Background-Tumor necrosis factor alpha-␣ (TNF-␣) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. Methods and Results-We performed a systematic evaluation of TNF-␣ and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64Ϯ12) consecutively admitted for myocardial infarction. We correlated their values to short-and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-␣ and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65Ϯ6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. Conclusions-sTNFR-1 is a major short-and long-term predictor of mortality and HF in patients with acute myocardial infarction. (Circulation. 2005;111:863-870.)

Background-Endothelial apoptosis of atherosclerotic lesions is a possible determinant for the stable-to-vulnerable plaque transition.Recent data support the notion that plaque activation may be a pan-coronary process, advocating the existence of circulating triggers. Methods and Results-Serum from 40 healthy subjects (group 1) and 73 patients with stable angina (nϭ32; group 2) or acute coronary syndromes (nϭ41; group 3) was incubated with human umbilical vein endothelial cells. The percentage of apoptosis by flow cytometry and Fas, Bax, and Bcl-2 protein expression by immunoblotting were evaluated at entry in patients and control subjects and repeated after 12 months in group 3. At baseline, apoptotic nuclei were higher in group 3 (14Ϯ6%) than in group 2 (3.3Ϯ1.8%) and group 1 (1.35Ϯ0.8%) (PϽ0.001). Fas and Bcl-2 were increased in group 3 with respect to groups 1 and 2 (PϽ0.01). Coincubation of group 3 serum with anti-tumor necrosis factor-␣ and anti-interleukin-6 monoclonal antibodies did not affect the human umbilical vein endothelial cell apoptotic process, whereas addition of Trolox decreased apoptosis to Ͻ50%. The percentage of apoptosis in group 3 significantly correlated to the numbers of coronary complex lesions at angiography (rϭ0.58, PϽ0.0005). In group 3, apoptosis and the Bax/Bcl-2 ratio decreased at 1 year (PϽ0.0001, PϽ0.05 respectively). Conclusions-Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells, supporting the theory of the existence of circulating triggers potentially able to activate atherosclerotic lesions.