Combined Effects of Inflammatory Status and Carotid Atherosclerosis

Atherosclerosis, a progressive disease characterized by the accumulation of lipids in medium-sized and large arteries, is the underlying cause of coronary artery disease and stroke and represents the leading cause of death worldwide. Inflammation plays a pivotal role in atherogenesis, from endothelial dysfunction and all stages of plaque formation and progression to its clinical complications. An abundance of evidence, including clinical as well as experimental studies, supports the idea that augmented proinflammatory responses promote plaque progression and its vulnerability to rupture. In recent decades, numerous inflammatory biomarkers predictive of cardiovascular outcome in patients with atherosclerotic diseases have been identified, including cytokines and chemokines, leukocyte subtypes, or proteolytic enzymes. However, the only circulatory biomarker frequently used for cardiovascular risk assessment in current clinical practice remains hsCRP (high-sensitivity C-reactive protein), which has been described as an independent risk factor in patients with coronary heart disease, atrial fibrillation, chronic kidney disease, and peripheral arterial disease, as well as in healthy subjects. We have previously shown, in the prospective ICARAS (Inflammation and Carotid Artery-Risk for Atherosclerosis Study) protocol, that serum levels of hsCRP are associated with morphological features of carotid atherosclerosis and progression of carotid narrowing, as well as with short-term cardiovascular events. Since those findings, it has been repeatedly verified that levels of hsCRP represent an important risk factor for the development and progression of carotid atherosclerosis. However, hitherto, no study has investigated whether or to what extent hsCRP might be predictive of mortality in patients with carotid stenosis. The primary goal of this investigation was, therefore, to assess the Background and Purpose—Inflammatory responses play a key role in atherogenesis. The aim of this study was to assess the prognostic value of hsCRP (high-sensitivity C-reactive protein) and to evaluate whether degree of carotid stenosis and serum levels of hsCRP jointly predict long-term mortality in asymptomatic patients with carotid atherosclerosis. Methods—One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. Results—During a median of 11.81 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. The risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of hsCRP (the adjusted hazard ratio for cardiovascular mortality per increase of 1 mg/dL of hsCRP levels was 1.47; P<0.001). Patients with a high degree of carotid stenosis and increased hsCRP levels were particularly at risk of adverse outcome. Patients with carotid narrowing over 50% and hsCRP levels >0.29 mg/dL (=median) had nearly twice as high a risk of cardiovascular mortality compared with patients with carotid stenosis of <50% and hsCRP levels <0.29 mg/dL (adjusted hazard ratio 1.89; P<0.001). Improvement in risk stratification with combined assessment of carotid stenosis and hsCRP was confirmed by an improvement of the continuous net reclassification improvement with 18% for all-cause mortality and 15% for cardiovascular mortality compared with the degree of carotid stenosis alone (P<0.01). Conclusions—Measurement of hsCRP in combination with ultrasound investigations of the carotid arteries at a single time point provides additional prognostic information for patients with asymptomatic carotid atherosclerosis. (Stroke. 2016;47:2952-2958. DOI: 10.1161/STROKEAHA.116.013647.)