A newly-published review is calling for more randomized trials to be carried out in order to further strengthen the relationship between obstructive sleep apnea (OSA) and cardiovascular mortality. In the first of a two-part review, the authors acknowledge that, while mechanisms linking poor sleep quality and quantity and OSA to cardiometabolic risk are well known, definitive randomized trials showing improvements in hard outcomes with interventions are lacking. The authors of the investigation, which appears in the September 24 issue of the Journal of the American College of Cardiology, go on to question whether OSA is truly an independent CVD risk factor. “Such studies are needed in children and adults, as well as in those with OHS, overlap syndrome, and OSA comorbid with type 2 diabetes mellitus and heart failure with preserved ejection fraction,” “Studies in women, particularly during pregnancy, are also lacking,” added the authors of the review, led by Shahrokh Javaheri, MD, of TriHealth Bethesda North Hospital, in Cincinnati, Ohio. OHS’ role in CV risk One of the review’s key takeaways focuses on the association of OSA with increased cardiovascular risk, amplified by obesity hypoventilation syndrome (OHS) and overlapping syndromes. Here, the authors reiterate the scale of the challenge, with the prevalence of people with severe obesity increasing from 3.1% to 6.9% in men, and from 6.2% to 11.5% in women, between 2005 and 2017. Complications arising from OSA are all the more urgent in patients with OHS, who are exposed to much more profound intermittent hypoxemia as well as severe sustained hypoxemia and hypercapnia, both during sleep and wakefulness. Not surprisingly, when compared with eucapnic OSA, patients with OHS have a higher pro-atherosclerotic RANTES chemokine, a more prominent decrease in the anti-inflammatory adipokine adiponectin, and increasingly impaired endothelial function. As the authors point out, these conditions are known to be strongly associated with increased CV risk. “In the Pickwick Study, participants with OHS had a significant burden of CV and metabolic morbidity, including systemic hypertension, impaired LV diastolic dysfunction and type 2 diabetes mellitus,” they cited. Differences in gender The review also discusses the presentation and cardiovascular implications of OSA that differ between men and women. Although the overall prevalence of sleep disordered breathing (SDB) is lower in women compared with men, the authors say that there are periods of increased vulnerability for SDB in women. This includes pregnancy and post menopause, and the degree of SDB may be mitigated with hormone replacement therapy. Multicenter epidemiologic data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort identified that as the cohort aged, women manifested greater SDB-related CV risk not observed in men, This includes increased incident heart failure and LV mass, and increasing high-sensitivity troponin levels, perhaps due to aging-related alterations in female hormone levels. “The physiological phenotype of SDB in women also seems to differ compared with men: women typically have an overall lower AHI, although higher REM-related apnea, shorter duration apnea and hypopnea [and] less pronounced oxygen desaturation…which affects sex-specific differential SDB drivers of CV outcomes.” Gut microbiota alterations The review also discusses potential mechanisms linking sleep apnea to incident CVD that may involve alterations in the gut microbiome. Preliminary studies suggest that OSA not only induces substantive modification in gut microbiome but that such changes underlie some of the end-organ morbidities of OSA. The review cites research which describes the effect an increased abundance of the genus Lachnospiraceae and reduced detection of the genus Coprococcus has in rats exposed to intermittent hypoxia-simulating features of OSA. This includes significant increases in T-helper 1, T-helper 17 and TNF-aþ cells in the gut, spleen and aorta, along with neuroinflammatory responses, all of which were further causally implicated in systemic hypertension. “It remains unclear and unexplored whether therapeutic interventions aimed at restoring the gut microbiome will mitigate the magnitude of CV morbidities or enhance the reversibility of such morbidities when CPAP treatment in instituted,” the authors concluded. Sources: Javaheri S, Javaheri S, Somers VK, et al. Interactions of Obstructive Sleep Apnea With the Pathophysiology of Cardiovascular Disease, Part 1. J Am Coll Cardiol. 2024;84:1208–1223. Image Credit: Waqas – stock.adobe.com