Fibrinogen, Stroke, and Obstructive Sleep Apnea
An Evolving Paradigm of Cardiovascular Risk

Abu S. M. Shamsuzzaman and Virend K. Somers

Divisions of Hypertension and Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

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Obstructive sleep apnea (OSA) has been linked increasingly to cardiovascular disease. Disturbances in inflammatory and coagulation profiles, particularly cytokines and fibrinogen, have emerged as possible mediators of cardiovascular pathophysiology in OSA. In the current issue of the Journal (pp. 2039-2042) Wessendorf and colleagues provide further insight into possible interactions between plasma fibrinogen and ischemic stroke in patients with OSA (1).

Fibrinogen, a plasma protein synthesized in the liver, is intimately involved in blood coagulation. Fibrinogen is also an acute-phase protein, increasing in response to infection and inflammation (2). Thrombosis superimposed on atherosclerosis contributes importantly to cardiovascular events (2). Fibrinogen enhances thrombosis and atherosclerosis by effects on platelet aggregation, blood rheology, and endothelial cell injury (3). Fibrinogen and its degradation products may also damage blood vessel walls by stimulating smooth muscle proliferation and migration (4).

Notwithstanding these theoretical constructs linking fibrinogen to vascular disease, what is the evidence that high fibrinogen is associated with increased cardiovascular events? The first clear epidemiologic data, from the Northwick Park Heart Study, showed that initial fibrinogen levels were associated with cardiovascular mortality independent of other risk factors (5). These early findings have been echoed by a series of other studies (2, 6). The data implicating fibrinogen are especially striking for myocardial infarction and stroke (7). In patients with unstable angina or non-Q wave myocardial infarction, high fibrinogen predicts subsequent myocardial infarction and death (8). A cerebrovascular correlate to this is that in stroke survivors hyperfibrinogenemia is an independent risk factor for subsequent stroke, heart attack, and cardiovascular death (9).

Like fibrinogen, OSA may also be implicated as a risk factor for first stroke, recurrent stroke, and poststroke mortality (1, 10). OSA patients have increased morning levels of fibrinogen (13). Elevated fibrinogen may be one mechanism linking OSA to stroke. The present study by Wessendorf and coworkers (1) of patients with ischemic stroke, describes first that stroke patients have a high prevalence of OSA, and second that stroke patients with OSA also have higher fibrinogen levels. The authors suggest that high fibrinogen may contribute to increased vascular morbidity in OSA patients, and make the important point that OSA should be considered when examining fibrinogen as a vascular risk factor.

As with any cross-sectional study, there are clear but understandable constraints and limitations regarding their data. Single measurements of fibrinogen in the morning leave open the question of whether fibrinogen rises after untreated OSA (13), or whether patients with OSA and stroke have persistently high prevailing levels of fibrinogen. There is a paucity of patients with severe sleep apnea, so that the regression slopes described are dependent on a small number of subjects with the most severe apnea. Nor does the study provide any suggestion as to what we are to make of those patients with comparatively severe apnea, but in whom fibrinogen levels were at the lower limits of measurements. Last, the strength of association described between OSA and fibrinogen is only modest, and no causality is demonstrated. Any etiologic link to stroke is extrapolation, pending more robust data.

Nevertheless, this study raises a number of interesting questions. First, the lack of severe apnea in their patient sample encourages speculation that patients with more severe apnea did not survive the stroke. Second, it is widely held that body mass index (BMI) and other measures of obesity are determinants of fibrinogen (14). Obesity is linked to a higher prevalence of sleep apnea. It is notable that Wessendorf and colleagues found that OSA, but not BMI, was independently associated with elevated fibrinogen (1). Perhaps if OSA were factored into epidemiologic studies of fibrinogen, the association with BMI would be weaker and less consistent. This caveat may be relevant to a host of measures of cardiovascular risk presently ascribed to obesity per se, and obtained without adjusting for the potential influence of OSA.

A third question concerns why patients with OSA should have high fibrinogen. It is conceivable that the myriad of biochemical, neurohumoral, inflammatory, and metabolic disturbances induced by OSA may elicit increases in fibrinogen. Less biologically plausible is that high fibrinogen may induce OSA. Could the high fibrinogen be merely a reflection of the acute-phase reaction to the stroke insult, with stroke being worse and fibrinogen consequently higher in those patients with preexisting OSA? Fibrinogen is itself highly variable, being influenced by behavioral, environmental, seasonal, pharmacologic, and other factors (3). Fibrinogen levels are high after stroke, and remain significantly elevated for at least 6 wk after a stroke (15). Data showing plasma cell infiltration and interstitial edema in the uvula mucosa of patients with OSA may also be relevant (16). The investigators postulate that soft palate inflammation may contribute to upper airway occlusion during sleep. These data also raise the speculative but provocative possibility that airway inflammation associated with OSA may induce increases in plasma fibrinogen.

A fourth issue is the difference between men and women not only in the prevelance of OSA, but also in the measurements and implications of fibrinogen. Average fibrinogen levels are higher in women (17). Plasma fibrinogen rises after menopause and may be reduced by hormone replacement (18), variables not addressed in the present study (1). Mechanisms linking fibrinogen to the development of cerebrovascular disease may be different in males and females. In the Framingham Heart Study, fibrinogen was linked to heart attack and stroke in men (6). In women, fibrinogen was also strongly linked to heart attack, but there was only a weak association with stroke.

Finally, and perhaps most important, can a reduction in fibrinogen be achieved, and will this affect cardiovascular outcomes in patients with OSA? Treatment of OSA with nasal continuous positive airway pressure (CPAP) may elicit small decreases in fibrinogen (13). A number of pharmacologic agents, many directed at lipid lowering, have serendipitously been found to also lower plasma fibrinogen (19). In the Bezafibrate Infarction Prevention Study (20), baseline fibrinogen was confirmed as an independent predictor of cardiovascular events in patients with coronary artery disease. Preliminary data suggest that in patients with high baseline fibrinogen levels, reduction of fibrinogen by bezafibrate therapy was linked to decreased cardiac death and ischemic stroke. Whether fibrinogen represents a surrogate for other more direct mediators of cardiovascular risk remains to be determined. This will be important for understanding the pathophysiologic interactions between fibrinogen, OSA, and stroke.

Acknowledgments: The authors appreciate the helpful suggestions and comments of Dr. John Greenwood, MBChB, PhD.

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