Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.

OBJECTIVES: This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI). BACKGROUND: Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways-high-sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels-would be a powerful predictor of death and MI. METHODS: Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors. RESULTS: Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP ≥3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP ≥1.0 µg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score. CONCLUSIONS: An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD.

Coronary microvascular dysfunction is associated with higher frequency of thin-cap fibroatheroma.

OBJECTIVE: Both coronary microvascular dysfunction and epicardial plaque vulnerability have been associated with adverse cardiovascular outcomes. However, whether microvascular dysfunction is a predictor of plaque vulnerability is not known. We hypothesized that microvascular dysfunction is associated with greater systemic inflammation and is a predictor of virtual histology-intravascular ultrasound (VH-IVUS)-defined coronary thin-cap fibroatheromas. METHODS: Invasive physiologic assessment and VH-IVUS were performed and serum high-sensitivity C-reactive protein (hs-CRP) was measured in 51 patients with non-obstructive CAD [fractional flow reserve (FFR)≥0.75]. Microvascular dysfunction was defined as coronary flow velocity reserve (CFVR)<2.0. Lumen area and plaque burden and composition were assessed in each VH-IVUS frame. Frequency of thin-cap fibroatheroma (TCFA) in each artery was defined as the percentage of VH-IVUS frames with plaque burden≥40% and confluent necrotic core≥10% in contact with lumen for at least 3 consecutive frames. RESULTS: Mean age was 57±12 years and 25% of patients presented with acute coronary syndrome. Despite similar amount of epicardial disease, characterized by lumen area (8.9±3.0 vs. 10.1±3.3mm(2), p=0.3) and FFR (0.90±0.08 vs. 0.92±0.07, p=0.2), patients with microvascular dysfunction had greater hs-CRP (4.2 [2.3, 7.6] vs. 1.0 [0.4, 4.2]ng/ml, p=0.006), greater plaque burden (47±10 vs. 36±13%, p=0.004), and higher frequency of TCFA (17±25 vs. 6±9%, p=0.02). After adjustment for cardiovascular risk factors, hs-CRP, and plaque burden, coronary microvascular dysfunction was an independent predictor of frequency of TCFA (ß=+0.42, p=0.033). CONCLUSION: In patients with non-obstructive CAD, coronary microvascular dysfunction is associated with higher serum hs-CRP and is an independent predictor of more TCFAs, a marker for increased epicardial plaque vulnerability.