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Obstructive sleep apnea, hypertension, and fibrin clot properties: a novel pathogenetic link with cardiovascular disease?

Doumas, Michaela,b; Stavropoulos, Konstantinosa; Imprialos, Konstantinosa

doi: 10.1097/HJH.0000000000001316

a2nd Propaedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece

bVA Medical Center, George Washington University, Washington, District of Columbia, USA

Correspondence to Michael Doumas, Konstantinoupoleos 49 Street, 54642, Thessaloniki, Greece. Tel: +30 2310 992899; e-mail:

Obstructive sleep apnea (OSA) is a relatively common syndrome that affects approximately 3–7% of the middle-aged individuals and becomes more prevalent with aging [1]. Over recent decades, the prevalence of the syndrome has been rising, potentially because of the increasing prevalence of obesity. OSA patients are in increased risk for hypertension (especially in a nondipping pattern) and drug-resistant hypertension, metabolic disorders, cardiovascular morbidity and mortality, cancer-related, and all-cause mortality [2–4]. Respiratory abnormalities during the night-time, including recurrent events of upper airways obstruction during sleep seem to be the predominant pathogenetic mechanism. Subsequent hypoxia leads to sympathetic stimulation, inflammation, and oxidative stress. These disorders are the major contributors of increased blood pressure (BP) and cardiovascular damage in OSA patients. Continuous positive airway pressure (CPAP) is presented as the first-line therapy for OSA via reversing upper airway obstruction and hypoxia [5]. Meta-analytic data also suggests that CPAP use could significantly reduce BP levels and the effect is more pronounced in higher adherence [6,7]. However, CPAP impact on attenuation of cardiovascular disorders in OSA stays inconclusive and several aspects such as duration and time of use is under consideration [5].

Fibrin clot abnormalities have been proposed as a crucial risk factor for cardiovascular disease [8]. In brief, architecture of fibrin network, mechanical properties of clot, and characteristic of fibrinolysis might determine whether a clot will be lysed sufficiently or lead to an occlusive or embolic event. Accumulating data suggests that a fibrin clot composed by tightly packed, thin fibers reduced permeability, and prolonged clot lysis time (CLT) is associated with a cluster of cardiovascular adverse events (myocardial infarction, coronary heart disease, stroke, thromboembolism, and so on) [8,9]. In addition, both hypertension and OSA are associated with atherosclerosis and hypercoagulability [10]. Rajzer et al.[11] conducted a prospective, randomized clinical study that included 61 hypertensive patients (stages 1 and 2) free of vascular disease to evaluate the fibrin clot properties and their modification by antihypertensive medication. It was observed that baseline 24-h ambulatory SBP monitoring was associated with CLT (r = 0.42; P < 0.05), permeability (r = −0.37; P < 0.05), and maximal D-dimer level released from fibrin clots (r = 0.45; P < 0.05).

In another study of 165 patients with clinical suspicion of OSA, CLT, plasminogen activator inhibitor-1 (PAI-1) antigen, activated thrombin-activatable fibrinolysis inhibitor, plasmin, and antiplasmin were measured prior to polysomnography [12]. Patients detected with OSA (66.7%) were found to have more prolonged CLT (by 12.8%) and higher PAI-1 antigen (by 18.1%) compared with patients excluded for OSA. Moreover, CLT, PAI-1 antigen, and thrombin-activatable fibrinolysis inhibitor were positively correlated with indicators of OSA severity, such as apnea–hypopnea index and desaturation index. Other important data are provided by a double-blind, randomized clinical trial that assigned 44 OSA patients to receive CPAP, 3 l/h nocturnal oxygen, or placebo CPAP in a 2-week follow-up [13]. At baseline, the PAI-1 antigen was found to be associated with both apnea–hypopnea index (r = 0.47; P = 0.001) and mean night-time oxyhemoglobin saturation (r = −0.32; P = 0.035). Also, the apnea–hypopnea index seemed to be a significant predictor of PAI-1 antigen (r2 = 0.219; P = 0.001), independent of age, BMI, and mean night-time oxyhemoglobin saturation. Of note, a weak time-by-treatment interaction for PAI-1 antigen was found (P = 0.041), and this remained statistically significant even after multivariable adjustment (P = 0.046). Importantly, posthoc analysis shows that only CPAP use was associated with a reduction in PAI-1 antigen (P = 0.039). Summarizing, OSA is associated with altered fibrin clot properties and coagulative status, partially related to comorbid hypertension and these alterations might lead to cardiovascular events. Also, CPAP treatment can ameliorate the abovementioned alterations.

Jóźwik-Plebanek et al.[14] conducted a really interesting clinical study examining fibrin clot parameters in hypertensive patients with (n = 50) and without OSA (control group; n = 38), and in healthy individuals (n = 40). In the current issue of the Journal of Hypertension, the authors report that patients with OSA had more compact fibrin clots and hypofibrinolysis compared with hypertensive patients free of OSA. Moreover, it was found that CPAP improved fibrin clot parameters in the subgroup of patients that used it for 3 months. Specifically, OSA patients were found to have similar office BP, but significantly higher night-time DBP (8 mmHg; P = 0.032) and less pronounced dipping status in 24-h ambulatory BP monitoring compared with controls. As regards hypertension-related organ damage, OSA patients have been identified with a higher left ventricular mass (P = 0.011) and left ventricular mass index (P = 0.047) than patients free of OSA. Also, plasma fibrinogen levels were higher by 22.3 mg/dl in patients with OSA than in controls (P = 0.047).

Analysis of hemostatic markers and fibrin clot properties unveiled significant differences between OSA patients and controls at baseline. A higher PAI-1 antigen (19.1%), longer CLT (16.8%), and higher maximum D-dimer levels (9.6%) were observed for OSA versus free of OSA patients. OSA patients were also characterized by a smaller size fibrin network, quicker formation of fibrin clot, and thicker fibrin fibres with more branches than controls. Similar differences were shown between hypertensive patients with and without OSA and healthy individuals, as well as OSA and control group separately compared with healthy participants. Of great interest, OSA severity status was associated with fibrin clot properties and SBP dipping was correlated with CLT (r = 0.30; P = 0.006), and clot permeability coefficient (r = −0.28; P = 0.011). The most innovative and important data come from CPAP treatment. The use of CPAP for 3 months in the OSA group led to an increase in clot permeability coefficient (27.7%) and lag phase (8.8%), decrease in PAI-1 antigen (−38.1%) and maximum D-dimer levels in the clot lysis assay (−12.8%), and shortening of CLT (−18.7%). These findings suggest a significant amelioration of prothrombotic and fibrin clot properties in OSA patients with CPAP use.

The prospective design and the balanced status of OSA and control groups are considered as significant advantages of the study by Jóźwik-Plebanek et al.[14]. The comparison of OSA patients with well matched hypertensive controls and healthy participants substantially restricts bias from cofounding factors. Another strength of the study is that BP measurements and OSA detection followed the guidelines recommendations by using 24-h ambulatory BP monitoring (in addition to office BP) and polysomnography, respectively [15]. Also, both OSA and controls equally used antihypertensive agents. The major study limitations are the small number of participants with OSA (n = 50) and the very small number of patients (n = 29) willing to use CPAP and finally adhering to it (only 14 patients). However, these limitations have been found in almost all studies in this field. Another important limitation is that 24-h urinary albumin excretion was not assessed. Albuminuria represents a major indicator of hypertension-related organ damage [16], and absence of this marker limits to some extent the interpretation of the findings.

Jóźwik-Plebanek et al.[14] conducted a really interesting study that offers innovative and clinically meaningful data in the field of OSA and thromboembolism risk. The study evaluates the effects of CPAP intervention on fibrin clot features, and beneficial effects are suggested for the first time. A link between OSA severity, SBP dipping, and fibrin clot properties is presented. Moreover, the study confirms for one more time the altered atherothrombotic profile of hypertensive OSA patients. Several novel and clinically meaningful aspects are emerging, relevant to the crucial issue of cardiovascular risk of such patients. First, it would be of paramount interest to investigate the long-term efficacy of CPAP on fibrin clot parameters, and whether this impact could lead to cardiovascular benefits. Second, a head-to-head comparison of CPAP versus alternative treatments, such as mandibular advancement splint therapy, could be very useful [17]. Last but not least, it would be really important and clinically meaningful to assess the link of fibrin clot properties with severity of OSA. An accurate determination of this link might lead to a more feasible strategy in everyday clinical practice supplementing the management of OSA with recurrent polysomnography. Relevant evaluation of the abovementioned issues in future, large randomized controlled clinical studies could elucidate new perspectives in the cardiovascular management of OSA patients.

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Conflicts of interest

There are no conflicts of interest.

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