Person: Sabatine, Marc
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Sabatine
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Sabatine, Marc
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Publication Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Theraphy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial(Elsevier BV, 2008) Morrow, David; Wang, Yunmei; Croce, Kevin; Sakuma, Masashi; Sabatine, Marc; Gao, Huiyun; Pradhan, Aruna; Healy, Aileen M.; Buros, Jacki; McCabe, Carolyn Hoss; Libby, Peter; Cannon, Christopher; Braunwald, Eugene; Simon, Daniel I.Background Using a transcriptional profiling approach, we recently identified myeloid-related protein 8/14 (MRP-8/14) to be expressed by platelets during acute myocardial infarction (MI). Elevated concentrations of MRP-8/14 are associated with a higher risk for future cardiovascular events in apparently healthy individuals but have not been assessed with respect to prognosis in patients with acute coronary syndrome. Methods We performed a nested case-control study (n = 237 case-control pairs) among patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Theraphy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial (mean follow-up 24 months) to investigate the risk of cardiovascular death or MI associated with MRP-8/14 measured at 30 days after an acute coronary syndrome. Results Patients with cardiovascular death or MI after 30 days (cases) had higher median [25th, 75th percentile] MRP-8/14 levels than patients who remained free of recurrent events (5.6 [2.8, 13.5] mg/L vs 4.0 [1.9, 10.1] mg/L, P = .020). The risk of a recurrent cardiovascular event increased with each increasing quartile of MRP-8/14 ( P-trend = 0.007) such that patients with the highest levels had a 2.0-fold increased odds (95% CI 1.1-3.6, P = .029) of a recurrent event after adjusting for standard risk indicators, randomized treatment, and C-reactive protein. Patients with elevated levels of MRP-8/14 and high-sensitivity C-reactive protein showed significantly increased risk of cardiovascular death or MI compared with patients with the lowest levels of both markers (adjusted odds ratio 2.1, 95% CI 1.2-3.8). Conclusions Myeloid-related protein 8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.Publication Lipoprotein(a) for Risk Assessment in Patients With Established Coronary Artery Disease(Elsevier BV, 2014) O, Michelle L.; Morrow, David; Tsimikas, Sotirios; Sloan, Sarah; Ren, Angela F.; Hoffman, Elaine Borland; Desai, Nihar R.; Solomon, Scott; Domanski, Michael; Arai, Kiyohito; Chiuve, Stephanie; Cannon, Christopher; Sacks, Frank; Sabatine, MarcOBJECTIVES: The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND: Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS: Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS: Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS: Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.Publication Traditional Risk Factors Versus Biomarkers for Prediction of Secondary Events in Patients With Stable Coronary Heart Disease: From the Heart and Soul Study(John Wiley & Sons, Ltd, 2015) Beatty, Alexis L; Ku, Ivy A; Bibbins-Domingo, Kirsten; Christenson, Robert H; DeFilippi, Christopher R; Ganz, Peter; Ix, Joachim H; Lloyd-Jones, Donald; Omland, Torbjørn; Sabatine, Marc; Schiller, Nelson B; Shlipak, Michael G; Skali, Hicham; Takeuchi, Madoka; Vittinghoff, Eric; Whooley, Mary ABackground: Patients with stable coronary heart disease (CHD) have widely varying prognoses and treatment options. Validated models for risk stratification of patients with CHD are needed. We sought to evaluate traditional and novel risk factors as predictors of secondary cardiovascular (CV) events, and to develop a prediction model that could be used to risk stratify patients with stable CHD. Methods and Results: We used independent derivation (912 participants in the Heart and Soul Study) and validation (2876 participants in the PEACE trial) cohorts of patients with stable CHD to develop a risk prediction model using Cox proportional hazards models. The outcome was CV events, defined as myocardial infarction, stroke, or CV death. The annual rate of CV events was 3.4% in the derivation cohort and 2.2% in the validation cohort. With the exception of smoking, traditional risk factors (including age, sex, body mass index, hypertension, dyslipidemia, and diabetes) did not emerge as the top predictors of secondary CV events. The top 4 predictors of secondary events were the following: N-terminal pro-type brain natriuretic peptide, high-sensitivity cardiac troponin T, urinary albumin:creatinine ratio, and current smoking. The 5-year C-index for this 4-predictor model was 0.73 in the derivation cohort and 0.65 in the validation cohort. As compared with variables in the Framingham secondary events model, the Heart and Soul risk model resulted in net reclassification improvement of 0.47 (95% CI 0.25 to 0.73) in the derivation cohort and 0.18 (95% CI 0.01 to 0.40) in the validation cohort. Conclusions: Novel risk factors are superior to traditional risk factors for predicting 5-year risk of secondary events in patients with stable CHD.Publication Genetic Risk, Coronary Heart Disease Events, and the Clinical Benefit of Statin Therapy: An Analysis of Primary and Secondary Prevention Trials(Elsevier BV, 2015-06-06) Mega, Jessica L.; Stitziel, Nathan O.; Smith, J. Gustav; Chasman, Daniel; Caulfield, Mark; Devlin, James J.; Nordio, Francesco; Hyde, Craig L.; Cannon, Christopher; Sacks, Frank; Poulter, Neil; Sever, Peter S.; Ridker, Paul; Braunwald, Eugene; Melander, Olle; Kathiresan, Sekar; Sabatine, MarcBackground Genetic variants have been associated with the risk of coronary heart disease (CHD). We tested whether a composite of these variants could identify the risk of both incident as well as recurrent CHD events and distinguish individuals who derived greater clinical benefit from statin therapy. Methods A community-based cohort and four randomized controlled trials of both primary (JUPITER and ASCOT) and secondary (CARE and PROVE IT-TIMI 22) prevention with statin therapy totaling 48,421 individuals and 3,477 events were included in these analyses. We examined the association of a genetic risk score based on 27 genetic variants with incident or recurrent CHD, adjusting for established clinical predictors. We then investigated the relative and absolute risk reductions in CHD events with statin therapy stratified by genetic risk. Data from studies were combined using meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient of risk for incident or recurrent CHD was demonstrated with the multivariable-adjusted HRs (95% CI) for CHD for the intermediate and high genetic risk categories vs. low genetic risk category being 1.32 (1.20-1.46, P<0.0001) and 1.71 (1.54-1.91, P<0.0001), respectively. In terms of the benefit of statin therapy in the four randomized trials, there was a significant gradient of increasing relative risk reduction across the low, intermediate, and high genetic risk categories (13%, 29%, and 48%, P=0.0277). Similarly, greater absolute risk reductions were seen in those individuals in higher genetic risk categories (P=0.0101), resulting in an approximate three-fold gradient in the number needed to treat (NNT) in the primary prevention trials. Specifically, in the primary prevention trials, the NNT to prevent one MACE over 10 years for the low, intermediate, and high GRS individuals was 66, 42, and 25 in JUPITER and 57, 47, and 20 in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent CHD events. Individuals with the highest burden of genetic risk derived the largest relative and absolute clinical benefit with statin therapy.Publication Myocardial Infarction Accelerates Atherosclerosis(Nature Publishing Group, 2012) Leuschner, Florian; Robbins, Clinton; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Lasitschka, Felix; Etzrodt, Martin; Waterman, Peter; Waring, Michael T.; Chicoine, Adam T.; van der Laan, Anja M.; Niessen, Hans W.M.; Piek, Jan J.; Rubin, Barry B.; Butany, Jagdish; Katus, Hugo A.; Murphy, Sabina A.; Pittet, Mikael; Lin, Charles; Dutta, Partha; Courties, Gabriel; Wei, Ying; Gorbatov, Rostic; Majmudar, Maulik; Stone, James; Morrow, David; Sabatine, Marc; Vinegoni, Claudio; Moskowitz, Michael; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasDuring progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE\(^{−/−}\) mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.