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Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.

ABSTRACT: 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.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 3428 participants (mean age, 59 years; 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 end point (P<0.001) except coronary events. Individuals with multimarker scores in the highest quartile had a 3-fold risk of death (adjusted hazard ratio, 3.2; 95% confidence interval, 2.2-4.7; P<0.001), 6-fold risk of heart failure (6.2; 95% confidence interval, 2.6-14.8; P<0.001), and 2-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).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.

SUBMITTER: Wang TJ

PROVIDER: S-EPMC3656719 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.

Wang Thomas J TJ Wollert Kai C KC Larson Martin G MG Coglianese Erin E McCabe Elizabeth L EL Cheng Susan S Ho Jennifer E JE Fradley Michael G MG Ghorbani Anahita A Xanthakis Vanessa V Kempf Tibor T Benjamin Emelia J EJ Levy Daniel D Vasan Ramachandran S RS Januzzi James L JL

Circulation 20120820 13

<h4>Background</h4>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.<h4>Methods and results</h4>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 3428 participants (mean age, ...[more]

PMID: 22907935

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Project description:In heart failure populations without aortic stenosis (AS), the prognostic utility of multiple biomarkers in addition to clinical factors has been demonstrated. We aimed to determine whether multiple biomarkers of cardiovascular stress are associated with mortality in patients with AS undergoing aortic valve replacement (AVR) independent of clinical factors.From a prospective registry of patients with AS, 345 participants who were referred for and treated with AVR (transcatheter (n=183) or surgical (n=162)) were included. Eight biomarkers were measured on blood samples obtained prior to AVR: growth differentiation factor 15 (GDF15), soluble ST2 (sST2), amino-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, high-sensitivity cardiac troponin T, myeloperoxidase, high-sensitivity C reactive protein and monocyte chemotactic protein-1. Biomarkers were evaluated based on median value (high vs low) in a Cox proportional hazards model for all-cause mortality and a parsimonious group of biomarkers selected. Mean follow-up was 1.9±1.2?years; 91 patients died.Three biomarkers (GDF15, sST2 and NTproBNP) were retained in the model. One-year mortality was 5%, 12%, 18% and 33% for patients with 0 (n=79), 1 (n=96), 2 (n=87) and 3 (n=83) biomarkers elevated, respectively (p<0.001). After adjustment for the Society of Thoracic Surgeons (STS) risk score, a greater number of elevated biomarkers was associated with increased mortality (referent: 0 elevated): 1 elevated (HR 1.47, 95% CI 0.60 to 3.63, p=0.40), 2 elevated (HR 2.89, 95% CI 1.24 to 6.74, p=0.014) and 3 elevated (HR 4.59, 95% CI 1.97 to 10.71, p<0.001). Among patients at intermediate or high surgical risk (STS score ?4), 1-year and 2-year mortality rates were 34% and 43% for patients with three biomarkers elevated versus 4% and 4% for patients with 0 biomarkers elevated. When added to the STS score, the number of biomarkers elevated provided a category-free net reclassification improvement of 64% at 1?year (p<0.001). The association between a greater number of elevated biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical AVR populations.These findings demonstrate the potential utility of multiple biomarkers to aid in risk stratification of patients with AS. Further studies are needed to evaluate their utility in clinical decision-making in specific AS populations.

Project description:BackgroundBiomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases.MethodsWe evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up (ΔeGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage ≥3 (cross-sectional), new-onset CKD stage ≥3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and ΔeGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function.ResultsIn cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with ΔeGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011±0.003 mL/min/1.73m2, p = 5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; -0.006±0.002 mL/min/1.73m2, p = 0.0001) concentration with eGFR.Discussion/conclusionsEight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.

Project description:BackgroundDecay products of radioactive materials may attach to ambient fine particles and form radioactive aerosol. Internal ionizing radiation source from inhaled radioactive aerosol may contribute to the fine particulate matter (PM2.5)-inflammation pathway. However, few studies in humans have examined the associations.ObjectivesTo examine the associations between particle radioactivity and biomarkers of oxidative stress and inflammation among participants from the Framingham Offspring and Third Generation cohorts.MethodsWe included 3996 participants who were not current smokers and lived within 50 km from our central air pollution monitoring station. We estimated regional mean gross beta radioactivity from monitors in the northeastern U.S. as a surrogate for ambient radioactive particles, and calculated the 1- to 28-day moving averages. We used linear regression models for fibrinogen, tumor necrosis factor α, interleukin-6, and myeloperoxidase which were measured once, and linear mixed effect models for 8-epi-prostaglandin F2α, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, and tumor necrosis factor receptor-2 that were measured up to twice, adjusting for demographics, individual- and area-level socioeconomic positions, time, meteorology, and PM2.5. We also examined whether the associations differed by median age, sex, diabetes status, PM2.5 levels, and black carbon levels.ResultsThe mean age was 54 years and 54% were women. An interquartile range (3 × 10-3 pCi/m3) higher beta radioactivity level at the 7-day moving average was associated with 5.09% (95% CI: 0.92, 9.43), 2.65% (1.10, 4.22), and 4.71% (95% CI: 3.01, 6.44) higher levels of interleukin-6, MCP-1, and P-selectin, but with 7.01% (95% CI: -11.64, -2.15) and 2.70% (95% CI: -3.97, -1.42) lower levels of 8-epi-prostaglandin F2α and ICAM-1, respectively.ConclusionsRegional mean particle radioactivity was positively associated with interleukin-6, MCP-1, and P-selectin, but negatively with ICAM-1 and 8-epi-prostaglandin F2α among our study participants.

Project description:OBJECTIVES:Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community. METHODS:We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time. RESULTS:Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r(2) = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity. CONCLUSION:Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors.

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Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.

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Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.

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