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Background: Left ventricular hypertrophy (LVH) combined with elevations in cardiac biomarkers reflecting myocardial injury and neurohormonal stress (malignant LVH) is associated with a high risk for heart failure and death., Objectives: The aim of this study was to determine the impact of intensive systolic blood pressure (SBP) control on the prevention of malignant LVH and its consequences., Methods: A total of 8,820 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were classified into groups based on the presence or absence of LVH assessed by 12-lead ECG, and elevations in biomarker levels (high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro-B-type natriuretic peptide ≥125 pg/mL) at baseline. The effects of intensive vs standard SBP lowering on rates of acute decompensated heart failure (ADHF) events and death and on the incidence and regression of malignant LVH were determined., Results: Randomization to intensive SBP lowering led to similar relative reductions in ADHF events and death across the combined LVH/biomarker groups (P for interaction = 0.68). The absolute risk reduction over 4 years in ADHF events and death was 4.4% (95% CI: -5.2% to 13.9%) among participants with baseline malignant LVH (n = 449) and 1.2% (95% CI: 0.0%-2.5%) for those without LVH and nonelevated biomarkers (n = 4,361). Intensive SBP lowering also reduced the incidence of malignant LVH over 2 years (2.5% vs 1.1%; OR: 0.44; 95% CI: 0.30-0.63)., Conclusions: Intensive SBP lowering prevented malignant LVH and may provide substantial absolute risk reduction in the composite of ADHF events and death among SPRINT participants with baseline malignant LVH., Competing Interests: Funding Support and Author Disclosures This ancillary study was supported by the National Heart, Lung, and Blood Institute (1R01HL144112-01 for Dr Berry). Analytical reagents for hs-cTnT and NT-proBNP measurements were donated by Roche. SPRINT was sponsored by the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, or the United States Government. Support was also received from the following CTSAs funded by the National Center for Advancing Translational Sciences: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134 and UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 and UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of California, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. Dr de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; has received consulting fees from Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel Cardiovascular, Inc, and Siemen’s Health Care Diagnostics; and has been named a co-owner on a patent awarded to the University of Maryland (US Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr Kitzman has received honoraria as a consultant outside the present study from Bayer, Merck, Pfizer, Corvia Medical, Boehringer Ingelheim, Ketyo, Rivus, Novo Nordisk, AstraZeneca, and Novartis; has received grant funding from Novartis, Bayer, Pfizer, Novo Nordisk, and AstraZeneca; and has stock ownership in Gilead Sciences. Dr Berry has received grant support from the National Institutes of Health, Roche Diagnostics, and Abbott Diagnostics; and has received consulting fees from Roche Diagnostics and the Cooper Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk., Objectives: This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories., Methods: Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors., Results: There were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to <300 or 300 pg/ml, compared with NT-proBNP <100 pg/ml) was associated with a graded increased risk for CVD events and mortality. Participants with SBP 130 to 139 mm Hg but NT-proBNP ≥300 pg/ml had a hazards ratio of 3.4 for CVD (95% confidence interval: 2.44 to 4.77) compared with a NT-proBNP of <100 pg/ml and SBP of 140 to 149 mm Hg., Conclusions: Elevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers: HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Dr. Selvin is supported by National Institutes of Health (grants K24-DK106414 and R01-DK089174). Drs. Selvin and Ballantyne are supported by National Institutes of Health (grant R01- HL134320). Dr Virani is supported by research support and a grant from Department of Veterans Affairs and World Heart Federation. Dr. Shah is supported by the National Institutes of Health (grants R01-HL135008, R01-HL143224, R01-HL150342, and K24-HL152008). Dr. Nambi is supported by a VA MERIT grant 1I01CX001112-01. Dr. de Lemos has received grant support and consulting income from Roche Diagnostics and Abbott Diagnostics; and has received consulting income from Ortho Clinical Diagnostics and Quidel Cardiovascular, Inc. Dr. Hoogeveen has received research grants (to his institution) and has been a consultant for Denka Seiken. Dr. Matsushita received nonfinancial research support from Roche Diagnostic Cooperation. Dr. Virani has received honorarium from the American College of Cardiology (Associate editor for Innovations acc.org); and has been a member of the Steering Committee for the PALM registry at Duke Clinical Research Institute (no financial remuneration). Dr Shah has received research support (significant; paid to institution, not individual) from Novartis; and has been a consultant (modest) for Philips Ultrasound. Dr. Selvin has received honoraria from Novo Nordisk. Dr. Ballantyne has received grants or research support (to his institution) from Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, and Roche Diagnostic; and has been a consultant for Abbott Diagnostics, Akcea, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Corvidia, Denka Seiken, Esperion, Intercept, Janssen, Matinas BioPharma Inc., Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Drs. Ballantyne and Nambi are named on provisional patent no. 61721475 “Biomarkers to Improve Prediction of Heart Failure Risk” filed by Baylor College of Medicine and Roche. Dr. Nambi has been a site principal investigator for a study sponsored by Merck and Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Background: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG., Objectives: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study., Methods: Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored., Results: RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10 -8 )., Conclusions: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Current prevention guidelines recommend using the Pooled Cohort Equation (PCE) for 10-year atherosclerotic cardiovascular disease (CVD) risk assessment. However, the PCE has serious limitations in older adults: it excludes heart failure (HF) hospitalization, estimates 10-year risk, which may not be the most relevant time frame, and is not indicated for individuals age >79 years., Objectives: This study sought to determine whether adding biomarkers to PCE variables improves global CVD (coronary heart disease, stroke, and HF) risk prediction in older adults over a shorter time period., Methods: Atherosclerosis Risk in Communities study participants without prevalent CVD including HF (n = 4,760; age 75.4 ± 5.1 years) were followed for incident global CVD events. Adding N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein to the PCE and a "lab model" with the biomarkers, age, race, and gender were assessed for prediction improvement. Area under the receiver operating characteristic curve (AUC) and net reclassification index (NRI) were calculated., Results: Over median follow-up of ∼4 years, incident HF was the leading CVD event (n = 193 vs. 118 coronary heart disease and 81 stroke events). Compared to the PCE, each biomarker improved risk prediction. The largest improvement in risk prediction metrics was with the addition of all 3 biomarkers (ΔAUC 0.103; continuous NRI 0.484). The lab model also performed better than the PCE model (ΔAUC 0.091, continuous NRI 0.355)., Conclusions: Adding biomarkers to the PCE or a simpler "lab model" improves short-term global CVD risk prediction and may be useful to inform short-term preventive strategies in older adults., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Among patients without cardiovascular disease (CVD) and low 10-year CVD risk, the risks of gastrointestinal bleeding and hemorrhagic strokes associated with aspirin use outweigh any potential atheroprotective benefit. According to the guidelines on primary prevention of CVD, aspirin use is considered appropriate only in patients with 10-year CVD risk ≥6% and inappropriate in patients with 10-year CVD risk <6%., Objectives: The goal of this study was to examine the frequency and practice-level variation in inappropriate aspirin use for primary prevention in a large U.S. nationwide registry., Methods: Within the National Cardiovascular Disease Registry's Practice Innovation and Clinical Excellence registry, we assessed 68,808 unique patients receiving aspirin for primary prevention from 119 U.S. practices. The frequency of inappropriate aspirin use was determined for primary prevention (aspirin use in those with 10-year CVD risk <6%). Using hierarchical regression models, the extent of practice-level variation using the median rate ratio (MRR) was assessed., Results: Inappropriate aspirin use frequency was 11.6% (7,972 of 68,808) in the overall cohort. There was significant practice-level variation in inappropriate use (range 0% to 71.8%; median 10.1%; interquartile range 6.4%) for practices; adjusted MRR was 1.63 (95% confidence interval [CI]: 1.47 to 1.77). Results remained consistent after excluding 21,052 women age ≥65 years (inappropriate aspirin use 15.2%; median practice-level inappropriate aspirin use 13.8%; interquartile range 8.2%; adjusted MRR 1.61 [95% CI: 1.46 to 1.75]) and after excluding patients with diabetes (inappropriate aspirin use 13.9%; median practice-level inappropriate aspirin use 12.4%; interquartile range 7.6%; adjusted MRR 1.55 [95% CI: 1.41 to 1.67])., Conclusions: More than 1 in 10 patients in this national registry were receiving inappropriate aspirin therapy for primary prevention, with significant practice-level variations. Our findings suggest that there are important opportunities to improve evidence-based aspirin use for the primary prevention of CVD., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding., Objectives: This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF., Methods: In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF., Results: Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes., Conclusions: Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We evaluated whether carotid intima-media thickness (CIMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF)., Background: Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the "low" and "intermediate" risk groups. On an ultrasound scan, CIMT and presence of plaque are associated with CHD, and therefore could potentially help improve CHD risk prediction., Methods: Risk prediction models (overall, and in men and women) considered included TRF only, TRF plus CIMT, TRF plus plaque, and TRF plus CIMT plus plaque. Model predictivity was determined by calculating the area under the receiver-operating characteristic curve (AUC) adjusted for optimism. Cox proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of subjects reclassified was determined. Observed events were compared with expected events, and the net reclassification index was calculated., Results: Of 13,145 eligible subjects (5,682 men, 7,463 women), approximately 23% were reclassified by adding CIMT plus plaque information. Overall, the CIMT plus TRF plus plaque model provided the most improvement in AUC, which increased from 0.742 (TRF only) to 0.755 (95% confidence interval for the difference in adjusted AUC: 0.008 to 0.017) in the overall sample. Similarly, the CIMT plus TRF plus plaque model had the best net reclassification index of 9.9% in the overall population. Sex-specific analyses are presented in the manuscript., Conclusions: Adding plaque and CIMT to TRF improves CHD risk prediction in the ARIC (Atherosclerosis Risk In Communities) study., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study is to describe the proportion of "JUPITER-eligible" (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) individuals and clinical outcomes of individuals based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C) strata in the ARIC (Atherosclerosis Risk in Communities) study., Background: Questions remain after the JUPITER study, including whether the observed cardiovascular disease (CVD) event rates would persist with time and how these event rates would compare with other populations (lower hs-CRP and/or higher LDL-C levels)., Methods: After stratification into 4 groups based on LDL-C and hs-CRP levels, with cutoffs at 130 mg/dl and 2.0 mg/l, respectively, incident CVD events were examined (mean follow-up, 6.9 years) and compared., Results: Of 8,907 age-eligible participants, 18.2% (n = 1,621) were JUPITER-eligible (hs-CRP > or = 2.0 mg/l, LDL-C <130 mg/dl) and had an absolute CVD risk of approximately 10.9% over a mean follow-up of 6.9 years (1.57% per year). If JUPITER hazard ratios were applied to this group, the number needed to treat to prevent 1 CVD event would be estimated at 38 over 5 years and 26 over 6.9 years., Conclusions: ARIC participants with elevated hs-CRP and low LDL-C had a CVD event rate of 1.57% per year over 6.9 years, similar to the CVD event rate noted in the JUPITER study placebo group (1.36% per year over 1.9 years). The association of hs-CRP > or = 2.0 mg/l with increased CVD risk and mortality regardless of LDL-C provides us a simple method of using age and hs-CRP level for identifying higher risk individuals. (Atherosclerosis Risk in Communities study; NCT00005131).