Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
* Corresponding author. Tel.: +1-507-284-2511/255-1144; fax: +1-507-255-7070
E-mail address: somers.virend{at}mayo.edu
doi: 10.1016/j.ehj.2004.02.008, 10.1016/j.ehj.2004.02.021
This editorial refers to "Benefits of obstructive sleep aponea treatment in coronary artery disease: a long term follow-up study" by O. Milleron et al. on page 728 and "Obstructive sleep apnoea is independently associated with an increased incidence of the metabolic syndrome" SR. Coughlin et al. on page 735.3
A growing body of evidence supports an association between obstructive sleep apnoea (OSA) and cardiovascular disease. Pathophysiologic mechanisms that are present in patients with OSA including sympathetic activation, endothelial dysfunction, oxidative stress, systemic inflammation, hypercoagulability, hyperleptinemia, and insulin resistance may influence the development and progression of cardiac and vascular pathology.1 OSA is widely prevalent in patients with obesity, diabetes, and hypertension.1 Our understanding of the relative importance and interactions of these cardiovascular disease mechanisms and risk factors in patients with OSA may have direct implications for the development of targeted preventive and therapeutic strategies.
Clustering of cardiovascular risk factors (termed "metabolic syndrome" in 1981) was recognised as early as the 1920s and is currently thought to be related to the underlying pathophysiology of insulin resistance and hyperinsulinemia.2 The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (2001) proposed a clinically practical approach that establishes the diagnosis of metabolic syndrome when an individual has three of these five characteristics: increased waist circumference, high blood pressure, increased fasting glucose, increased triglycerides, and decreased high-density lipoprotein (HDL) cholesterol. Other important features of the metabolic syndrome include microalbuminuria, hypercoagulability, increased inflammation, endothelial dysfunction, poor cardiorespiratory fitness, and sympathetic activation.2
The clustering of cardiovascular disease mechanisms in the metabolic syndrome and OSA are remarkably similar. Patients with OSA have abnormalities in each of the "core" components of the metabolic syndrome high blood pressure, high fasting glucose, increased waist circumference, low HDL cholesterol, and high triglycerides as well as in many of its other features, including sympathetic activation, endothelial dysfunction, systemic inflammation, hypercoagulability, and insulin resistance.1 It has even been suggested that the metabolic syndrome ("Syndrome X`') should encompass OSA ("Syndrome Z").3 However, there is little information about the extent to which the cardinal features of the metabolic syndrome are present simultaneously in patients with OSA.
An important study by Coughlin and colleagues4 in this issue of the Journal addresses this question directly. They performed a cross-sectional study of 61 otherwise healthy subjects with OSA and 29 subjects without OSA. To mitigate confounding due to obesity, they also matched 34 of the OSA patients by body-mass index (BMI) to the 29 controls. Their results suggest that the prevalence of metabolic syndrome (by NCEP) is about 40% greater in patients with OSA. The obesity epidemic and its impact on the prevalence of both metabolic syndrome and OSA make these data especially relevant and timely.
Some limitations to interpreting and applying their findings are more related to the definition of metabolic syndrome than to the study design itself. It is of interest that HDL cholesterol was the only discrete component of the metabolic syndrome that differed between BMI-matched subjects with and without OSA. Waist circumference, blood pressure, triglycerides, and fasting glucose did not differ significantly. Despite this, the prevalence of metabolic syndrome was significantly higher in subjects with OSA. While this may be due partly to sample size, it also highlights one of the limitations of the definition of metabolic syndrome: each of its components reflects a physiologic spectrum that correlates with risk. Nevertheless, a necessarily arbitrary threshold value for each component must be used to establish diagnostic criteria for metabolic syndrome.
Several intriguing questions arise from the Coughlin study. First, does OSA occur as part of the fundamental pathophysiology of metabolic syndrome, or does OSA, via repetitive nocturnal hypoxaemia and other mechanisms, promote the components of the metabolic syndrome? In this regard, given what is known about OSA, it is surprising that blood pressure and fasting glucose were not higher in patients with OSA after controlling for obesity. Second, is the magnitude of cardiovascular risk attributable to coexisting metabolic syndrome and OSA additive, synergistic, or redundant? Here, part of the uncertainty is due to the fact that studies of the metabolic syndrome thus far have not addressed the important question of whether metabolic syndrome per se contributes to cardiovascular risk above and beyond the risk attributable to each of its components and/or traditional risk factors. Third, does treatment of OSA attenuate abnormalities in the components of the metabolic syndrome, hence lowering the overall prevalence of the metabolic syndrome in patients with OSA? If so, what consequences does this have for cardiovascular risk? Effective treatment of OSA with continuous positive airway pressure (CPAP) decreases blood pressure5 and may increase insulin sensitivity.6 Reductions in blood pressure lower cardiovascular risk. Therapies that increase insulin sensitivity also improve cardiovascular risk factors and surrogate endpoints, and outcomes trials are currently underway. As such, effective OSA therapy, via these mechanisms alone, might be expected to reduce cardiovascular morbidity and mortality.
Further insight into this question is provided by Milleron and colleagues, also in this issue of the Journal.7 These investigators conducted a prospective cohort study of the effects of OSA therapy on cardiovascular morbidity and mortality. They studied 54 patients who had 70% coronary artery stenosis during elective coronary angiography (
86% underwent revascularisation) and subsequently had a polysomnogram that confirmed OSA. Patients were offered therapy and then followed up for an average of 7 years for a composite endpoint of cardiovascular death, acute coronary syndrome, coronary revascularisation, or hospitalisation for heart failure. Patients who accepted OSA therapy (regardless of noncompliance or later discontinuation) experienced only one third of the risk for the composite endpoint compared to those who refused OSA therapy.
As with the Coughlin study, the Milleron study has potentially important implications for cardiovascular disease prevention. It is therefore important that the limitations be recognised clearly. Some of these, including the lack of randomisation, have been noted by the authors. Other limitations necessitate caution in generalising the results of their study to all patients with OSA. The criteria used for the diagnosis of OSA are not completely described. The study enrolled an average of only 6 patients per year for 9 years, which likely reflects selection bias in patient enrollment. This increases the chance of the sample incorporating unmeasured patient characteristics that relate to prognosis, and makes it less likely that the sample is representative of the population of patients with OSA and established coronary disease. Furthermore, the small size of the study and low number of outcomes in each group make the results less reliable. Identification of the mechanisms by which CPAP acts to mitigate cardiovascular risk would also be of great interest. Understandably, this is not easily accomplished, given the number of variables of interest, complex comorbidities, and medication use. There is precedent for expecting that prevention of nocturnal hypoxaemia, sympathetic activation, and pressor surges, in addition to the reduction of daytime sympathetic activity,8 blood pressure,5 and insulin resistance6 by CPAP would improve cardiovascular outcomes. Whether and how other components of cardiovascular risk change with CPAP is not clear.
These limitations notwithstanding, the data are thought-provoking and important, building on other prospective studies of cardiovascular morbidity and/or mortality associated with treated and untreated OSA. The results are similar in direction and magnitude to those of two other studies comprising over 460 patients with established heart disease, in whom the presence of OSA increased the risk of cardiovascular outcomes over a period of about 5 years.9,10 The present study adds further evidence that OSA is not only associated with, but may indeed predispose to cardiovascular morbidity and, perhaps, mortality.
The past decade has seen a rapid increase in the breadth of the studies investigating the pathophysiology, disease associations, and treatment implications of OSA. Coughlin et al. and Milleron et al. contribute considerably to the burgeoning evidence linking OSA with cardiovascular risk and outcomes. It is clear that OSA and the metabolic syndrome share a similar pathophysiologic milieu that would be expected to increase the risk of cardiovascular disease. In patients with established coronary artery disease, treatment of OSA may confer long-term cardiovascular benefits. Both of these studies highlight the need for rigorous experimental approaches to understanding the pathophysiology and implications of OSA. Randomised controlled trials of OSA therapy need to recognise the effects of untreated OSA on daytime somnolence, quality of life, and motor vehicle accidents. In the absence of randomised trials, large, population-based, prospective studies of sufficient duration are required to clarify causal relationships and explore the potential for OSA therapy to mitigate cardiovascular risk factors and outcomes. Given the obesity epidemic at hand, the prevalences of both metabolic syndrome and OSA are rising. The implications of these trends for cardiovascular disease are enormous.
Acknowledgments
The authors are supported by NIH Grants HL61560, HL65176, HL73211, and M01-RR00585, and the Mayo Clinic College of Medicine.
Footnotes
1 The authors have no other financial or conflict of interest disclosures.
2 Dr. Somers has consulted for Respironics and Resmed.
3 10.1016/j.ehj.2004.02.008, 10.1016/j.ehj.2004.02.021.
References
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