A gene expression signature that classifies human atherosclerotic plaque by relative inflammation status.

BACKGROUND: Atherosclerosis is a complex disease requiring improvements in diagnostic techniques and therapeutic treatments. Both improvements will be facilitated by greater exploration of the biology of atherosclerotic plaque. To this end, we carried out large-scale gene expression analysis of human atherosclerotic lesions. METHODS AND RESULTS: Whole genome expression analysis of 101 plaques from patients with peripheral artery disease identified a robust gene signature (1514 genes) that is dominated by processes related to Toll-like receptor signaling, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction, and lysosomal activity. Further analysis of gene expression in microdissected carotid plaque samples revealed that this signature is differentially expressed in macrophage-rich and smooth muscle cell-containing regions. A quantitative PCR gene expression panel and inflammatory composite score were developed on the basis of the atherosclerotic plaque gene signature. When applied to serial sections of carotid plaque, the inflammatory composite score was observed to correlate with histological and morphological features related to plaque vulnerability. CONCLUSIONS: The robust mRNA expression signature identified in the present report is associated with pathological features of vulnerable atherosclerotic plaque and may be useful as a source of biomarkers and targets of novel antiatherosclerotic therapies.

Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study.

BACKGROUND AND AIM: Sitosterolemia, a rare genetic disorder characterized by profoundly elevated plasma sitosterol concentrations, is associated with premature atherosclerosis in some individuals. This study was conducted to evaluate if the modest sitosterol elevations seen in the general population are also associated with the occurrence of coronary events. METHODS AND RESULTS: A nested case-control study using stored samples from male participants in the Prospective Cardiovascular Münster (PROCAM) study was performed. Each of 159 men who suffered a myocardial infarction or sudden coronary death (major coronary event) within 10 years of follow-up in PROCAM was matched with 2 controls (N = 318) by age, smoking status, and date of investigation. Analysis was performed using conditional logistic regression. Plasma sitosterol concentrations were elevated in cases compared with controls (4.94 +/- 3.44 micromol/L versus 4.27 +/- 2.38 micromol/L; P = 0.028). The upper quartile of sitosterol (>5.25 micromol/L) was associated with a 1.8-fold increase in risk (P < 0.05) compared with the lower three quartiles. Among men with an absolute coronary risk > or = 20% in 10 years as calculated using the PROCAM algorithm, high sitosterol concentrations were associated with an additional 3-fold increase in the incidence of coronary events (P = 0.032); a similar, significant relationship was observed between a high sitosterol/cholesterol ratio and coronary risk (P = 0.030). CONCLUSIONS: Elevations in sitosterol concentrations and the sitosterol/cholesterol ratio appear to be associated with an increased occurrence of major coronary events in men at high global risk of coronary heart disease. Further evaluations are warranted to confirm these preliminary findings.

Postponed development of disability in elderly runners: a 13-year longitudinal study.

BACKGROUND: The magnitude and duration of the benefit of running and other aerobic exercise on disability and mortality in elderly persons are not well understood. We sought to quantify the benefits of aerobic exercise, including running, on disability and mortality in elderly persons and to examine whether morbidity can be compressed into later years of life by regular exercise. METHODS: A 13-year prospective cohort study of 370 members of a runners' club for persons aged 50 and older and 249 control subjects initially aged 50 to 72 years (mean, 59 years), with annual ascertainment of the Health Assessment Questionnaire disability score, noting any deaths and their causes. Linear mixed models were used to compute postponement in disability, and survival analysis was conducted to determine the time to and causes of death. RESULTS: Significantly (P<.001) lower disability levels in runners' club members vs controls and in ever runners vs never runners were sustained for at least 13 years. Reaching a Health Assessment Questionnaire disability level of 0.075 was postponed by 8.7 (95% confidence interval [CI], 5.5-13.7) years in runners' club members vs controls. Running club membership and participation in other aerobic exercise protected against mortality (rate ratio, 0.36 [95% CI, 0.20-0.65] and 0.88 [95% CI, 0.77-0.99], respectively), while male sex and smoking were detrimental (rate ratio, 2.4 [95% CI, 1.4-4.2] and 2.2 [95% CI, 1.1-4.6], respectively). Controls had a 3.3 times higher rate of death than runners' club members, with higher death rates in every disease category. Accelerated rates of disability and mortality were still not seen in the runners' club members; true compression of morbidity was not yet observable through an average age of 72 years. CONCLUSION: Running and other aerobic exercise in elderly persons protect against disability and early mortality, and are associated with prolongation of a disability-free life.