Prognostic Utility of Novel Biomarkers of Cardiovascular Stress

Abstract

Background Biomarkers for predicting cardiovascular events in community-based populations have not consistently added information to standard risk factors. A limitation of many previously studied biomarkers is their lack of cardiovascular specificity. Methods and Results To determine the prognostic value of 3 novel biomarkers induced by cardiovascular stress, we measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3,428 participants (mean age 59, 53% women) in the Framingham Heart Study. We performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. We also constructed a “multimarker” score composed of the 3 biomarkers, in addition to B-type natriuretic peptide and high-sensitivity C-reactive protein. During a mean follow-up of 11.3 years, there were 488 deaths, 336 major cardiovascular events, 162 heart failure events, and 142 coronary events. In multivariable-adjusted models, the 3 new biomarkers were associated with each endpoint (p<0.001) except for coronary events. Individuals with multimarker scores in the highest quartile had a 3-fold risk of death (adjusted hazard ratio, 3.2, 95% CI, 2.2–4.7; p<0.001), 6-fold risk of heart failure (6.2, 95% CI, 2.6–14.8; p<0.001), and 2-fold risk of cardiovascular events (1.9, 95% CI, 1.3–2.7; p=0.001). Addition of the multimarker score to clinical variables led to significant increases in the c-statistic (p=0.007 or lower) and net reclassification improvement (p=0.001 or lower). Conclusions Multiple biomarkers of cardiovascular stress are detectable in ambulatory individuals, and add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.

Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community‐Dwelling Population

“…The addition of sST2 to demographics and clinical risk factors only modestly improved discrimination and risk reclassification for incident HF and cardiovascular death. However, similar to other cohorts, increasing levels of ST2 in older adults in a cross‐sectional analysis were associated with higher risk demographics, increased comorbidities, and increasing levels of cardiac specific and noncardiac specific biomarkers that have been independently associated with poorer outcomes 18, 27, 28, 39…”

“…The association between sST2 and incident cardiovascular events has been examined in three general population cohorts previously: the Dallas Heart Study (DHS), FHS, and the FINRISK97 study 17, 18, 40. Compared to the CHS, the DHS cohort was significantly younger with a mean age of 43 years.…”

“…Studies in patients with shortness of breath,11, 12, 13, 14 chest pain,15 and those referred for outpatient echocardiograms16 have shown poorer prognosis among those with higher concentrations of circulating sST2, irrespective of the final clinical diagnosis. Among population‐based studies, the Dallas Heart Study reported increased all‐cause and cardiovascular mortality in younger and middle‐aged adults with greater circulating sST2,17 and there was an increased risk of HF, death, and major cardiovascular events among middle‐aged adults with greater sST2 in the Framingham Heart Study (FHS) 18…”

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

“…Whereas GDF15, NT‐proBNP, ADM, cystatin‐C, fibroblast growth factor 23 (FGF23), and CRP are known to predict incident CVD and other outcomes,13, 14, 15, 16 there are a number of novel associations in our study to highlight. Specifically, a number of regulators of metabolic and adipocyte homeostasis appeared to predict adverse events in our study: IGF1 is involved in adipocyte proliferation and differentiation, and whereas some studies support a protective role with respect to atherosclerosis, others have not shown any association with coronary artery disease 17, 18.…”

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin‐3, and NT‐ProBNP Before Cardiac Surgery

“…Additionally, Galectin‐3 has been found to be associated with increased risk for all‐cause mortality in the Framingham Offspring Cohort 23. ST2 has been shown to be a sensitive biomarker of cardiac stress with statistically significant differences in concentration when stratified by age or sex 24, 25. We hypothesized that the use of these 3 biomarkers will improve the current risk prediction model used by the American College of Cardiology/American Heart Association CABG guidelines 26, 27, 28…”