Soluble ST2 (sST2) is a cardiac biomarker whose concentration rises in response to myocardial strain. Increased sST2 concentrations may predict adverse outcomes in patients with heart failure and myocardial infarction. Because sST2 was largely undetectable with first-generation assays in ambulatory individuals, there are few data regarding its distribution and correlates in community-based populations.
We measured sST2 using a highly sensitive ELISA in 3450 Framingham Heart Study participants who attended a routine examination. We used multivariable linear regression models to identify covariates associated with sST2 in the general sample. We obtained a reference sample (n = 1136) by excluding individuals with prevalent coronary disease, heart failure, atrial fibrillation, diabetes, hypertension, obesity, valvular disease, left ventricular systolic dysfunction, and pulmonary and renal dysfunction. We used empiric and quantile regression techniques to estimate the 2.5th, 50th, 97.5th, and 99th quantiles.
In the general sample (mean age 59 years, 55% women), systolic blood pressure (P = 0.006), antihypertensive medication use (P = 0.03), and diabetes (P < 0.001) were associated with sST2 concentrations. In the reference sample (mean age 55, 59% women), male sex (P < 0.0001) and older age (P = 0.004) were predictive of higher sST2 concentrations. Quantile and empirical methods were used to define the reference intervals. Using the empirical approach, upper 99% percentile values in different age groups ranged from 46.6 to 64.4 μg/L in men and 36.7 to 53.0 μg/L in women.
In a well-characterized, community-based cohort, values for sST2 differ between men and women, increase with age, and are associated with diabetes and hypertension.
Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the US population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariable Cox proportional hazards regression adjusting for established AF risk factors (age, sex, systolic blood pressure, hypertension treatment, PR interval, significant heart murmur, heart failure and body mass index). Of the 3,023 eligible participants (55% women; mean age 59 years) representing 4,583 persons-examinations (Framingham Offspring 5th and 7th examination cycles), 279 individuals developed AF (9.3%) up to 10 years of follow-up. With multivariable modeling, insulin resistance was not significantly associated with incident AF (hazard ratio comparing the top with the other three quartiles of homeostatic model assessment index (HOMA) 1.18, 95% confidence interval 0.84 to 1.65, p = 0.34). In a community-based cohort with up to 10 years follow-up, no significant association was observed between insulin resistance and incident AF.
Insulin resistance; atrial fibrillation; risk factors; epidemiology
Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.
We studied 1,948 Framingham Heart Study participants (mean age, 66±9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.
In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β=−0.052±0.011, P<0.001 and β=−0.030±0.011, P=0.008, respectively) and with higher carotid-brachial pulse wave velocity (β=0.144±0.043, P=0.001 and β=0.112±0.043, P=0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β=−0.229±0.094, P=0.015) However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.
In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.
angiogenesis; vascular function; risk factors; endothelium; epidemiology
In the primary prevention of cardiovascular disease, the study of biomarkers to identify at-risk individuals is an expanding field. Several developments have fueled this trend, including improved understanding of the pathophysiological processes underlying atherosclerosis, advances in imaging technology to enable the quantification of subclinical disease burden, and the identification of new genetic susceptibility variants for cardiovascular disease. Furthermore, the advent of high-throughput platforms for molecular profiling has increased the pace of biomarker discovery. The rising interest in biomarkers has been balanced by the recognition that standardized and rigorous statistical approaches are needed to evaluate the clinical utility of candidate risk markers. This article reviews the issues surrounding the evaluation of biomarkers, evidence from studies of existing biomarkers, and recent applications of biomarker discovery platforms.
N-terminal-pro-B-type natriuretic peptide (NT-proBNP) is a commonly measured cardiovascular biomarker in both ambulatory and hospital settings. Nonetheless, there are limited data regarding “normal” ranges for NT-proBNP in healthy individuals, despite the importance of such information for interpreting natriuretic peptide measurements. We examined a healthy reference sample free of cardiovascular disease from the Framingham Heart Study Generation 3 cohort; there were 2,285 subjects (mean age 38 years, 56% women). Plasma NT-proBNP levels were measured using the Roche Diagnostics Elecsys 2010 assay, and reference values (2.5, 50, 97.5 quantiles) were determined using empiric and quantile regression methods. Gender, age, and body mass index accounted for approximately 33% of the inter-individual variability in NT-proBNP in the reference sample. NT-proBNP values were substantially higher in women compared with men at every age, and levels increased with increasing age for both sexes. Using quantile regression, the upper reference values (97.5 quantile) for NT-proBNP were 42.5 pg/ml to 106.4 pg/ml in men (depending on age), and 111.0 pg/ml to 215.9 pg/ml in women. Intra-individual variability was assessed in an additional 12 healthy individuals, who had serial NT-proBNP measurements over a month. Intra-class correlation was 0.85, indicating that most of the variability in NT-proBNP concentrations was among-persons rather than within-persons. However, the reference change value was 100%, suggesting that small proportional differences in NT-proBNP could be attributable to analytic variability. In conclusion, the reference limits obtained from this large, healthy community-based sample may aid in the evaluation of NT-proBNP concentrations measured for both clinical and research purposes.
Natriuretic peptides; Cardiac Biomarkers; Heart Failure
Lower plasma B-type natriuretic peptide (BNP) concentrations in obese individuals (‘natriuretic handicap’) may play a role in the pathogenesis of obesity-related hypertension. Whether this phenomenon may contribute to hypertension in African Americans is unknown. We tested the hypothesis that body mass index (BMI) is inversely related to BNP concentrations in African Americans.
Methods and Results
We examined the relation of plasma BNP to BMI in 3,742 Jackson Heart Study participants (mean age: 55±13, 62% women) without heart failure using multivariable linear and logistic regression, adjusting for clinical and echocardiographic covariates. The multivariable adjusted mean BNP was higher for lean participants compared to obese participants in both normotensive (p<0.0001) and hypertensive (p<0.0012) groups. In sex-specific analyses, the adjusted mean BNP was higher in lean-hypertensive individuals compared to obese-hypertensive individuals for both men (20.5 pg/mL vs. 10.9 pg/mL; p=0.0009) and women (20.0 pg/mL vs. 13.8 pg/mL; p=0.011) respectively. The differences between lean and obese participants were more pronounced in normotensive participants (men, 9.0 pg/mL vs. 4.4 pg/mL; p<0.0001 and women, 12.8 pg/mL vs. 8.4 pg/mL; p=0.0005). For both hypertensive and normotensive individuals in the pooled sample, multivariable adjusted BNP was significantly related to both continuous BMI (p<0.05 and p<0.0001 respectively) and categorical BMI (p for trend <0.006 and <0.0001 respectively).
Our cross-sectional study of a large community-based sample of African-Americans demonstrates that higher BMI is associated with lower circulating BNP concentrations, thereby extending the concept of a ‘natriuretic handicap’ in obese individuals observed in non-Hispanic whites to this high-risk population.
Natriuretic peptide; obesity; hypertension
To assess the relationship between sex hormones and natriuretic peptide levels in community-based adults
Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion.
We measured plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone binding globulin (SHBG) in 4,056 men and women (mean age 40±9 years) from the Framingham Heart Study Third Generation cohort. Sex/hormone status was grouped as: 1) men, 2) postmenopausal women not receiving hormone replacement therapy, 3) premenopausal women not receiving hormonal contraceptives, 4) postmenopausal women receiving hormone replacement therapy and 5) premenopausal women receiving hormonal contraceptives.
Circulating NT-proBNP was associated with sex/hormone status (overall P<0.0001). Men had lower NT-proBNP than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP than women who were not receiving hormone therapy (all P<0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, FT decreased and SHBG increased in tandem with increasing NT-proBNP. In sex-specific analyses, NT-proBNP decreased across increasing quartiles of free testosterone in men (P for trend<0.01) and in women (P for trend<0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations.
These findings suggest that lower circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
natriuretic peptides; sex; hormones
Salt sensitivity, a trait characterized by a pressor blood pressure (BP) response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity.
Methods and Results:
We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55±9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially ‘salt-sensitive’ if their serum aldosterone was >sex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic BP on follow-up (median 4 years). Participants who were ‘salt-sensitive’ (N=437) experienced significantly greater increases in BP (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and −0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and −0.2 mmHg; on higher versus lower sodium diet, respectively; p=0.033 and p=0.0127 for differences between groups in Δ systolic and Δ diastolic BP, respectively).
Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.
salt sensitivity; aldosterone; N-terminal proatrial natriuretic peptide; ANP
This study was carried out to investigate the prognostic utility of biomarkers in advanced stage heart failure (HF) patients requiring ICU admission for pulmonary artery catheter (PAC) guided therapy.
Thirty patients admitted to an ICU for PAC guided HF therapy were enrolled; concentrations of soluble ST2 (sST2), highly sensitive troponin I, an experimental ultrasensitive troponin I, amino-terminal pro-B type natriuretic peptide, cystatin C, and myeloperoxidase were measured over the first 48 hours. Outcomes included response of filling pressures and hemodynamics to tailored therapy and 90-day event-free survival (death, left ventricular assist device implantation, transplant).
Of the biomarkers evaluated, only sST2 concentrations were higher in those who failed to achieve goals for central venous pressure ((CVP), 225.3 versus 104.6 ng/mL; P = 0.003) and pulmonary capillary wedge pressure ((PCWP), 181.7 versus 88.2 ng/mL; P = 0.05). Only sST2 concentrations were associated with adverse events (186.7 versus 92.2 ng/mL; P = 0.01). In age-adjusted Cox proportional hazards analysis, an elevated sST2 during the first 48 hours following ICU admission independently predicted 90-day outcomes (Hazard Ratio = 5.53; P = 0.03) superior to the Simplified Acute Physiology Score for this application; in Kaplan-Meier analysis the risk associated with elevated sST2 concentrations was present early and sustained through the duration of follow-up (log rank P = 0.01).
In patients undergoing HF therapy guided by invasive monitoring, sST2 concentrations were associated with impending failure to reduce filling pressures and predicted impending events. Elevated sST2 values early in the ICU course theoretically could assist therapeutic decision-making in advanced stage HF patients.
ClinicalTrials.gov Identifier: NCT00595738
Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.
RESEARCH DESIGN AND METHODS
We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.
Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3).
Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.
Animal studies suggest that local adipocyte-mediated activity of the renin-angiotensin-aldosterone system (RAAS) contributes to circulating levels, and may promote the development of obesity-related hypertension in rodents.
We examined relations of systemic RAAS activity, as assessed by circulating plasma renin activity (PRA), serum aldosterone level, and aldosterone:renin ratio (ARR), with specific regional adiposity measures in a large, community-based sample. Third Generation Framingham Heart Study participants underwent multidetector computed tomography assessment of SAT and VAT volumes during Exam 1 (2002 and 2005). PRA and serum aldosterone were measured after approximately 10 minutes of supine rest; results were log-transformed for analysis. Correlation coefficients between log-transformed RAAS measures and adiposity measurements were calculated, adjusted for age and sex. Partial correlations between log-transformed RAAS measures and adiposity measurements were also calculated, adjusted for standard CVD risk factors.
Overall, 992 women and 897 men were analyzed (mean age 40 years; 7% hypertension; 3% diabetes). No associations were observed with SAT (renin r = 0.04, p = 0.1; aldosterone r = -0.01, p = 0.6) or VAT (renin r = 0.03, p = 0.2; aldosterone r = -0.03, p = 0.2). Similar results were observed for ARR, in sex-stratified analyses, and for BMI and waist circumference. Non-significant partial correlations were also observed in models adjusted for standard cardiovascular risk factors.
Regional adiposity measures were not associated with circulating measures of RAAS activity in this large population-based study. Further studies are required to determine whether adipocyte-derived RAAS components contribute to systemic RAAS activity in humans.
Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial.
Methods and Results
In 3120 Framingham cohort participants (mean age 58.4±9.7, 54% women), we related 10 biomarkers representing inflammation (C-reactive protein [CRP], fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP], N-terminal pro-atrial natriuretic peptide), oxidative stress (homocysteine), renin-angiotensin-aldosterone system (renin, aldosterone), thrombosis and endothelial function (D-dimer, plasminogen-activator inhibitor 1 [PAI-1]), and microvascular damage (urine albumin excretion, n=2673) with incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05–12.8 years).
In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise selection models (P<0.01 for entry and retention), log-transformed BNP, hazard ratio [HR] per standard deviation 1.62 (95% confidence interval [CI] 1.41–1.85, P<0.0001), and CRP, HR 1.25 (95% CI 1.07–1.45, P=0.004), were chosen.
The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95%CI 0.75–0.81 to 0.80 (95% CI 0.78–0.83), and showed an integrated discrimination improvement of 0.03 (95% CI 0.02–0.04, P<0.0001) with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and CRP did not appreciably improve risk prediction over the model incorporating BNP in addition to the risk factors.
BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention needs further investigation.
atrial fibrillation; biomarkers; epidemiology; cohort; risk assessment
We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other race/ethnic groups.
We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n=4764 participants) and two geographically and ethnically diverse cohorts: AGES (Age, Gene/Environment Susceptibility-Reykjavik Study, n=4238), and CHS (Cardiovascular Health Study, n=5410 of whom 874 (16.2%) were African Americans (AA)); aged 45–95 years. The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR-interval, hypertension treatment, and heart failure.
We observed 1359 incident AF events in 100,074 person-years of follow-up. Unadjusted five-year event-rates differed by cohort (AGES 12.8 cases/1000 person-years; CHS whites 22.7 cases/1000 person-years; FHS 4.5 cases/1000 person-years) and race/ethnicity (CHS AA 18.4 cases/1000 person-years).
The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm performed reasonably well in all samples (AGES C-statistic 0.67, 95% confidence interval 0.64–0.71; CHS whites, 0.68, 0.66–0.70; CHS AA 0.66, 0.61–0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population attributable risk.
Risk of incident AF in community-dwelling whites and AA can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% percent of risk.
atrial fibrillation; risk score; epidemiology; cohort study; race/ethnicity
To assess the predictive accuracy of conventional cardiovascular risk factors for incident heart failure(HF) and atrial fibrillation(AF) and the added benefit of multiple biomarkers reflecting diverse pathophysiological pathways.
HF and AF are interrelated cardiac diseases associated with substantial morbidity and mortality and increasing incidence. Data on prediction and prevention of these diseases in healthy individuals is limited.
In 5,187 individuals from the community-based Malmö Diet and Cancer study, we studied the performance of conventional risk factors and six biomarkers including midregional pro-atrial natriuretic peptide(MR-proANP), N-terminal pro-B-type natriuretic peptide(Nt-proBNP), midregional pro-adrenomedullin, cystatin C, C-reactive protein(CRP) and copeptin.
During a mean follow-up of 14 years,112 individuals were diagnosed with HF and 284 individuals with AF. Nt-proBNP(HR=1.63 per SD,95%CI=1.29–2.06,p<0.001), CRP(HR=1.57 per SD,95%CI=1.28–1.94,p<0.001) and MR-proANP(HR=1.26 per SD,95%CI=1.02-1-56,p=0.03) predicted incident HF independently of conventional risk factors and other biomarkers. MR-proANP(HR=1.62,95%CI=1.42-1.84,p<0.001) and CRP(HR=1.18,95%CI=1.03–1.34,p=0.01) independently predicted AF. Addition of biomarkers to conventional risk factors improved C-statistics from 0.815 to 0.842 for HF and from 0.732 to 0.753 for AF and the Integrated discriminatory index for both diseases(p<0.001). Net reclassification improvement with biomarkers was observed in 22% of individuals for HF(NRI,p<0.001) and in 7% for AF(NRI,p=0.06), mainly due to up-classification of individuals who developed disease(HF:29%,AF:19%). Addition of CRP to natriuretic peptides did not improve discrimination or reclassification.
Conventional cardiovascular risk factors predict incident HF and AF with reasonable accuracy in middle-aged individuals free from disease. Natriuretic peptides, but not other biomarkers, improve discrimination modestly for both diseases above and beyond conventional risk factors and substantially improve classification for HF.
Atrial Fibrillation; Heart failure; Prediction; Natriuretic peptides; Risk factors; Epidemiology
Several biological pathways are activated in ventricular remodeling and in overt heart failure (HF). There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community.
Methods and Results
We related a multi-biomarker panel to the incidence of a first HF event in 2754 Framingham Heart Study participants (mean age 58 years; 54% women), who were free of HF and underwent routine assays for 6 biomarkers (c-reactive protein, plasminogen activator inhibitor-1, homocysteine, aldosterone-to-renin ratio, b-type natriuretic peptide [BNP] and urinary albumin-to-creatinine ratio [UACR]). We estimated model c-statistic, calibration and net reclassification improvement (NRI) to assess the incremental predictive usefulness of biomarkers. We also related biomarkers to incidence of non-ischemic HF in participants without prevalent coronary heart disease.
On follow-up (mean 9.4 years), 95 first HF events occurred (54 in men). In multivariable-adjusted models, the biomarker panel was significantly related to HF risk (p=0.00005). Upon backwards elimination, BNP and UACR emerged as key biomarkers predicting HF risk: hazards ratio (HR; confidence interval [CI]) per standard deviation increment in log-marker were 1.52 (1.24-1.87) and 1.35 (1.11-1.66), respectively. BNP and UACR significantly improved the model c-statistic (CI) from 0.84 (0.80-0.88) in standard models to 0.86 (0.83-0.90), enhanced risk reclassification (NRI = 0.13; p=0.002), and were also independently associated with non-ischemic HF risk.
Using a multimarker strategy, we identified BNP and UACR as key risk factors for new-onset HF with incremental predictive utility over standard risk factors.
Biomarkers; heart failure; risk; prediction
Experimental studies have linked hypomagnesemia with the development of vascular dysfunction, hypertension, and atherosclerosis. Prior clinical studies have yielded conflicting results, but were limited by the use of self-reported magnesium intake or short follow-up periods.
We examined the relationship between serum magnesium concentration and incident hypertension, cardiovascular disease, and mortality in 3,531 middle-aged adult participants in the Framingham Heart Study offspring cohort. Analyses were performed using Cox proportional hazards regressions, adjusted for traditional cardiovascular disease risk factors.
Follow up was 8 years for new-onset hypertension (551 events) and 20 years for cardiovascular disease (554 events). There was no association between baseline serum magnesium and the development of hypertension (multivariable-adjusted hazards ratio per 0.15 mg/dl, 1.03, 95% confidence interval [CI], 0.92-1.15; p=0.61), cardiovascular disease (0.77, 95% CI, 0.44-1.37; p=0.49) or all-cause mortality (0.64, 95% CI, 0.32-1.26; p=0.42). Similar findings were observed in categorical analyses, in which serum magnesium was modeled in categories (<1.5, 1.5-2.2, >2.2 mg/dl) or in quartiles.
In conclusion, data from this large, community-based cohort do not support the hypothesis that low serum magnesium is a risk factor for developing hypertension or cardiovascular disease.
Magnesium; hypomagnesemia; hypertension; cardiovascular disease; mortality
Left ventricular remodeling is characterized by increased collagen deposition in the extracellular matrix. Levels of plasma pro-collagen type III amino-terminal peptide (PIIINP), a marker of collagen turnover, are elevated in the setting of recent myocardial infarction, heart failure, and cardiomyopathy. Whether plasma PIIINP levels are a useful indicator of subclinical left ventricular abnormalities in ambulatory individuals has not been studied.
We examined 967 Framingham Heart Study participants (mean age 56 years; 60% women) who underwent routine echocardiography and measurement of plasma PIIINP levels. All participants were free of prior myocardial infarction or heart failure. Multivariable regression analyses were performed to examine the clinical and echocardiographic correlates of PIIINP levels.
Plasma PIIINP levels increased with age and body mass index, but did not significantly correlate with other cardiovascular risk factors including hypertension and diabetes. In multivariable models, there was no association between plasma PIIINP levels and left ventricular mass (p=0.89), left ventricular fractional shortening (p=0.15), left ventricular end-diastolic dimension (p=0.51), or left atrial size (p=0.68). Plasma PIIINP levels were positively correlated with tissue inhibitor of metalloproteinase-1 levels (multivariable-adjusted p=0.001).
The use of biomarkers of extracellular matrix turnover has generated recent interest, with plasma PIIINP being the most commonly studied biomarker in acute settings. However, our findings in a large, community-based cohort suggest that plasma PIIINP has limited utility for the detection of structural heart disease in ambulatory individuals.
In the setting of acute myocardial infarction, prolongation of the QRS interval on an electrocardiogram identifies patients at risk of needing permanent pacemaker implantation. However, the implications of a prolonged QRS in healthy individuals are unclear, especially since the QRS prolongation encountered in this setting is typically mild. We studied the relation between QRS duration and incident pacemaker implantation in a community-based cohort of 8,311 individuals (mean age 54 years, 55% women) who attended 17,731 routine examinations with resting 12-lead electrocardiography. QRS duration was analyzed as both a continuous and categorical variable (<100 milliseconds [ms]; 100 to <120 ms; ≥120 ms). During up to 35 years of follow up, 157 participants (56 women) developed need for a permanent pacemaker. In multivariable Cox regression models adjusting for cardiovascular risk factors and prior or incident myocardial infarction or heart failure, mild QRS prolongation was associated with a 3-fold risk of pacemaker implantation (adjusted hazards ratio [HR] 2.90; 95% confidence interval [CI] 1.81–4.66; P<0.0001), and bundle-branch block was associated with a 4-fold risk of pacemaker implantation (HR 4.43; 95% CI 2.94–6.68; P<0.0001). Each standard deviation increment in QRS duration (11 ms) was associated with an adjusted hazards ratio of 1.14 (95% CI 1.11–1.18; P<0.0001) for pacemaker placement. This association remained significant after excluding individuals with QRS ≥120 ms. In conclusion, individuals with a prolonged QRS duration, even without bundle-branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease.
epidemiology; risk factors; pacemaker; conduction disease
To examine the association of serum gamma glutamyl transferase (GGT) to incident heart failure.
Methods and Results
We related serum GGT to the incidence of heart failure in 3544 (mean age 44.5yrs; 1833 women) Framingham Study participants who were free of heart failure and myocardial infarction. On follow-up (mean 23.6yrs), 188 participants (77 women) developed new-onset heart failure. In multivariable Cox models adjusting for standard risk factors and alcohol consumption as time-varying covariates (updated every 4 years), each standard deviation increase in log-GGT was associated with a 1.39-fold risk of heart failure (95% confidence intervals [CI] 1.20-1.62). The linearity of the association was confirmed by multivariable-adjusted splines and the relations remained robust upon additional adjustment for hepatic aminotransferases and C-reactive protein. Participants with serum GGT ≥median had a 1.71-fold risk of heart failure (95% CI 1.21-2.41) compared to individuals with GGT concentrations below the median. GGT marginally increased the model c-statistic from 0.85 to 0.86, but improved the risk reclassification modestly (net reclassification index 5.7%, p=0.01).
In our prospective study of large community-based sample higher serum GGT concentrations within the ‘normal’ range were associated with greater risk of heart failure and incrementally improved prediction of heart failure risk.
To evaluate the association of serum phosphorus with cardiac structure/function and incident heart failure.
Methods and results
We related serum phosphorus to echocardiographic left ventricular (LV) measurements cross-sectionally, and to incident heart failure prospectively in 3300 participants (mean age 44 years, 51% women) free of heart failure, myocardial infarction, and chronic kidney disease (estimated glomerular filtration rate [eGFR]<60 mL/min/1.73 m2). Cross-sectionally, serum phosphorus was related positively to LV mass, internal dimensions, and systolic dysfunction. On follow-up (mean 17.4 years), 157 individuals developed heart failure. In models adjusting for established risk factors as time-varying covariates, each mg/dL increment in serum phosphorus was associated with a 1.74-fold risk of heart failure [95% confidence intervals (CI) 1.17–2.59]. Individuals in the highest serum phosphorus quartile experienced a two-fold (95% CI 1.28–3.40) risk of heart failure compared with participants in the lowest quartile. These relations were maintained upon additional adjustment for LV mass/dimensions and systolic dysfunction. In analyses restricted to individuals with eGFR >90 mL/min/1.73 m2, no proteinuria and serum phosphorus <4.5 mg/dL, the association of serum phosphorus with heart failure remained robust.
In our community-based sample, higher serum phosphorus was associated with greater LV mass cross-sectionally, and with an increased risk of heart failure prospectively.
Phosphorus; Congestive heart failure; Ventricle; Epidemiology; Risk factors
Obesity represents an important risk factor for atrial fibrillation (AF). We tested the hypothesis that pericardial fat, a unique fat deposit in close anatomic proximity to cardiac structures and autonomic fibers, is associated with prevalent AF.
Methods and Results
Participants from the Framingham Heart Study underwent multi-detector computed tomography from 2002–2005. We estimated the association between quantitative pericardial, intra-thoracic and visceral adipose tissue volumes (per standard deviation [SD] of volume) with prevalent AF adjusting for established AF risk factors (age, sex, systolic blood pressure, blood pressure treatment, PR interval and clinically significant valvular disease). Of the 3217 eligible participants (mean age 50.6±10.1 years, 48% women), 54 had a confirmed diagnosis of AF. Pericardial fat, but not intra-thoracic or visceral abdominal fat, was associated with prevalent AF in multivariable-adjusted models (Odds Ratio [OR] per SD of pericardial fat volume 1.28, 95% confidence intervals [CI] 1.03–1.58). Further adjustments for body mass index, heart failure, myocardial infarction and intra-thoracic fat volume did not materially change the association between pericardial fat and AF.
Pericardial fat was associated with prevalent AF even after adjustment for AF risk factors, including body mass index. If this association is replicated, further investigations into the mechanisms linking pericardial fat to AF are merited.
Atrial fibrillation; pericardial; adipose tissue; obesity; epidemiology; risk factor
Leucocyte telomere length (LTL) chronicles the cumulative burden of oxidative stress and inflammation over a life course. Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased oxidative stress and inflammation. Therefore, LTL may be related to circulating biomarkers of the RAAS.
We evaluated the cross-sectional relations of LTL (dependent variable) to circulating renin and aldosterone concentrations and the renin-aldosterone ratio (all logarithmically-transformed; independent variables) in 1203 Framingham Study participants (mean age 59 years, 51% women). We used multivariable linear regression and adjusted for age, blood pressure, hypertension treatment, smoking, diabetes, body mass index, hormone replacement therapy, serum creatinine and the urine sodium-creatinine ratio.
Overall, multivariable-adjusted LTL was inversely related to renin (beta coefficient per unit increase [β]=-0.038; p= 0.036), directly related to aldosterone (β=0.099; p= 0.002), and inversely related to the renin-aldosterone ratio (β=-0.049; p= 0.003). Relations of LTL to biomarkers were stronger in those with hypertension, although a formal test of interaction was not statistically significant (p=0.20). Individuals with hypertension displayed significant associations of LTL with renin (β=-0.060; p= 0.005), aldosterone (β=0.134; p= 0.002) and renin-aldosterone ratio (β=-0.072; p<0.001). Participants with hypertension who were in the top tertile of the renin-aldosterone ratio had LTL that was 182 base pairs shorter relative to those in the lowest tertile.
In our community-based sample, LTL was shorter in individuals with a higher renin-aldosterone ratio, especially so in participants with hypertension. Additional investigations are warranted to confirm our observations.
Telomere; Renin; Aldosterone; Hypertension; Epidemiology; Association; Salt; Oxidative stress
Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.
We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L.
Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26).
Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.
Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines, and other polar metabolites were profiled in baseline specimens using liquid chromatography-tandem mass spectrometry. Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes: isoleucine, leucine, valine, tyrosine, and phenylalanine. A combination of three amino acids predicted future diabetes (>5-fold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential importance of amino acid metabolism early in the pathogenesis of diabetes, and suggest that amino acid profiles could aid in diabetes risk assessment.