress and inflammation.…”

“…Notably, OSAS is strongly associated with cardiovascular complications, including systemic hypertension, arrhythmias, coronary artery disease, and stroke [50,57,66,73]. The link between OSAS and hypertension is particularly significant, with up to 80% of patients with resistant hypertension potentially suffering from OSAS [73].…”

Recent progresses in gut microbiome mediates obstructive sleep apnea‐induced cardiovascular diseases

“…These findings are consistent with the clinically observed phenotype. Patients with OSA exhibit reduced circulating NO and impaired endothelium‐dependent vasodilation 81 . In addition, as a well‐studied pathological process, the LPS/TLR4 pathway has been implicated in the disease phenotype of OSA.…”

(Mal)adaptative responses of arterial chemoreceptors: O2‐dependent and ‐independent mechanisms

“…Another paper in this series relating OSA and cardiovascular outcomes, by Arnaud et al (2023) and the intensity and duration of CIH on cardio -hypertension, atrial fibrillation and heart failure -and renal dysfunction, and focused on the mechanisms such as sympathovagal imbalance, oxidative stress, inflammation, dysregulated HIF-1α transcriptional responses and resultant pro-apoptotic endoplasmic reticulum stress, calcium dysregulation and mitochondrial dysfunction driving myocardial injury and failure. Moreover, they provide several insights into the indirect and direct effects of CIH in the kidney that contribute to hypertension and later to chronic kidney disease.…”