Robert Wolk

Elevated C-Reactive Protein in Patients With Obstructive Sleep Apnea

Background—Obstructive sleep apnea (OSA) has been increasingly linked to cardiovascular and cerebrovascular disease. Inflammatory processes associated with OSA may contribute to cardiovascular morbidity in these patients. We tested the hypothesis that OSA patients have increased plasma C-reactive protein (CRP). Methods and Results—We studied 22 patients (18 males and 4 females) with newly diagnosed OSA, who were free of other diseases, had never been treated for OSA, and were taking no medications. We compared CRP measurements in these patients to measurements obtained in 20 control subjects (15 males and 5 females) who were matched for age and body mass index, and in whom occult OSA was excluded. Plasma CRP levels were significantly higher in patients with OSA than in controls (median [range] 0.33 [0.09 to 2.73] versus 0.09 [0.02 to 0.9] mg/dL, P <0.0003). In multivariate analysis, CRP levels were independently associated with OSA severity (F=6.8, P =0.032). Conclusions—OSA is associated with elevated levels of CRP, a marker of inflammation and of cardiovascular risk. The severity of OSA is proportional to the CRP level.

Sleep-Disordered Breathing and Cardiovascular Disease

Sleep apnea is defined as repetitive episodes of decreased or total cessation of respiratory airflow during sleep, leading to a fall in oxygen saturation of ≥4% and sleep fragmentation. Sleep apnea can be central or obstructive. Central sleep apnea (CSA) is characterized by apneas secondary to diminution or cessation of thoraco-abdominal respiratory movements (due to dysfunction of central respiratory control mechanisms). Obstructive sleep apnea (OSA) is caused by upper airway collapse during inspiration and is accompanied by strenuous breathing efforts. When defined as >5 episodes of apnea or hypopnea per hour of sleep, OSA is relatively common, affecting 24% and 9% of middle-aged men and women, respectively.1 CSA is primarily seen in patients with congestive heart failure (CHF), although it occasionally may occur in healthy normal subjects, in people at high altitudes, and in association with central neural lesions. Sleep apnea constitutes a major public health problem because of its high prevalence and its emerging association with cardiovascular morbidity. ### Central Sleep Apnea CSA is especially relevant to CHF. The prevalence of CSA in CHF patients is dependent on various factors, such as heart failure etiology, gender, age, ejection fraction, and hemodynamic status, and has been estimated at 40% to 60%.2,3 Cheyne-Stokes respiration occurs during CSA and is a distinct pattern of periodic breathing with alternating crescendo-decrescendo sequences of hyperventilation and apnea (ie, complete breathing cessation). CSA may have an important influence on prognosis, in that its presence is associated with increased mortality in CHF patients.3 This effect appears to be independent of other known risk factors, such as left ventricular ejection fraction or peak oxygen consumption. Although the association of CSA with CHF has been recognized for decades, it is unclear whether CSA directly affects CHF pathophysiology and can therefore be causally linked to prognosis, or whether it is rather …

Obesity, Sleep Apnea, and Hypertension

Abstract—Obesity has a high and rising prevalence and represents a major public health problem. Obstructive sleep apnea (OSA) is also common, affecting an estimated 15 million Americans, with a prevalence that is probably also rising as a consequence of increasing obesity. Epidemiologic data support a link between obesity and hypertension as well as between OSA and hypertension. For example, untreated OSA predisposes to an increased risk of new hypertension, and treatment of OSA lowers blood pressure, even during the daytime. Possible mechanisms whereby OSA may contribute to hypertension in obese individuals include sympathetic activation, hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and inflammatory stress, endothelial dysfunction, impaired baroreflex function, and perhaps by effects on renal function. The coexistence of OSA and obesity may have more widespread implications for cardiovascular control and dysfunction in obese individuals and may contribute to some of the clustering of abnormalities broadly defined as the metabolic syndrome. From the clinical and therapeutic perspectives, the presence of resistant hypertension and the absence of a nocturnal decrease in blood pressure in obese individuals should prompt the clinician to consider the diagnosis of OSA, especially if clinical symptoms suggestive of OSA (such as poor sleep quality, witnessed apnea, excessive daytime somnolence, and so forth) are also present.

Independent Association Between Plasma Leptin and C-Reactive Protein in Healthy Humans

Background—C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables. Methods and Results—We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P =0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R =0.61, P <0.0001) and men (R =0.55, P <0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P =0.01) and men (F=5.69, P =0.02). When only subjects with BMI <25 kg/m2 were considered (n=47), CRP was not linked to BMI (R =0.02, P =0.96), but a significant association between leptin and CRP was still evident (R =0.55, P <0.0001). Conclusions—Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.

Body Mass Index: A Risk Factor for Unstable Angina and Myocardial Infarction in Patients With Angiographically Confirmed Coronary Artery Disease

Background—In patients with coronary artery disease (CAD), acute thrombosis frequently occurs in coronary arteries with only mild or moderate stenoses. Obesity increases the risk of atherosclerosis, but it is not known whether it also increases the risk of coronary thrombosis. We hypothesized that body mass index (BMI) might be an independent predictor of an acute coronary syndrome in patients with established coronary atherosclerosis. Methods and Results—Of 504 patients undergoing coronary angiography, those with evidence of >10% coronary artery stenoses were divided into 2 groups, with either stable (n=226) or unstable CAD (unstable angina or myocardial infarction; n=156). After adjusting for other risk factors (age, gender, blood pressure, lipid levels, insulin resistance, leptin, fibrinogen, C-reactive protein (CRP), CAD severity on angiography, smoking status, and a history of myocardial infarction or hypertension), BMI had a significant independent association with an acute coronary syndrome, with an odds ratio of 1.49 (P =0.014). This positive relation between BMI and the risk of acute coronary events was evident for even mildly elevated BMI values. Multivariate analysis also showed that CRP and the number of coronary lesions were independent predictors of risk of an acute coronary event. Conclusions—In patients with established coronary atherosclerosis, BMI, as well as CRP and number of coronary lesions, are independently associated with acute coronary syndromes. There is evidence of increased risk even at mildly elevated BMI levels.

Sleep and the metabolic syndrome

The metabolic syndrome represents a clustering of several interrelated risk factors of metabolic origin that are thought to increase cardiovascular risk. It is still uncertain whether this clustering results from multiple underlying risk factors or whether it has a single cause. One metabolic abnormality that may underlie several clinical characteristics of the metabolic syndrome is insulin resistance. This review discusses the evidence that sleep disturbances (obstructive sleep apnoea, sleep deprivation and shift work) may independently lead to the development of both insulin resistance and individual clinical components of the metabolic syndrome. The converse may also be true, in that metabolic abnormalities associated with the metabolic syndrome and insulin resistance may potentially exacerbate sleep disorders. The notion that sleep disturbances exert detrimental metabolic effects may help explain the increasing prevalence of the metabolic syndrome and insulin resistance in the general population and may have important implications for population‐based approaches to combat the increasing epidemic of metabolic and cardiovascular disease.

Leptin Induces C-Reactive Protein Expression in Vascular Endothelial Cells

Objective—There is increasing evidence of an association between leptin and increased cardiovascular risk. Higher leptin levels are associated with increased levels of C-reactive protein (CRP), which itself elicits proatherogenic effects in the vascular endothelium. We tested the hypothesis that leptin induces CRP expression in human coronary artery endothelial cells (HCAECs). Methods and Results—We confirmed the presence of both long and short isoforms of the leptin receptor in cultured HCAECs. Leptin but not IFN&agr;A/D nor tumor necrosis factor (TNF) &agr;, induced expression of CRP. A dose dependent increase of CRP mRNA and protein was observed with increasing concentration of leptin (0 to 400 ng/mL). This increased CRP expression was attenuated in the presence of anti-leptin receptor antibodies and also by inhibition of ERK1/2 by PD98059 (20 to 40 &mgr;mol/L). Time (0 to 60 minutes) and leptin concentration (0 to 200 ng/mL)-dependence of ERK1/2 phosphorylation were evident in response to leptin treatment. Leptin also elicited ROS generation. Inhibition of ROS by catalase (200 &mgr;g/mL) prevented ERK1/2 phosphorylation and CRP mRNA transcription. Conclusion—Leptin induces CRP expression in HCAECs via activation of the leptin receptor, increased ROS production, and phosphorylation of ERK1/2. These studies suggest a mechanism for the proatherogenic effects of leptin.

Cardiovascular consequences of obstructive sleep apnea.

Sleep apnea is associated with several cardiovascular disease conditions. A causal relationship between sleep apnea and each of these diseases is likely, but remains to be proven. The clearest evidence implicating OSA in the development of new cardiovascular disease involves data that show an increased prevalence of new hypertension in patients with OSA followed over 4 years [3]. Circumstantial evidence and data from small study samples suggest that OSA, in the setting of existing cardiovascular disease, may exacerbate symptoms and accelerate disease progression. The diagnosis of OSA always should be considered in patients with refractory heart failure, resistant hypertension, nocturnal cardiac ischemia, and nocturnal arrhythmias, especially in individuals with risk factors for sleep apnea (e.g., central obesity, age, and male gender). Treating sleep apnea may help to achieve better clinical control in these diseases and may improve long-term cardiovascular prognosis.

Functional, structural, and dynamic basis of electrical heterogeneity in healthy and diseased cardiac muscle: implications for arrhythmogenesis and anti-arrhythmic drug therapy☆

The electrophysiological properties of the ventricular myocardium are extremely heterogeneous. There are intrinsic electrical differences between the myocytes from different regions of the heart (most notably between the epicardium, midmyocardium, and endocardium), which are the result of different contributions of ionic currents to the transmembrane action potential. Sources of local anisotropy include directional differences in the distribution of gap junctions between adjacent myocytes and the presence of intercalated non-myocytes (e.g., fibroblasts), propagation boundaries, and wavefront collisions, which can lead to local variability of electrical load and, therefore, to nonuniform depolarisation and repolarisation. In addition, the complex anatomical arrangement of the myocardial fibres and nonuniform distribution of transmural mechanical stresses also contribute to electrical heterogeneity. Finally, dispersion of repolarisation is dynamically modified by the restitution properties of individual myocytes, stimulation rate, and the direction of conduction. All aspects of this electrical heterogeneity can be affected by different pathological conditions, such as myocardial ischaemia and cardiac hypertrophy. In particular, differential responses of various myocyte populations to these pathological stimuli and a marked increase in nonuniform anisotropy may be responsible for increased pro-arrhythmic potential in these conditions. In addition, the clinical effectiveness of anti-arrhythmic drugs may be related to their effects on electrical heterogeneity.

Obesity‐related cardiovascular disease: implications of obstructive sleep apnea

Obesity and obstructive sleep apnea (OSA) often coexist. OSA has been linked to cardiovascular disease. Thus, OSA may contribute to the cardiovascular consequences of obesity. In this review, we explore clinical and pathophysiological interactions between obesity, cardiovascular disease and OSA. We discuss the mechanisms whereby OSA may contribute to hypertension, atherosclerosis, insulin resistance and atrial fibrillation associated with obesity, and emphasize the potential implications for understanding why only a subgroup of obese patients develop cardiovascular disease. Identification of the OSA‐dependent and OSA‐independent pathways in the cardiovascular pathophysiology of obesity may hold clinical and therapeutic promise.