Higher left ventricular (LV) mass, wall thickness, and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates ...and types of HF incidence is unclear. In this study, 4,768 Framingham Heart Study participants (mean age 50 years, 56% women) were classified into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy) using American Society of Echocardiography–recommended thresholds of echocardiographic LV mass indexed to body surface area and relative wall thickness, and these groups were related to HF incidence. Whether risk for HF types (HF with reduced ejection fraction <45% vs preserved ejection fraction ≥45%) varied by hypertrophy pattern was then evaluated. On follow-up (mean 21 years), 458 participants (9.6%, 250 women) developed new-onset HF. The age- and gender-adjusted 20-year HF incidence increased from 6.96% in the normal left ventricle group to 8.67%, 13.38%, and 15.27% in the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to the normal left ventricle group (p = 0.0002); eccentric hypertrophy carried the greatest risk (hazard ratio HR 1.89, 95% confidence interval CI 1.41 to 2.54), followed by concentric hypertrophy (HR 1.40, 95% CI 1.04 to 1.87). Participants with eccentric hypertrophy had a higher propensity for HF with reduced ejection fraction (HR 2.23, 95% CI 1.48 to 3.37), whereas those with concentric hypertrophy were more prone to HF with preserved ejection fraction (HR 1.66, 95% CI 1.09 to 2.51). In conclusion, in this large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HF with reduced and preserved ejection fraction, respectively.
Summary On Sept 29, 2013, the Framingham Heart Study will celebrate 65 years since the examination of the first volunteer in 1948. During this period, the study has provided substantial insight into ...the epidemiology and risk factors of cardiovascular disease. The origins of the study are closely linked to the cardiovascular health of President Franklin D Roosevelt and his premature death from hypertensive heart disease and stroke in 1945. In this Review we describe the events leading to the foundation of the Framingham Heart Study, and provide a brief historical overview of selected contributions from the study.
Background Serum β-trace protein (BTP) and β2 -microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with ...diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. Study Design Prospective cohort study. Setting & Participants 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). Predictors BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFRcr ), measured GFR, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. Outcomes ESRD, all-cause mortality, and new-onset cardiovascular disease. Results During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFRcr ( P vs eGFRcr ≤ 0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFRcr for all outcomes. Limitations Filtration markers measured at one time point; measured GFR available in subset of cohort. Conclusions BTP and B2M levels may contribute additional risk information beyond eGFRcr , and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.
Background Prior research yielded conflicting results about the magnitude of the association between body mass index (BMI) and chronic kidney disease (CKD). Study Design Prospective cohort study. ...Settings & Participants Framingham Offspring participants (n = 2,676; 52% women; mean age, 43 years) free of stage 3 CKD at baseline who participated in examination cycles 2 (1978-1981) and 7 (1998-2001). Predictor BMI. Outcome Stage 3 CKD (estimated glomerular filtration rate < 59 mL/min/1.73 m2 for women and < 64 mL/min/1.73 m2 for men). Measurements Age-, sex-, and multivariable-adjusted (diabetes, systolic blood pressure, hypertension treatment, current smoking status, and high-density lipoprotein cholesterol level) logistic regression models were used to examine the relationship between BMI at baseline and incident stage 3 CKD and incident dipstick proteinuria (trace or greater). Results At baseline, 36% of the sample was overweight and 12% was obese; 7.9% (n = 212) developed stage 3 CKD during 18.5 years of follow-up. Relative to participants with normal BMI, there was no association between overweight individuals and stage 3 CKD incidence in age- and sex-adjusted models (odds ratio OR, 1.29; 95% confidence interval CI, 0.93 to 1.81; P = 0.1) or multivariable models (OR, 1.06; 95% CI, 0.75 to 1.50; P = 0.8). Obese individuals had a 68% increased odds of developing stage 3 CKD (OR, 1.68; 95% CI, 1.10 to 2.57; P = 0.02), which became nonsignificant in multivariable models (OR, 1.09; 95% CI, 0.69 to 1.73; P = 0.7). Similar findings were observed when BMI was modeled as a continuous variable or quartiles. Incident proteinuria occurred in 14.4%; overweight and obese individuals were at increased odds of proteinuria in multivariable models (OR, 1.43; 95% CI, 1.09 to 1.88; OR, 1.56; 95% CI, 1.08 to 2.26, respectively). Limitations BMI is measure of generalized obesity and not abdominal obesity. Participants are predominantly white, and these findings may not apply to different ethnic groups. Conclusions Obesity is associated with increased risk of developing stage 3 CKD, which was no longer significant after adjustment for known cardiovascular disease risk factors. The relationship between obesity and stage 3 CKD may be mediated through cardiovascular disease risk factors.
Impact of Impaired Fasting Glucose on Cardiovascular Disease: The Framingham Heart Study Yamini S. Levitzky, Michael J. Pencina, Ralph B. D’Agostino, James B. Meigs, Joanne M. Murabito, Ramachandran ...S. Vasan, Caroline S. Fox Participants in the Framingham Offspring Study free of cardiovascular disease were categorized according to both the 1997 and 2003 impaired fasting glucose (IFG) definitions and followed from 1983 to 2004 for incident coronary heart disease (CHD) and cardiovascular disease events. Although neither IFG definition predicted events in men, in women, both IFG definitions yielded greater odds of CHD events. Additionally, the odds of a CHD event in women with fasting plasma glucose 110 to 125 mg/dl approached the odds for patients with diabetes, suggesting that women may be at risk for CHD events at a lower glucose threshold than men.
Abstract Cardiovascular disease (CVD) is a leading cause of death worldwide and continues to increase in prevalence compared to previous decades, in part because of the aging of the world population. ...Atherosclerotic CVD starts at a very young age and progresses over time allowing sufficient time for screening and early detection of the condition. Advances in biomarker research and developments related to CVD over the past 30 years have led to more sensitive screening methods, a greater emphasis on its early detection and diagnosis, and improved treatments resulting in more favorable clinical outcomes in the community. However, the use of biomarkers for different purposes in CVD remains an important area of research that has been explored by scientists over the years and many new developments are still underway. Therefore, a detailed description of all CVD biomarkers that are currently been used or investigated for future use in the field of cardiovascular medicine is out of scope for any review article. In the present review, we do not intend to replicate the information from previous exhaustive review on biomarkers, but highlight key statistical and clinical issues with an emphasis on methods to evaluate the incremental yield of biomarkers, including their clinical utility, a prerequisite before any putative novel biomarker is utilized in clinical practice. In addition, we will summarize information regarding recent novel heart failure biomarkers in current practice, which are undergoing scrutiny before they can be available for clinical use, and their impact on clinical outcomes.
Objectives The aim of this study was to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community. Background Gal-3 is an emerging ...prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown. Methods Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years; 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression. Results Gal-3 was associated with increased left ventricular mass in age-adjusted and sex-adjusted analyses (p = 0.001); this association was attenuated in multivariate analyses (p = 0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up period of 11.2 years. Gal-3 was associated with risk for incident HF (hazard ratio HR: 1.28 per 1 SD increase in log Gal-3; 95% confidence interval CI: 1.14 to 1.43; p < 0.0001) and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR: 1.23; 95% CI: 1.04 to 1.47; p = 0.02). Gal-3 was also associated with risk for all-cause mortality (multivariable-adjusted HR: 1.15; 95% CI: 1.04 to 1.28; p = 0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the C-statistic and minor improvements in net reclassification improvement. Conclusions Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk for incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
Heart failure, a strong risk factor for atrial fibrillation (AF), is often accompanied by elevated liver transaminases. The aim of this study was to test the hypothesis that elevated transaminases ...are associated with the risk for incident AF in the community. A total of 3,744 participants (mean age 65 ± 10 years, 56.8% women) from the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure, were studied. Cox proportional-hazards models adjusted for standard AF risk factors (age, gender, body mass index, systolic blood pressure, electrocardiographic PR interval, antihypertensive treatment, smoking, diabetes, valvular heart disease, and alcohol consumption) were examined to investigate associations between baseline serum transaminase levels (alanine transaminase and aspartate transaminase) and the incidence of AF over up to 10 years (29,099 person-years) of follow-up. During follow-up, 383 subjects developed AF. The 2 transaminases were significantly associated with greater risk for incident AF (hazard ratio expressed per SD of natural logarithmically transformed biomarker: alanine transaminase hazard ratio 1.19, 95% confidence interval 1.07 to 1.32, p = 0.002; aspartate transaminase hazard ratio 1.12, 95% confidence interval 1.01 to 1.24, p = 0.03). The associations between transaminases and AF remained consistent after the exclusion of participants with moderate to severe alcohol consumption. However, when added to known risk factors for AF, alanine transaminase and aspartate transaminase only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
Background A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2 -microglobulin (B2M) are ...associated with these outcomes in adults with type 2 diabetes is not known. Study Design Longitudinal cohort study. Setting & Participants 250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). Predictors Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr ) or cystatin C level (eGFRcys ). Outcomes & Measurements Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFRcys with mGFR or eGFRcr ) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). Results During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 95% CI, 1.01-2.30; 1/B2M, 1.54 95% CI, 0.98-2.42). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. Limitations Small sample size, single measurements of markers. Conclusions In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population.
Background We sought to investigate whether higher concentrations of resistin and lower concentrations of adiponectin relate to incident atrial fibrillation (AF) and whether this association is ...mediated by AF risk factors and inflammation. Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure. Methods We studied the relations between circulating concentrations of both adipokines and incident AF in participants of the Framingham Offspring Study. Results Participants (n = 2,487) had a mean age of 61 ± 10 years, and 54% were women. During a mean follow-up of 7.6 ± 2.0 years, 206 (8.3%) individuals (96 women) developed incident AF. Plasma resistin concentration was significantly associated with incident AF (multivariable-adjusted hazard ratio HR 1.17 per SD 0.41 ng/mL of natural logarithmically transformed resistin, 95% CI 1.02-1.34, P = .028). The resistin-AF association was attenuated after further adjustment for C-reactive protein (HR per SD increase resistin 1.14, 95% CI 0.99-1.31, P = .073). Adiponectin concentrations were not significantly associated with incident AF (multivariable-adjusted HR of 0.95 per SD 0.62 μ g/mL of logarithmically transformed adiponectin, 95% CI 0.81-1.10, P = .478). Conclusion In our community-based longitudinal study, higher mean concentrations of resistin were associated with incident AF, but the relation was attenuated by adjustment for C-reactive protein. We did not detect a statistically significant association between adiponectin and incident AF. Additional studies are needed to clarify the potential role of adipokines in AF and mechanisms linking adiposity to AF.
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