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Rochester, MN
Drs. Olson and Somers are affiliated with the Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Foundation.
Correspondence to: Lyle Olson, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: olson.lyle{at}mayo.edu
Cardiovascular disorders are the most common cause of morbidity and mortality in the Western World.1 Obstructive sleep apnea (OSA), which is estimated to affect > 15 million people in the United States, is also highly prevalent.2 Large, cross-sectional epidemiologic studies3 have demonstrated an association between OSA and the risk for hypertension, stroke, congestive heart failure, and coronary artery disease. However, confounding factors have made it difficult to definitively establish causal relationships, with the exception of systemic hypertension.4 Available studies have suggested that OSA is a risk factor for coronary artery disease, although the level of risk appears to be low. In the Sleep Heart Health study cohort,5 the odds ratio for coronary artery disease in the highest apnea-hypopnea index (AHI) quartile (AHI, > 11) was 1.27 compared to that in the lowest quartile (AHI, < 1.4). On the other hand, observational studies6 have suggested a significant increase in ischemic cardiac events in patients with untreated severe OSA, compared to those receiving treatment with continuous positive airway pressure (CPAP).
Potential mechanistic links between OSA and atherogenesis have been attributed to repetitive surges of sympathetic activity, BP and oxidative stress associated with recurrent apnea, hypoxemia, and the resumption of breathing, which may initiate vascular and endothelial injury via cyclic vasoconstriction and reoxygenation.5 Subsequent to endothelial injury, atherosclerosis may be promoted by an inflammatory response with leukocyte accumulation and adhesion. Moreover, circulating inflammatory mediators have been associated with an increased risk for cardiovascular events; the prototypic inflammatory marker is C-reactive protein (CRP) which may play a direct role in atherogenesis and thrombus formation.7
In patients with OSA without overt cardiovascular disease, CRP levels are elevated compared to those in healthy control subjects8 and may be lowered by therapy with CPAP.9 CRP levels are also increased in children with OSA.10 The elevation of homocysteine levels has also been associated with increased cardiovascular risk, although a link with OSA has not been firmly established. Prior studies have not shown consistent differences in homocysteine levels between subjects with OSA and control subjects,1112 although some data suggest that therapy with CPAP lowered homocysteine levels.13
In this context of OSA and cardiovascular risk factors, the report of Can and colleagues in this issue of CHEST (see page 233),14 which confirms increased concentrations of CRP as well as elevated homocysteine levels in a cohort of patients with OSA (AHI, > 5) compared to non-OSA patients (AHI, < 5), is considered. Several methodological concerns need to be factored into the interpretation of the data. These include the absence of more detailed information regarding comorbidities and medication use, each of which may affect circulating concentrations of CRP and homocysteine. The gender of the healthy control group is not provided, and the mean body mass index reported for this group appears to be considerably lower than the other two study groups (see Table 1 in the article).14 This is important because concentrations of both CRP and homocysteine have been previously related to obesity.711 Homocysteine and CRP levels appear to be rather high in many of the OSA patients. Nevertheless, some findings are of interest. The strength of the association between OSA and both CRP and homocysteine appears to be modest; an analysis by linear regression did not demonstrate a significant relationship with AHI. Whether cardiovascular risk mechanisms are activated as a consequence of the AHI, the magnitude of hypoxemia, or the number of arousals remains to be determined.
If the elevation of CRP and homocysteine levels is indeed due to OSA, and are lowered consistently by CPAP therapy, does this in turn lower the risk for cardiovascular events? Would any benefits of CPAP therapy be incremental to the proven benefits of treating coronary artery disease with ß-blockers, antiplatelet drugs, smoking cessation, and statin therapy?
The epidemic of obesity in the United States is associated with an increased prevalence of OSA, which is often present even in nonsleepy individuals. If CPAP therapy lowers the cardiovascular risk, the criteria for the implementation of CPAP therapy may need to be expanded to include an intervention for nonsleepy individuals with OSA. Alternatively, interventions that target metabolic dysregulation and inflammatory disease mechanisms, such as therapy with folate and statins, may conceivably have a role even in OSA patients who do not tolerate CPAP therapy. The implementation of such strategies will require rigorously designed studies that account for potentially confounding comorbidities by use of appropriate control subjects in order to identify mechanisms of disease pathogenesis and to test treatment interventions.
Footnotes
This research was supported by National Institutes of Health grants HL-71478, HL-65176, HL-61560, HL-70302, HL-73211, and M01-RR00585, and American Heart Association grant 04–50103Z.
References
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