Vijay Nambi

Cardiac Troponin T Measured by a Highly Sensitive Assay Predicts Coronary Heart Disease, Heart Failure, and Mortality in the Atherosclerosis Risk in Communities Study

Background— We evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the Atherosclerosis Risk in Communities (ARIC) Study. Methods and Results— Associations between increasing cTnT levels and CHD, mortality, and HF hospitalization were evaluated with Cox proportional hazards models adjusted for traditional CHD risk factors, kidney function, high-sensitivity C-reactive protein, and N-terminal pro–B-type natriuretic peptide in 9698 participants aged 54 to 74 years who at baseline were free from CHD and stroke (and HF in the HF analysis). Measurable cTnT levels (≥0.003 &mgr;g/L) were detected in 66.5% of individuals. In fully adjusted models, compared with participants with undetectable levels, those with cTnT levels in the highest category (≥0.014 &mgr;g/L; 7.4% of the ARIC population) had significantly increased risk for CHD (hazard ratio=2.29; 95% confidence interval, 1.81 to 2.89), fatal CHD (hazard ratio=7.59; 95% confidence interval, 3.78 to 15.25), total mortality (hazard ratio=3.96; 95% confidence interval, 3.21 to 4.88), and HF (hazard ratio=5.95; 95% confidence interval, 4.47 to 7.92). Even minimally elevated cTnT (≥0.003 &mgr;g/L) was associated with increased risk for mortality and HF (P<0.05). Adding cTnT to traditional risk factors improved risk prediction parameters; the improvements were similar to those with N-terminal pro–B-type natriuretic peptide and better than those with the addition of high-sensitivity C-reactive protein. Conclusions— cTnT detectable with a highly sensitive assay was associated with incident CHD, mortality, and HF in individuals from a general population without known CHD/stroke.

Age and Sex Dependent Upper Reference Limits for the High Sensitivity Cardiac Troponin T Assay

OBJECTIVES The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts. BACKGROUND The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization. METHODS Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race. RESULTS The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold. CONCLUSIONS Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.

Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome The VISTA-16 Randomized Clinical Trial

IMPORTANCE Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130246.

Common carotid artery intima–media thickness is as good as carotid intima–media thickness of all carotid artery segments in improving prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study

AIMS Carotid intima-media thickness (CIMT) and plaque information can improve coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). However, obtaining adequate images of all carotid artery segments (A-CIMT) may be difficult. Of A-CIMT, the common carotid artery intima-media thickness (CCA-IMT) is relatively more reliable and easier to measure. We evaluated whether CCA-IMT is comparable to A-CIMT when added to TRF and plaque information in improving CHD risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS Ten-year CHD risk prediction models using TRF alone, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque were developed for the overall cohort, men, and women. The area under the receiver operator characteristic curve (AUC), per cent individuals reclassified, net reclassification index (NRI), and model calibration by the Grønnesby-Borgan test were estimated. There were 1722 incident CHD events in 12 576 individuals over a mean follow-up of 15.2 years. The AUC for TRF only, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque models were 0.741, 0.754, and 0.753, respectively. Although there was some discordance when the CCA-IMT + plaque- and A-CIMT + plaque-based risk estimation was compared, the NRI and clinical NRI (NRI in the intermediate-risk group) when comparing the CIMT models with TRF-only model, per cent reclassified, and test for model calibration were not significantly different. CONCLUSION Coronary heart disease risk prediction can be improved by adding A-CIMT + plaque or CCA-IMT + plaque information to TRF. Therefore, evaluating the carotid artery for plaque presence and measuring CCA-IMT, which is easier and more reliable than measuring A-CIMT, provide a good alternative to measuring A-CIMT for CHD risk prediction.

Associations Between Lipoprotein(a) Levels and Cardiovascular Outcomes in Black and White Subjects The Atherosclerosis Risk in Communities (ARIC) Study

Background— On the basis of studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in blacks. We evaluated associations between Lp(a) and incident CVD events in blacks and whites in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results— Plasma Lp(a) was measured in blacks (n=3467) and whites (n=9851). Hazards ratios (HRs) for incident CVD events (coronary heart disease and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in blacks (median [interquartile range], 12.8 [7.1–21.7] mg/dL) than whites (4.3 [1.7–9.5] mg/dL; P<0.0001). At 20 years of follow-up, 676 CVD events occurred in blacks, and 1821 events occurred in whites. Adjusted HRs (95% confidence interval) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident coronary heart disease, and 1.21 (1.06–1.39) for ischemic strokes in blacks. For whites, the respective HRs (95% confidence intervals) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95% confidence interval], 1.35 [1.06–1.74] for blacks and 1.27 [1.10–1.47] for whites). Similar results were obtained with the use of Lp(a) cutoffs of ⩽10 mg/dL, >10 to ⩽20 mg/dL, >20 to ⩽30 mg/dL, and >30 mg/dL. Conclusions— Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in blacks compared with whites.

Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the atherosclerosis risk in communities study

Background—A single-nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to predict coronary heart disease (CHD) in whites. We evaluated whether adding the 9p21 allele to traditional risk factors (RFs) improved CHD risk prediction in whites from the Atherosclerosis Risk in Communities study and whether changes in risk prediction would modify lipid therapy recommendations. Methods and Results—Whites (n=9998) in the Atherosclerosis Risk in Communities study for whom the 9p21 genotype and traditional RF information was available were included. Using Cox proportional hazards models, the Atherosclerosis Risk in Communities Cardiovascular Risk Score, which is based on traditional RFs, was determined. A total of 1349 individuals (13.5%) developed incident CHD events during a period of 14.6 years. Adding the 9p21 allele to traditional RFs was associated with a hazard ratio of incident CHD of 1.2 per allele (P<0.000003) and a significant increase in the area under the curve of the receiver operating characteristic from 0.782 to 0.786 (95% CI, 0.001, 0.007). The 9p21 allele’s greatest influence to the Atherosclerosis Risk in Communities Cardiovascular Risk Score was observed in the intermediate-low (>5% to ≤10% 10-year CHD risk) and intermediate-high (>10% to ≤20% 10-year CHD risk) categories, with 12.1% and 12.6% reclassified, respectively. This may impact therapy because 90% of these reclassified individuals had low-density lipoprotein cholesterol >100 mg/dL. Conclusion—Adding the 9p21 allele to traditional RFs in whites in the Atherosclerosis Risk in Communities study modestly improved CHD risk prediction in the intermediate categories.

Carotid Arterial Wall Characteristics Are Associated With Incident Ischemic Stroke But Not Coronary Heart Disease in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Ultrasound measurements of arterial stiffness are associated with atherosclerosis risk factors, but limited data exist on their association with incident cardiovascular events. We evaluated the association of carotid ultrasound-derived arterial stiffness measures with incident coronary heart disease (CHD) and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Methods— Carotid arterial strain and compliance, distensibility and stiffness indices, pressure–strain, and Young elastic moduli were measured in 10 407 individuals using ultrasound. Hazard ratios for incident CHD (myocardial infarction, fatal CHD, coronary revascularization) and stroke in minimally adjusted (age, sex, center, race) and fully adjusted models (minimally adjusted model+diabetes, height, weight, total cholesterol, high-density lipoprotein cholesterol, tobacco use, systolic blood pressure, antihypertensive medication use, and carotid intima-media thickness) were calculated. Results— The mean age was 55.3 years. Over a mean follow-up of 13.8 years, 1267 incident CHD and 383 ischemic stroke events occurred. After full adjustment for risk factors and carotid intima-media thickness, all arterial stiffness parameters (carotid arterial strain hazard ratio [HR], 1.14 [95% CI, 1.02–1.28]; arterial distensibility HR, 1.19 [1.02–1.39]; stiffness indices HR, 1.14 [1.04–1.25]; pressure–strain HR, 1.17 [1.06–1.28]; Young elastic moduli HR, 1.13 [1.03–1.24]), except arterial compliance (HR, 1.02 [0.90–1.16], were significantly associated with incident stroke but not with CHD. Conclusions— After adjusting for cardiovascular risk factors, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events despite that the 2 outcomes sharing similar risk factors. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00005131.

Biomarkers of Chronic Cardiac Injury and Hemodynamic Stress Identify a Malignant Phenotype of Left Ventricular Hypertrophy in the General Population

OBJECTIVES The goal of this study was to determine if biomarkers of subclinical myocardial injury and hemodynamic stress identify asymptomatic individuals with left ventricular hypertrophy (LVH) at higher risk for heart failure (HF) and death. BACKGROUND The interaction between LVH, low but detectable cardiac troponin T (cTnT), and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) on cardiovascular (CV) outcomes in the general population is unknown. METHODS Participants in the Dallas Heart Study without clinical HF, LV dysfunction, or chronic kidney disease underwent measurement of LV mass by magnetic resonance imaging (MRI), cTnT by highly sensitive assay, and NT-proBNP analysis (n = 2,413). Subjects were stratified according to LVH and by detectable cTnT (≥3 pg/ml) and increased NT-proBNP (>75th age- and sex-specific percentile) levels. For each analysis, participants were categorized into groups based on the presence (+) or absence (-) of LVH and biomarker levels above (+) or below (-) the predefined threshold. RESULTS Nine percent of participants were LVH+, 25% cTnT+, and 24% NT-proBNP+. Those LVH+ and cTnT+ and/or NT-proBNP+ (n = 144) were older and more likely to be male, with a greater risk factor burden and more severe LVH compared with those who were LVH+ biomarker- (p < 0.01 for each). The cumulative incidence of HF or CV death over 8 years among LVH+ cTnT+ was 21% versus 1% (LVH- cTnT-), 4% (LVH- cTnT+), and 6% (LVH+ cTnT-) (p < 0.0001). The interactions between LVH and cTnT (p(interaction) = 0.0005) and LVH and NT-proBNP (p(interaction) = 0.014) were highly significant. Individuals who were LVH+ and either cTnT+ or NT-proBNP+ remained at >4-fold higher risk for HF or CV death after multivariable adjustment for CV risk factors, renal function, and LV mass compared with those who were LVH- biomarker-. CONCLUSIONS Minimal elevations in biomarkers of subclinical cardiac injury and hemodynamic stress modify the association of LVH with adverse outcomes, identifying a malignant subphenotype of LVH with high risk for progression to HF and CV death.

Lipoprotein-Associated Phospholipase A2 and High-Sensitivity C-Reactive Protein Improve the Stratification of Ischemic Stroke Risk in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. Methods— In a prospective case–cohort (n=949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA2 and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA2 and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. Results— In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA2 significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA2 together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA2 and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA2, and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively. Conclusion— Lp-PLA2 and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.