Prognostic Utility of Novel Biomarkers of Cardiovascular Stress: The Framingham Heart Study

Study Questions:

What is the individual and collective utility of soluble ST2, growth differentiation factor (GDF)-15, and high-sensitivity troponin I (hsTnI) for predicting cardiovascular outcomes in the community?


To determine the prognostic value of three novel biomarkers induced by cardiovascular stress, the investigators measured soluble ST2, GDF-15, and hsTnI in 3,428 participants (mean age, 59 years; 53% women) in the Framingham Heart Study. They performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. The authors also constructed a “multimarker” score composed of the three 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 three new biomarkers were associated with each endpoint (p < 0.001) except coronary events. Individuals with multimarker scores in the highest quartile had a three-fold risk of death (adjusted hazard ratio, 3.2; 95% confidence interval, 2.2-4.7; p < 0.001), six-fold risk of heart failure (6.2; 95% confidence interval, 2.6-14.8; p < 0.001), and two-fold risk of cardiovascular events (1.9; 95% confidence interval, 1.3-2.7; p = 0.001). Addition of the multimarker score to clinical variables led to significant increases in the c-statistic (p = 0.005 or lower) and net reclassification improvement (p = 0.001 or lower).


The authors concluded that 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.


The study suggests that concentrations of soluble ST2, GDF-15, and hsTnI predict the future risk of death, heart failure, and overall cardiovascular events, even in the context of robust clinical risk models. Addition of these biomarkers improves discrimination and may lead to potentially relevant changes in risk classification and intervention. Given the value of the markers studied, this hypothesis warrants validation and testing in future prospective clinical studies.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Heart Diseases, Bone Morphogenetic Protein 15, C-Reactive Protein, Biological Markers, Troponin I, Growth Differentiation Factor 15, Heart Failure, Confidence Intervals, Drugs, Chinese Herbal, Natriuretic Peptide, Brain

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