High plasma levels of endothelin-1 enhance the predictive value of preclinical atherosclerosis for future cerebrovascular and cardiovascular events: a 20-year prospective study

Background and purpose Clinical and experimental evidence suggests that endothelin-1 (ET-1) plays a role in cardiac and vascular disease. In the present study, we investigated the prognostic significance of ET-1 for cerebrovascular and cardiovascular outcome, in a 20-year follow-up. Methods We studied 82 originally healthy individuals, referred to our Unit of Cardiovascular Prevention, to evaluate the presence of asymptomatic carotid lesions. We subdivided these individuals into two groups, according to the plasma values of ET-1 (respectively <= or >2.7 pg/ml). Traditional cardiovascular risk factors were investigated, and by carotid ultrasound examination, we distinguished between normal individuals and those with intima-media thickening or asymptomatic carotid plaque. Results Major cardiac and cerebral events (all-cause death, myocardial infarction, revascularization procedures, fatal and nonfatal stroke) were registered in 41 individuals and significantly more in those with high vs. low ET-1 levels (95 vs. 5%; P<0.0001). Furthermore, by logistic multivariate regression analysis, we found that among all evaluated baseline clinical and laboratory variables, hypertension [odds ratio (OR): 20.4 (3.3-127), P=0.001], high ET-1 concentrations [OR: 1.4 (1.0-1.8), P=0.02] and the presence of intima-media thickness or asymptomatic carotid plaque [OR: 3.7 (1.14-12.1), P=0.02] were independent predictors of future events. Finally, integrating technical and laboratory data, high levels of ET-1 have defined a high risk of major cardiac and cerebral event and stroke at follow-up, which increased in relation to the progression of carotid atherosclerosis (P<0.05). Conclusion ET-1 plasmatic levels significantly influence the cardiovascular and cerebrovascular risk profile, beyond traditional cardiovascular risk factors and preclinical carotid atherosclerosis.