The importance of understanding the role of biochemical markers of systemic inflammation, oxidative stress, and prothrombosis is readily apparent in terms of characterizing underlying biology, developing predictive models to inform risk stratification and personalized medicine strategies as well as identifying appropriate targets for clinical trials. These biomarker profiles have been studied in many disease states and have been a focus over the past several decades in advancing our knowledge of obstructive sleep apnea (OSA) and cardiovascular biologic interrelationships in both translational and experimental studies. Operating likely via pathways of OSA-induced intermittent hypoxia and arousal mechanisms, several broad-spectrum, circulating markers of systemic inflammation have been shown to be upregulated in OSA, including C-reactive protein, interleukin-6, soluble interleukin-6 receptor, and tumor necrosis factor-alpha.1
In a departure from investigation of conventional biomarkers, in the current issue of the Journal of Clinical Sleep Medicine, Matsumura and colleagues examined the association of circulating anti-coatomer protein complex subunit epsilon antibody (COPE-Ab), as a potential novel marker of atherosclerosis, and cardiovascular disease in patients with OSA.2 The investigation is borne out of preliminary studies from this group using serological identification of antigen by recombinant complementary DNA expression cloning (SEREX) utilizing the COPE antigen to characterize immunoreactivity and identify COPE-Ab levels in those with atherosclerosis. In this Japan-based study, there were 82 participants with OSA and 64 healthy controls without history of OSA. Overall, controls were middle-aged and with median body mass index (BMI) of 23.1 kg/m2. As anticipated, the group with OSA were older with slightly higher median BMI (25.9 kg/m2), higher levels of comorbidity, and a severe degree of OSA: median apneahypopnea index = 36.7 (66% with severe OSA), nadir oxygen saturation = 78% and arousal index = 37.3. Higher levels of COPE-Ab were observed in those with OSA compared to controls and most notable in the moderate and severe OSA groups. In the OSA group, those with increased COPE-Ab levels had a 3.9-fold higher odds of cardiovascular disease and/or stroke after adjustment for age, BMI, and cardiovascular risk factors.
The current work is of interest not only given the quest to identify and refine biochemical marker profiles in OSA which are predictive of cardiovascular risk, but also given the recent focus on the role of circulating autoantibodies such as those against apolipoprotein B-100 as potential causal contributors to atherosclerosis.3,4 Specifically, COPE-Ab is a coatomer, i.e., a protein complex that coats membrane-bound vesicles.5 It is involved with transport of vesicles from the Golgi apparatus to the endoplasmic reticulum and is involved with the processing, activity, and recycling of low-density lipoprotein receptors. Unlike many prior studies that have not effectively elucidated morbidity biomarkers in OSA,6 the current work clearly demonstrates a significant association of COPE-Ab and cardiovascular disease and stroke, suggesting a possible beneficial role in risk stratification to identify those with OSA most likely to have cardiovascular risk.
That said, although biologic plausibility of COPE-Ab as a candidate marker for OSA-associated cardiovascular risk is based on preliminary data from the authors and its role in lipid biology, there are few other studies that have examined this marker in cardiovascular disease let alone in this context, thereby emphasizing the need for cautious interpretation. For example, replication and validation studies are needed to further clarify the association of COPE-Ab in OSA and cardiovascular disease. As the current sample studied has relatively lower levels of obesity compared to other ethnicities, it remains unclear whether COPE-Ab levels as a biomarker involved in lipid regulation would garner similar presence and magnitude of associations in individuals with differing ethnic backgrounds and adiposity. Ascertainment of generalizability of findings in women and in those with lesser OSA burden is warranted given male predominance of the sample and relatively high burden of OSA and hypoxia. Moreover, clarification of biomarker measurement variability is also of key importance in understanding the effect on examination of associations of interest. COPE-Ab as a novel biomarker of interest based on emerging preliminary data warrants further experimental data to better understand its role in atherogenesis models and responses to OSA-related pathophysiologic consequences such as intermittent hypoxia and sympathetic nervous system activation.
It is clear that biomarkers of cardiovascular risk in OSA could provide a powerful approach for prognostication—and thereby inform dedication of preventative efforts and allocation of resources to those at highest risk for adverse downstream cardiovascular health consequences.7 In general, development of prediction profiles has been a focus spanning many areas including genomics, proteomics, metabolomics, and bioinformatics in an effort to link biologic markers to clinical prediction of cardiovascular outcomes. Notwithstanding inherent limitations of suboptimal CPAP adherence, although data from a large recent randomized clinical trial do not support improvement in cardiovascular outcomes with CPAP usage, sleepiness symptoms were improved, suggesting that there may be a certain phenotype or subgroup of individuals who may respond to OSA pathophysiology reversal.8 This may be either symptom-based or perhaps be related to cardiovascular vulnerability detected by valid and reliable biomarker profiles to identify those at highest risk.
Although compelling, the jury is still out on the role of COPE-Ab in OSA and cardiovascular risk prediction because more data are needed. What remains certain is the need to continue to investigate biologically meaningful biomarkers that are cost-effective, valid, and precise to accurately predict cardiovascular risk in OSA to inform personalized medicine strategies and potentially identify those most likely to benefit from therapy, thereby informing future clinical trials.
Dr. Mehra has received research support from the NIH, Philips Respironics, and Resmed; receives salary from Cleveland Clinic; has received speaking honorarium from the American Academy of Sleep Medicine; and receives royalties from Up to Date.
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