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 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). Conclusion—: 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.

Background— Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated. Methods and Results— We related plasma ADMA, l -arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence ( P >0.10). Conclusions— In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.

Background— The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited. Methods and Results— Using multilevel modeling, we analyzed up to 4 serial echocardiographic observations obtained over a 16-year period in 4062 Framingham Heart Study participants (mean age 45 years, 54% women; 11 485 person-observations). We related left ventricular (LV) wall thickness, LV systolic and diastolic dimensions, and fractional shortening to age, sex, body mass index, blood pressure (including antihypertensive medication use), smoking, and diabetes mellitus (separate analyses for each echocardiographic measure). With advancing age, LV dimensions decreased, whereas fractional shortening and LV wall thickness increased concomitantly. Male sex, body mass index, and blood pressure indices/hypertension treatment were significantly related to both greater LV dimensions and LV wall thickness. The effect of age on cardiac remodeling was influenced by key covariates ( P <0.05 for all interactions): Women and individuals with diabetes mellitus experienced greater age-associated increases in LV wall thickness; presence of diabetes or a higher blood pressure was associated with a lesser decrease in LV diastolic dimensions with increasing age; and antihypertensive medication use was a marker of an attenuated increase in fractional shortening with aging. Conclusions— Cardiac remodeling over the adult life course is characterized by a distinct pattern of increasing LV wall thickness, decreasing LV dimensions, and increasing fractional shortening with advancing age. Overall, female sex, greater blood pressure load, and presence of diabetes mellitus serve to attenuate this remodeling pattern. These observations suggest a mechanism for the preponderance of women with hypertension and individuals with diabetes among patients with diastolic heart failure.

Background—: The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence, but the mechanisms underlying this association warrant exploration. Methods and Results—: We related the CVH score to circulating biomarkers and prevalent subclinical CVD (defined as ≥1 of the following: increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [by ECG or echocardiography], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle-brachial index) in 2680 Framingham Study participants (mean age, 58 years; 55% women). After adjustment for age and sex, an ideal CVH score (nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose; 1 point for each) was associated with higher circulating concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels ( P <0.001 for all), as well as lower odds of subclinical disease (odds ratio, 0.74 per 1-unit increase in CVH score; 95% confidence interval, 0.68–0.80). The incidence of CVD (267 events over 16 years) was inversely associated with the CVH score in age- and sex-adjusted models (hazard ratio, 0.77 per 1-unit increase in CVH score; 95% confidence interval, 0.70–0.86), which was slightly attenuated upon adjustment for biomarkers and subclinical disease (hazard ratio, 0.87; 95% confidence interval, 0.78–0.97). Conclusion—: In our prospective community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and subclinical disease.

Background: Arterial stiffness increases with age and is associated with an increased risk of adverse outcomes on short-term follow-up (typically <10 years). Data regarding associations of arterial stiffness with health outcomes on longer-term follow-up are lacking. Methods: We evaluated 7283 Framingham Study participants (mean age 50 years, 53% women) who underwent assessment of carotid-femoral pulse wave velocity (a marker of arterial stiffness) via applanation tonometry at one or more routine examinations. We used time-dependent Cox proportional hazards regression models to relate carotid-femoral pulse wave velocity to the incidence of health outcomes (updating carotid-femoral pulse wave velocity and all covariates at serial examinations). Results: On long-term follow-up (median 15 years; minimum-maximum, 0–20), participants developed cardiometabolic disease (hypertension [1255 events]; diabetes [381 events]), chronic kidney disease (529 events), dementia (235 events), cardiovascular disease (684 events) and its components (coronary heart disease [314 events], heart failure [191 events], transient ischemic attacks or stroke [250 events]), and death (1086 events). In multivariable-adjusted models, each SD increment in carotid-femoral pulse wave velocity was associated with increased risk of hypertension (hazard ratio [HR], 1.32 [95% CI, 1.21–1.44]), diabetes (HR, 1.32 [95% CI, 1.11–1.58]), chronic kidney disease (1.19 [95% CI, 1.05–1.34]), dementia (HR 1.27 [95% CI, 1.06–1.53]), cardiovascular disease (HR, 1.20 [95% CI, 1.06–1.36]) and its components (coronary heart disease, HR 1.37 [95% CI, 1.13–1.65]; transient ischemic attack/stroke, HR, 1.24 [95% CI, 1.00–1.53]), and death (HR, 1.29 [95% CI, 1.17–1.43]). The association with heart failure was borderline nonsignificant (HR, 1.21 [95% CI, 0.98–1.51], P =0.08). Conclusions: Our prospective observations of a large community-based sample establish the long-term prognostic importance of arterial stiffness for multiple health outcomes.