Biomarkers in the prevention and treatment of atherosclerosis: need, validation, and future.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in the developed world, and there is a clear need to develop novel therapeutic strategies to reduce cardiovascular risk further than is currently possible. Traditionally, the effectiveness of new cardiovascular drugs has been evaluated in clinical trials using cardiovascular outcomes as endpoints. However, such trials require large numbers of patients followed over long periods of time. Clinical trials using surrogate markers for CVD may be shorter in duration and involve fewer participants. Measurement of atherosclerotic progression is an ideal surrogate marker as it is predictive of future cardiovascular events. The "gold standard" for detecting and defining the severity, extent, and rate of atherosclerotic progression has been quantitative coronary angiography. However, this technique has fundamental limitations. More recently, measurement of carotid intima-media thickness using B-mode ultrasound and measurement of atheroma volume using intravascular ultrasound have emerged as more accurate techniques for detecting atherosclerotic progression. Both of these techniques have potential utility as surrogate endpoints in place of cardiovascular outcomes in clinical trials. Their use might facilitate the more rapid development of novel, safe, and effective therapies.

Superiority of big endothelin-1 and endothelin-1 over natriuretic peptides in predicting survival in severe congestive heart failure: a 7-year follow-up study.

BACKGROUND: Plasma concentrations of atrial and brain natriuretic peptides (ANP, BNP), of their N-terminal pro-peptides, of endothelin-1 (ET-1), and big endothelin-1 (big ET-1) have diagnostic and prognostic significance in congestive heart failure (CHF). However, their respective values as a predictor of survival remain controversial and have never been directly compared in severe CHF. METHODS AND RESULTS: We analyzed, in 47 patients with severe CHF (New York Heart Association [NYHA] class III to IV; age 66 +/- 8 years, ejection fraction 20 +/- 6%), the prognostic performance of a panel of neurohormones and assays (N-terminal pro-ANP 1-25, 68-98 by radioimmunoassay [RIA], and 1-98 by enzyme-linked immunosorbent assay [ELISA], BNP by RIA and immunoradiometric assay [IRMA], N-terminal pro-BNP by Elisa, ET-1 by RIA, and big ET-1 by RIA and Elisa. Data were compared with 40 patients with mild to moderate CHF [NYHA I-II] and 30 healthy subjects. After a follow-up of 81 +/- 15 months, there were 34 deaths and 1 heart transplant. All neurohormones were significantly higher at baseline in patients with severe than in mild to moderate CHF or healthy subjects (all P < .001). Although all neurohormones but BNP IRMA were significant predictors of survival in univariate analysis, only big ET-1 RIA and ET-1 were independent predictors of survival (improvement chi(2): 7.5 and 4.6, P < .01 and P < .05). Using medians as cutpoints of big ET-1 RIA and ET-1, 2 severe CHF populations were defined with a different outcome (5-year survival: 55 versus 18%, P < .01). CONCLUSIONS: Big ET-1 and ET-1 are strong independent predictors of survival in patients with severe CHF and better for this purpose than natriuretic peptides or their pro-peptides. These markers allow easily to identify a population with a very high risk mortality eligible for more aggressive therapies.