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Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants., Materials and Methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed., Results: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m 2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants., Conclusion: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects., Methods: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643  800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model., Results: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF., Conclusions: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure., Competing Interests: Disclosures Dr Bhatt discloses the following relationships: advisory boards for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; boards of directors for Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; chair/inaugural chair of the American Heart Association Quality Oversight Committee; consultant for Broadview Ventures and Hims; data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT Trial); honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair of the ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Behring), Belvoir Publications (editor in chief of Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief of the Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair for interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director of Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national coleader, funded by Bayer), Slack Publications (chief medical editor of Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Wiley (steering committee); other: clinical cardiology (deputy editor), NCDR-ACTION Registry steering committee (chair), and VA CART Research and Publications Committee (chair); named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital (assigned to Lexicon; neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (editor of Braunwald’s Heart Disease); site co- investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee of the American College of Cardiology; and unfunded research from FlowCo and Takeda. Dr McGuire reports receiving executive committee fees and consulting fees from Boehringer Ingelheim, Sanofi US, and AstraZeneca; data monitoring committee fees from CSL Behring; executive committee fees, consulting fees, and advisory board fees from Lilly USA and Novo Nordisk; executive committee fees from Lexicon and Eisai; steering committee fees from Esperion; consulting fees from Metavant, Applied Therapeutics, Bayer, and Afimmune; and advisory board fees from Pfizer, Merck Sharp, and Dohme. Dr Sattar has consulted for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi, and received grant support from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. The other authors report no conflicts.

Background: THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA 1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention., Objectives: In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors., Methods: Outcomes were analyzed across baseline diabetes duration, HbA 1c , and antihyperglycemic medications., Results: In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA 1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA 1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA 1c , and antihyperglycemic medications., Conclusion: Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population., Competing Interests: Funding Support and Author Disclosures The THEMIS study was funded and sponsored by AstraZeneca Research & Development. The statistical analyses were conducted independently from but with funding from AstraZeneca. Dr. Leiter has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, HLS, Janssen, Novartis, Novo Nordisk, and Sanofi; has received grants from Esperion, GSK, Kowa, Lexicon, Novartis, and The Medicines Company; and has received personal fees from Merck and Servier. Dr. Bhatt served as the co-chair and co–principal investigator of THEMIS and THEMIS-PCI with research funding from AstraZeneca to Brigham and Women’s Hospital; and has served on the advisory board for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado has served on the Biosciences; has served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair of American Heart Association Quality Oversight Committee; has served on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim, and AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry steering committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; has been a trustee of American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr. McGuire has received honoraria for clinical trials leadership from AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Lilly USA, Merck, Novo Nordisk, Pfizer, and Sanofi; and has received honoraria for consultancy from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Lilly USA, Merck, Metavant, Novo Nordisk, and Sanofi. Dr. Teoh has received personal fees from Boehringer Ingelheim, Merck, and Servier. Dr. Fox has received fees, honoraria, and travel expenses from AstraZeneca, Broadview Ventures, Celixir, Servier, TaurX, and UCB; and has served as a director of Vesalius Trials. Dr. Simon has received grants to the institution from AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Sanofi; and has received consulting fees or honoraria from AstraZeneca, Bristol Myers Squibb, Novartis, and Sanofi. Dr. Mehta has received research grants to Population Health Research Institute from AstraZeneca, Abbott, Boston Scientific, and Sanofi; and has received honoraria for consultancy from AstraZeneca, Bayer, Biosensors, and Sanofi. Dr. Kiss has received speaker honoraria from Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, and Pfizer. Dr. Dalby has served on South African advisory boards for Aspen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Sanofi, and Servier; has received honoraria from AstraZeneca and Servier; and has received travel sponsorship from Bayer, Boehringer Ingelheim, Novartis, and Sanofi. Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 and PI17/01799), Sociedad Española de Cardiología, AstraZeneca, Bayer, Bristol Myers Squibb, and Novartis; has received honoraria for consultancy from AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, Novartis, and Medscape. Dr. Ridderstråle is an employee of AstraZeneca. Dr. Himmelmann is an employee of AstraZeneca. Dr. Kosiborod has received research support from AstraZeneca and Boehringer Ingelheim; and has received honoraria for clinical trial leadership and consultancy for Amarin, Applied Therapeutics, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Eisai, Glytec, GlaxoSmithKline, Intacia, Janssen, Eli Lilly, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and Vifor Pharma. Dr. Steg has received personal fees and nonfinancial support from AstraZeneca; has received grants and personal fees from Amarin, Bayer/Janssen, Merck, Sanofi, and Servier; and has received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Lilly, Novartis, Novo Nordisk, Pfizer, and Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Evidence-based therapies are generally underused for cardiovascular risk reduction; however, less is known about contemporary patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Methods and Results Pharmacy and medical claims data from within Anthem were queried for patients with established atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Using an index date of April 18, 2018, we evaluated the proportion of patients with a prescription claim for any of the 3 evidence-based therapies on, or covering, the index date ±30 days: high-intensity statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist. The potential benefit of achieving 100% adoption of all 3 evidence-based therapies was simulated using pooled treatment estimates from clinical trials. Of the 155 958 patients in the sample, 24.7% were using a high-intensity statin, 53.1% were using an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 9.9% were using either an sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonists. Overall, only 2.7% of the population were covered by prescriptions for all 3 evidence-based therapies, and 37.4% were on none of them. Over a 12-month period, 70.6% of patients saw a cardiologist, while only 18% saw an endocrinologist. Increasing the use of evidence-based therapies to 100% over 3 years of treatment could be expected to reduce 4546 major atherosclerotic cardiovascular events (myocardial infarction, stroke, or cardiovascular death) in eligible but untreated patients. Conclusions Alarming gaps exist in the contemporary use of evidence-based therapies in this large population of insured patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor., Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population)., Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction =0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction =0·012. Benefit was present irrespective of time from most recent PCI., Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk., Funding: AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Previous studies suggest that among patients with stable coronary artery disease, patients with diabetes mellitus (DM) have less angina and more silent ischemia when compared with those without DM. However, the burden of angina in diabetic versus nondiabetic patients after elective percutaneous coronary intervention (PCI) has not been recently examined., Methods and Results: In a 10-site US PCI registry, we assessed angina before and at 1, 6, and 12 months after elective PCI with the Seattle Angina Questionnaire angina frequency score (range, 0-100, higher=better). We also examined the rates of antianginal medication prescriptions at discharge. A multivariable, repeated-measures Poisson model was used to examine the independent association of DM with angina over the year after treatment. Among 1080 elective PCI patients (mean age, 65 years; 74.7% men), 34.0% had DM. At baseline and at each follow-up, patients with DM had similar angina prevalence and severity as those without DM. Patients with DM were more commonly prescribed calcium channel blockers and long-acting nitrates at discharge (DM versus not: 27.9% versus 20.9% [ P =0.01] and 32.8% versus 25.5% [ P =0.01], respectively), whereas β-blockers and ranolazine were prescribed at similar rates. In the multivariable, repeated-measures model, the risk of angina was similar over the year after PCI in patients with versus without DM (relative risk, 1.04; range, 0.80-1.36)., Conclusions: Patients with stable coronary artery disease and DM exhibit a burden of angina that is at least as high as those without DM despite more antianginal prescriptions at discharge. These findings contradict the conventional teachings that patients with DM experience less angina because of silent ischemia., (© 2017 American Heart Association, Inc.)

Background: Patients with diabetes mellitus (DM) experience higher rates of in-stent restenosis and greater benefit from drug-eluting stents implant at the time of percutaneous coronary intervention (PCI), necessitating prolonged dual anti-platelet therapy (DAPT). While DAPT reduces risk of ischemic events post-PCI, it also increases risk of bleeding. Whether bleeding rates differ among patients with and without DM, receiving long-term DAPT is unknown., Methods: Among patients who underwent PCI and were maintained on DAPT for 1 year in a multicenter US registry, we assessed patient-reported bleeding over one year following PCI in patients with and without DM. Multivariable, hierarchical Poisson regression was used to evaluate the association of DM with bleeding during follow-up., Results: Among 2334 PCI patients from 10 US hospitals (mean age 64, 54% ACS), 32.6% had DM. In unadjusted analyses, patients with DM had fewer bleeding events over the year following PCI (DM vs no DM: BARC = 1: 78.0% vs 87.7%, P < .001; BARC ≥2: 4.3% vs 5.3%, P = .33). Following adjustment, patients with (vs without DM) had a lower risk of BARC ≥1 bleeding during follow-up (relative risk [RR] 0.89, 95% CI 0.83-0.96). This decreased bleeding risk persisted after removing bruising from the endpoint definition., Conclusions: In a real-world PCI registry, patients with DM experienced lower risk of bleeding risk on DAPT. As patients with DM also derive greater ischemic benefit from drug-eluting stents, which requires prolonged DAPT, our findings suggest that the balance between benefit and risk of this therapeutic approach may be even more favorable in patients with DM than previously considered., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Current diabetes guidelines recommend an individualized approach to glycaemic control. There are limited data on the contemporary and comprehensive management of patients with diabetes in relation to coronary artery disease (CAD)., Methods and Results: The Diabetes Mellitus Status in Canada (DM-SCAN) survey included 5123 patients with type 2 diabetes seen in primary care in November 2012. Primary care physicians (PCPs) collected clinical data and specified the A1C target for each patient on standardized forms. We compared management strategies and achievement of treatment targets in patients with and without CAD. Among the 4994 patients with data on CAD history, 22.5% had CAD. Primary care physicians were more likely to select a higher A1C target for patients with CAD (≤7.5 or ≤8.0%) versus without (≤7.0%). There was no difference in median A1C or in the proportion of patients with A1C ≤7.0% between the two groups. Compared with the group without known CAD, patients with CAD had a higher reported prevalence of hypoglycaemia in the preceding 6 months; more frequently received aspirin, statins, ACE inhibitors, or angiotensin receptor blockers, and were more likely to achieve blood pressure and low-density lipoprotein-cholesterol targets. Only 15.4 and 12.0% of patients with and without CAD (P = 0.002), respectively, achieved all three guideline-recommended targets., Conclusion: Compared with patients with diabetes without CAD, those with CAD more frequently had a less stringent A1C target selected by their PCPs but achieved similar glycaemic control. Overall, risk factor management remained suboptimal in both groups. There remains an important opportunity to improve the care and outcome of patients with diabetes.

Background: Current guidelines recommend surgical revascularization (coronary artery bypass graft [CABG]) over percutaneous coronary intervention (PCI) in patients with diabetes mellitus and multivessel coronary artery disease. Few data are available describing revascularization patterns among these patients in the setting of non-ST-segment-elevation myocardial infarction., Methods and Results: Using Acute Coronary Treatment and Intervention Outcomes Network Registry-Get with the Guidelines (ACTION Registry-GWTG), we compared the in-hospital use of different revascularization strategies (PCI versus CABG versus no revascularization) in diabetes mellitus patients with non-ST-segment-elevation myocardial infarction who had angiography, demonstrating multivessel coronary artery disease between July 2008 and December 2014. Factors associated with use of CABG versus PCI were identified using logistic multivariable regression analyses. A total of 29 769 patients from 539 hospitals were included in the study, of which 10 852 (36.4%) were treated with CABG, 13 760 (46.2%) were treated with PCI, and 5157 (17.3%) were treated without revascularization. The overall use of revascularization increased over the study period with an increase in the proportion undergoing PCI (45% to 48.9%; Ptrend=0.0002) and no change in the proportion undergoing CABG (36.1% to 34.7%; ptrend=0.88). There was significant variability between participating hospitals in the use of PCI and CABG (range: 22%-100%; 0%-78%, respectively; P value <0.0001 for both). Patient-level, but not hospital-level, characteristics were statistically associated with the use of PCI versus CABG, including anatomic severity of the disease, early treatment of adenosine diphosphate receptor antagonists at presentation, older age, female sex, and history of heart failure., Conclusions: Among patients with diabetes mellitus and multivessel coronary artery disease presenting with non-ST-segment-elevation myocardial infarction, only one third undergo CABG during the index admission. Furthermore, the use of PCI, but not CABG, increased modestly over the past 6 years., (© 2016 American Heart Association, Inc.)

Background: Thirty-eight patients with intermediate (30%-60% diameter stenosis) saphenous vein graft lesions were randomized to extended-release niacin (ER-niacin) or placebo for 12 months. We sought to evaluate the impact of ER-niacin on carotid intima media thickness (CIMT), endothelial function, and endothelial progenitor cell (EPC) mobilization., Methods: Carotid B-mode ultrasound was used to image the common and internal carotid arteries, at baseline and at 12 months after enrollment. Reactive hyperemia peripheral arterial tonometry, as assessed with EndoPAT 2000 (Itamar Medical, Inc) and EPC mobilization assessed with flow cytometry, were measured at enrollment, and at 1 and 12 months., Results: The baseline clinical characteristics were similar in the two study groups. High-density lipoprotein cholesterol levels tended to increase more in the ER-niacin group (5.9 ± 8.7 mg/dL vs 1.4 ± 7.1 mg/dL; P=.14). Between baseline and 12 months, right common carotid artery (0.96 ± 0.44 mm vs 0.70 ± 0.24 mm; P=.04), and left common carotid artery (0.80 ± 0.30 mm vs 0.70 ± 0.20 mm; P=.08) CIMT tended to decrease in the ER-niacin group, compared with no change in the placebo group. The change in logarithmic reactive hyperemia index between 1 month and 12 months was similar in patients receiving ER-niacin vs placebo (0.003 ± 0.12 vs -0.058 ± 0.12; P=.39), whereas EPC mobilization increased in the ER-niacin group and decreased in the placebo group (8.65 ± 28.41 vs -5.87 ± 30.23 EPC colony forming units/mL of peripheral blood; P=.02)., Conclusions: ER-niacin did not have a significant impact on CIMT or endothelial function, but increased EPC mobilization.

Objectives: This study sought to assess the effect of coronary artery calcium (CAC) on coronary heart disease (CHD) risk prediction in a younger population., Background: CAC measured by computed tomography improves CHD risk classification in older adults, but the effectiveness of CAC in younger populations has not been fully assessed., Methods: In the DHS (Dallas Heart Study), a multiethnic probability-based population sample, traditional CHD risk factors and CAC were measured in participants without baseline cardiovascular disease or diabetes. Incident CHD-defined as CHD death, myocardial infarction, or coronary revascularization-was assessed over a median follow-up of 9.2 years. Predicted CHD risk was assessed with a Weibull model inclusive of traditional risk factors before and after the addition of CAC as ln(CAC + 1). Participants were divided into 3 10-year risk categories, <6%, 6% to <20%, and ≥20%, and the net reclassification improvement (NRI) was calculated. We also performed a random-effects meta-analysis of NRI from previous studies inclusive of older individuals., Results: The analysis comprised 2,084 participants; mean age was 44.4 ± 9.0 years. CAC was independently associated with incident CHD (hazard ratio per SD: 1.90, 95% confidence interval [CI] 1.51 to 2.38; p < 0.001). The addition of CAC to the traditional risk factor model resulted in significant improvement in the C-statistic (delta = 0.03; p = 0.003). Among participants with CHD events, the addition of CAC resulted in net correct upward reclassification of 21%, and among those without CHD, a net correct downward reclassification of 0.5% (NRI: 0.216, p = 0.012). Results remained significant when the outcome was restricted to CHD death and myocardial infarction and when individuals with diabetes were included. The NRI observed in this study was similar to the pooled estimate from previous studies (0.200, 95% CI: 0.140 to 0.258) and the addition of our study to the meta-analysis did not result in significant heterogeneity (I(2) = 0%)., Conclusions: CAC scoring also improves CHD risk classification in younger adults., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: While patients with diabetes mellitus (DM) have more extensive coronary disease and worse survival after acute myocardial infarction (AMI) than patients without DM, data on whether they experience more angina are conflicting., Methods: We examined angina prevalence over the year following AMI among 3367 patients, including 1080 (32%) with DM, from 24 US hospitals enrolled in the TRIUMPH registry from 2005 to 2008., Results: Patients with vs. without DM were more likely to be treated with antianginal medications both at discharge and over follow up. Despite more aggressive angina therapy, patients with vs. without DM had higher prevalence and severity of angina prior to AMI (49 vs. 43%, p = 0.001) and at each follow-up assessment, although rates of angina declined in both groups over time. In a hierarchical, multivariable, repeated-measures model that adjusted for multiple demographic and clinical factors including severity of coronary disease and in-hospital revascularization, DM was associated with a greater odds of angina over the 12 months of follow up; this association increased in magnitude over time (12-month OR 1.18, 95% CI 1.01-1.37; DM*time pinteraction = 0.008)., Conclusions: Contrary to conventional wisdom, angina is more prevalent and more severe among patients with DM, both prior to and following AMI. This effect is amplified over time and independent of patient and treatment factors, including the presence of multivessel disease and coronary revascularization. This increased burden of angina may be due to more diffuse nature of coronary disease, more rapid progression of coronary disease over time, or greater myocardial demand among DM patients., (© The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, pinteraction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (pinteraction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals., Approach and Results: We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ≥ 2 arteries with ≥ 70% stenosis (or ≥ 50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (P(trend) = 0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07-1.60]) and quartile 4 (1.29 [1.03-1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein)., Conclusions: We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome.

Objectives: This study sought to evaluate whether the relationship between C-reactive protein (CRP) and atherosclerosis is modified by body mass index (BMI)., Background: CRP levels are affected by obesity, and it is unknown whether the associations between CRP and cardiovascular (CV) disease differ between obese and nonobese individuals., Methods: We measured CRP and multiple atherosclerosis phenotypes, including coronary artery calcification (CAC) (n = 2,685), aortic wall thickness (AWT) (n = 2,238), and aortic plaque burden (APB) (n = 2,224), in subjects ages 30 to 65 years from the Dallas Heart Study. The associations of CRP with CAC, AWT, and APB were compared across categories of BMI (normal, 18.5 to <25 kg/m(2); overweight, 25 to <30 kg/m(2); obese, ≥30 kg/m(2)) in sex-stratified analyses., Results: The overall prevalence of obesity was 38% in men and 53% in women. Increasing CRP levels (<1 mg/l, 1 to 3 mg/l, >3 mg/l) were associated with increased CAC prevalence in normal and overweight men and in normal weight women (p < 0.01), but not in obese subjects of either sex. Likewise, the correlations between CRP and AWT and APB diminished with increasing BMI and were nonsignificant in obese individuals (p < 0.05 in nonobese, p > 0.1 in obese). Interaction tests between CRP and obesity were significant for all atherosclerosis measures in men and for AWT and ABP in women (p interaction <0.05 each). In both sexes, the c-statistics of CRP for all 3 atherosclerosis measures were greater for normal weight than obese individuals., Conclusions: In a large, population-based study, the association between CRP and multiple measures of atherosclerosis is diminished in obese individuals. The role of CRP for predicting CV outcomes in obese subjects requires further evaluation., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined., Methods: We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths)., Results: Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15≥1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC≥100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T., Conclusions: GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

Objective: Myeloperoxidase (MPO) is a leukocyte-derived enzyme that appears to be directly involved in atherosclerosis development. We evaluated the association of circulating MPO with coronary and aortic atherosclerosis in a large, multiethnic population., Methods and Results: Plasma levels of MPO were measured in 3294 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcification (CAC) was measured by EBCT, and abdominal aorta plaque prevalence (AP) and burden (APB), as well as abdominal aorta wall thickness (AWT) were determined by MRI. Associations between MPO and atherosclerosis phenotypes were assessed in multivariable analyses adjusting for traditional atherosclerosis risk factors. MPO levels in the 4th compared with 1st quartile independently associated with prevalent AP (OR 1.41, 95% CI 1.08-1.84), APB (beta coefficient 0.23, p = 0.02), and AWT (beta coefficient 0.04, p = 0.03), but not with prevalent CAC (OR 0.84, 95% CI 0.61-1.17). MPO remained associated with aortic atherosclerosis phenotypes but not coronary calcification after adjustment for other inflammatory biomarkers. A significant interaction was observed between race/ethnicity, MPO and AP (p(interaction) = 0.038), such that MPO levels in the 4th vs 1st quartile associated with prevalent AP in African Americans, (OR 1.81, 95% CI 1.23-2.65) but not in White or Hispanic participants (OR 0.99, 95% CI 0.68-1.44)., Conclusion: Higher levels of MPO associated with aortic but not coronary atherosclerosis, with significant associations limited to African American participants. These findings suggest that MPO might be a novel risk factor contributing to racial disparities in peripheral vascular disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The global prevalence of diabetes mellitus (DM) continues to climb, and is accompanied by an increase in DM associated complications, most often manifesting as coronary heart disease. Platelet dysfunction has been implicated as a central contributor to the increased risk of coronary artery disease in patients with DM, and it is not surprising that the anti-platelet agent, clopidogrel, has been shown to have efficacy in both short and long term outcomes in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. However, accumulating data suggest a clinically relevant sub-optimal clopidogrel response in some patients with DM. The exact mechanism of these observations is not yet fully understood, but appears to be related to reduced concentrations of circulating clopidogrel active metabolite, with less variability in pharmacodynamic and clinical response suggested by the evaluation of newer P2Y(12) antagonists, such as prasugrel and ticagrelor. More research is needed to better understand both the pharmacology and clinical consequences of these observations.

Background: Metabolic syndrome (MetSyn) is associated with increased cardiovascular risk in the general population. Its prognostic implications are less well defined in patients with coronary artery disease., Methods and Results: We analyzed patients in the Duke Database for Cardiovascular Disease with a diagnosis of incident obstructive coronary artery disease. Diabetes mellitus (DM) was classified as a clinical history of DM, use of hypoglycemic drugs, or fasting glucose of >or=126 mg/dL. MetSyn was defined as having 3 of 5 characteristics: fasting glucose >or=100 and <126 mg/dL, low high-density lipoprotein cholesterol (men, <40 mg/dL; women, <50 mg/dL), triglycerides >150 mg/dL, blood pressure >or=130/85 mm Hg, or use of antihypertensive therapy, or body mass index >or=27. Death, myocardial infarction, or stroke was assessed at 6 months, 1 year, then annually. Cox proportional hazards models were generated to compare mortality and cardiovascular events between groups. The primary cohort consisted of 5744 patients; 1831 (31.9%) had DM, 2491 (43.4%) had MetSyn, and 1422 (24.7%) had no DM/MetSyn. Median follow-up was 5 years. Compared with no DM/MetSyn patients, DM patients had a higher adjusted risk for mortality (hazard ratio, 1.47; 95% CI, 1.28 to 1.69) but MetSyn patients did not (hazard ratio, 0.94; 95% CI, 0.81 to 1.08). Similar results were found for the combined end points of death or myocardial infarction, and death, myocardial infarction, or stroke., Conclusions: In a population of consecutive patients with a new diagnosis of coronary artery disease by angiography, MetSyn without DM was not an independent predictor of mortality or cardiovascular events.

Background: A strategy using coronary artery calcium (CAC) screening to refine coronary heart disease risk assessment in moderately high risk (MHR) subjects (10-year risk 10%-20%) has been suggested. The potential impact of this strategy is unknown., Methods: Coronary artery calcium screening strategies focused on MHR subjects were modeled in 2,610 subjects aged 30 to 65 years undergoing Framingham risk scoring and CAC assessment in the Dallas Heart Study. The proportions of subjects eligible for imaging and reclassified from MHR to high risk (HR) (10-year risk >20%) based upon CAC scores were determined., Results: Only 1.0% of women and 15.4% of men were at MHR by Framingham risk scoring and thus eligible for imaging, and <0.1% and 1.1% respectively, changed from MHR to HR using a CAC threshold > or = 400. Coronary artery calcium imaging targeting MHR subjects was also relatively inefficient (>100 women, 14.3 men scanned per subject reclassified). Restricting to an older age range (45-65 years) or expanding the MHR group to 6% to 20% risk had virtually no impact on risk assessment in women. In a secondary analysis, a proposed imaging strategy targeting promotion of subjects from lower risk to MHR was more efficient and had greater yield than current recommendations targeting promotion from MHR to HR., Conclusions: Coronary artery calcium screening strategies focused on MHR subjects will have a negligible impact on risk assessment in women and a modest impact in men. Further studies are needed to optimize the use of CAC screening as an adjunct to coronary heart disease risk assessment, especially for women and those at seemingly lower risk.

Background: Our aim was to characterize the association of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) with coronary and aortic atherosclerosis in a large population-based study., Methods: Lp-PLA(2) mass and activity were measured in 2171 subjects 30-65 years old participating in the Dallas Heart Study. We examined the association of Lp-PLA(2) levels with 3 atherosclerosis phenotypes: coronary artery calcium (CAC) measured by electron-beam computed tomography and abdominal aortic plaque (AAP) and aortic wall thickness (AWT) measured by magnetic resonance imaging., Results: CAC and AAP were detected in 21% and 40% of subjects, respectively, and mean AWT (SD) was 1.70 (0.32) mm. In univariable analyses, Lp-PLA(2) mass (but not activity) was higher in both men (P = 0.04) and women (P = 0.02) with detectable CAC. Lp-PLA(2) mass and activity were higher (P = 0.004 and P = 0.01, respectively) and AWT was greater (P < 0.001 and P = 0.02, respectively) in women with aortic atheroma, but not in men. After adjustment for traditional atherosclerosis risk factors and C-reactive protein concentrations, Lp-PLA(2) mass and activity were not associated with AAP or AWT in either sex, but Lp-PLA(2) mass remained modestly associated with detectable CAC only in men (odds ratio 1.20 per 1 standard deviation increase, 95% CI 1.01-1.42, P = 0.04)., Conclusions: Although Lp-PLA(2) mass was independently associated with CAC in men, it was not associated with AAP or AWT in men or with any of the atherosclerosis phenotypes in women. These findings suggest that if Lp-PLA(2) independently influences clinical events, it does so by promoting atherosclerotic plaque instability rather than by stimulating atherogenesis.

Aims: Most lipoprotein-associated phospholipase A2 (Lp-PLA2) studies included mainly white men. We sought to determine whether Lp-PLA2 levels differ according to race and sex., Methods: Lp-PLA2 mass and activity were measured in 3332 subjects age 30-65 participating in the Dallas Heart Study, a multiethnic, population-based, probability sample. Lp-PLA2 levels were compared between different race and sex groups., Results: Mean age was 45+/-9 years and 44% were men; 30% were white, 17% hispanic, and 53% black. Mean Lp-PLA2 activity and mass were 146+/-40 nmol/min/mL and 191+/-60 ng/mL, respectively. Lp-PLA2 activity was lower in women compared with men (134+/-35 vs. 161+/-40, p=0.001) and was lowest in black (136+/-38), intermediate in hispanic (151+/-36), and highest in white subjects (161+/-39) (trend p=0.0001). In multivariable linear regression models, after adjusting for age, body mass index (BMI), smoking, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and high sensitivity C-reactive protein (hsCRP), Lp-PLA2 activity was 19 nmol/min/mL higher in men vs. women (p<0.001); compared with black subjects, adjusted Lp-PLA2 activity was 11 and 20 nmol/min/mL higher in white and hispanic subjects, respectively (both p<0.001). Similar race and sex differences were observed for Lp-PLA2 mass., Conclusion: Race and sex independently influence Lp-PLA2 activity and mass. Thresholds to define Lp-PLA2 elevation may need to be sex and race specific.

Diabetes mellitus (DM) has been termed a "coronary disease equivalent", yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk. Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging. Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1-1.8; OR 1.8, 95% CI 1.3-2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6-3.2). All analyses of AAP yielded qualitatively similar results. In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.

Background: The Screening for Heart Attack Prevention and Education (SHAPE) Task Force recommends noninvasive atherosclerosis imaging of all asymptomatic men (aged 45-75 years) and women (aged 55-75 years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms., Methods: Among 2611 participants in the Dallas Heart Study aged 30 to 65 years who underwent computed tomography to measure coronary artery calcification, low-density lipoprotein cholesterol (LDL-C) therapeutic targets were calculated using both National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and SHAPE algorithms. The proportion of subjects reclassified as being "at goal" for LDL-C vs "not at goal" after implementation of the SHAPE recommendations was determined., Results: More subjects were identified with LDL-C levels greater than or equal to goal based on SHAPE than on NCEP-ATP III (27.4% vs 21.6%), with 7.0% of individuals reclassified as having unmet LDL-C goals and 1.1% of individuals reclassified as at goal. When more aggressive optional LDL-C goals were implemented, 31.7% had LDL-C levels greater than or equal to goal using SHAPE recommendations vs 28.1% using NCEP-ATP III recommendations, with 6.3% of subjects reclassified as being not at goal and 2.7% as being at goal., Conclusions: The SHAPE recommendations resulted in bidirectional reclassification of eligibility for lipid-lowering therapy in subjects aged 30 to 65 years. While broad implementation of these recommendations would modestly increase cholesterol-lowering drug use in this age range, the magnitude of the increase depends on whether standard or optional LDL-C goals are targeted.

The increased burden of cardiovascular disease in chronic kidney disease cannot be explained by traditional risk factors alone. Here, we evaluated the impact of non-traditional factors on the association of chronic kidney disease with coronary artery calcification using logistic regression among 2672 Dallas Heart Study patients of whom 220 had chronic kidney disease. The prevalence of coronary calcification significantly increased across all chronic kidney disease stages and this remained independently associated with coronary calcification after adjusting for traditional factors. The calcium x phosphorus product, homocysteine, and osteoprotegerin each diminished the magnitude of association between kidney disease and coronary calcification. After adjustment for these, the association between kidney disease and coronary calcification was no longer significant with the effects most prominent in the stages 3-5 subgroup. Our study has identified three non-traditional independent predictors of coronary calcification that diminished the association between chronic kidney disease and coronary calcification. These factors may represent novel mechanistic links warranting further investigation.

Objective: Although IL-18 promotes atherogenesis in animal studies and predicts cardiovascular risk in humans, it is unknown whether elevated IL-18 levels are associated with coronary atherosclerosis in the general population., Methods and Results: IL-18 plasma levels were determined by ELISA in 2231 subjects from the Dallas Heart Study. In univariable analysis, IL-18 levels associated with traditional cardiovascular risk factors and particularly with components of the metabolic syndrome (MS, P<0.01 for trend across the number of MS components); IL-18 also associated with coronary artery calcium (CAC) scores measured by electron beam computed tomography and aortic plaque measured by MRI (P<0.01 for each). In multivariable analyses, IL-18 remained associated with multiple components of the MS but not with CAC or aortic plaque., Conclusions: In a large population-based sample, elevated IL-18 plasma levels associated with risk factors for atherosclerosis and with the metabolic syndrome. The association between IL-18 and atherosclerosis diminished after accounting for traditional cardiovascular risk factors. These data suggest that IL-18 does not add independently to detection of atherosclerotic burden in asymptomatic individuals.

Family history of myocardial infarction (FHMI) is an independent risk factor for cardiovascular (CV) events but may be more informative in certain subgroups. The association between FHMI and the presence of coronary artery calcium (CAC) was examined in various age and risk factor groups in the Dallas Heart Study (DHS), a population-based probability sample of subjects aged 30 to 65 years. Analyses were stratified by age (with the young group composed of men aged <45 years and women aged <55 years) and by the presence of 0, 1, 2, or >2 CV risk factors. In the overall cohort of 2,743 subjects, FHMI was an independent predictor of CAC (adjusted odds ratio 1.3, 95% confidence interval 1.1 to 1.7), attributable to an independent association between FHMI and CAC in the young group (adjusted odds ratio 1.5, 95% confidence interval 1.0 to 2.1) that was not evident in the older subset (adjusted odds ratio 1.2, 95% confidence interval 0.91 to 1.6, interaction p = 0.02). In the young cohort, the association between FHMI and CAC was particularly robust in those with > or = 2 risk factors (FHMI-by-risk factor interaction p = 0.04). In older subjects, FHMI was not associated with CAC for any risk factor category (p >0.05 for each). In conclusion, this study suggests that FHMI is a more important predictor of atherosclerosis in young compared with older adults and, among the young, in those with multiple CV risk factors.

Circulating osteoprotegerin (OPG) has been shown to be elevated in patients with vascular disease. The role of OPG as a biomarker for atherosclerosis in a large, unselected population is not well known. Plasma OPG levels were measured in 3,386 subjects in the Dallas Heart Study, a multiethnic, population-based probability sample of adults aged 30 to 65 years. Coronary artery calcium (CAC) was measured by electron beam computed tomography. Aortic plaque was assessed by magnetic resonance imaging. Multivariable logistic regression was used to assess associations among OPG, cardiovascular risk factors, CAC, and aortic plaque. Age, female gender, black race, smoking, personal and family history of coronary artery disease (CAD), diabetes mellitus, hyperlipidemia, CAC, and aortic plaque were significantly associated with higher plasma OPG levels (p <0.01) in univariable analyses. The prevalence of CAC and aortic plaque increased across OPG quartiles (p <0.001 for each). An OPG level in the fourth quartile was independently associated with CAC (RR 1.39, 95% confidence interval 1.01 to 1.93) and aortic plaque (RR 1.42, 95% confidence interval 1.09 to 1.86) after adjustment for age, gender, smoking, diabetes, hyperlipidemia, and family history of premature CAD. In conclusion, plasma OPG is independently associated with CAC and aortic plaque in an unselected population, suggesting it may be a novel biomarker for atherosclerosis in humans.

Background: Whether the absence of coronary artery calcium, or conversely the presence of high volumes of coronary artery calcium, may alter assessment of coronary heart disease risk based on traditional risk factors is uncertain. We sought to identify a potential threshold of coronary artery calcium for clinical use and examine the predictive power of coronary artery calcium in individuals categorized using conventional coronary heart disease risk assessment., Methods: The study included 10,746 men and women (36.3%) with a mean age of 53.8+/-9.9 years who were either physician- or self-referred for electron beam tomography scanning to a preventive medical clinic. Coronary heart disease risk factors were elicited by use of a questionnaire., Results: During a mean follow-up of 3.5 years, 81 primary events (coronary heart disease death or nonfatal myocardial infarction) occurred. Among individuals with a coronary artery calcium score of zero, the primary event rate was very low (0.4 events per 1000 person-years of observation). When participants were stratified by self-reported coronary heart disease risk factors (0-2, or 3-4), a coronary artery calcium score >or=100 was associated with substantially increased risk of coronary heart disease events within each level of stratification. In a subgroup of participants with available clinical data, similar results were found when participants were categorized by Framingham risk scores., Conclusions: Coronary artery calcium score can identify individuals at increased risk for coronary heart disease events who otherwise would be considered low-risk based on clinical assessment. A coronary artery calcium score of zero is associated with very low risk for coronary heart disease in the short to intermediate term ( approximately 3.5 years) regardless of the number of risk factors present.

Patients with left bundle branch block (LBBB) and concomitant coronary artery disease (CAD) have a worse prognosis than those with LBBB without CAD. In addition, subjects with CAD and concomitant LBBB have a higher cardiovascular mortality than those with a similar extent of CAD but without LBBB. Because the presence of LBBB makes the noninvasive identification of CAD problematic, patients with LBBB often are referred for coronary angiography to assess the presence and severity of CAD. To determine the clinical and demographic variables that might help identify those with CAD, we analyzed data from 336 consecutive patients with LBBB referred for coronary angiography. Of the 336, 54% had CAD. In conclusion, those with CAD were likely to be older, Caucasian, and men; they were more likely to have angina pectoris, myocardial infarction, and diabetes mellitus; and they were more likely to have a left ventricular ejection fraction <0.50. In contrast, patients with heart failure were less likely to have CAD.

Background: Elevated levels of C-reactive protein (CRP) are associated with increased risk for incident cardiovascular events on the basis of observations from several prospective epidemiological studies. However, less is known regarding the relationship between CRP levels and atherosclerotic burden., Methods and Results: We measured CRP in 3373 subjects 30 to 65 years of age who were participating in the Dallas Heart Study, a multiethnic, population-based, probability sample. Electron-beam CT scans were used to measure coronary artery calcification (CAC) in 2726 of these subjects, and MRI was used to measure aortic plaque in 2393. CRP levels were associated with most traditional cardiovascular risk factors. Subjects with CAC had higher median CRP levels than those without CAC (men: median, 2.4 versus 1.8 mg/L, P<0.001; women: median, 5.2 versus 3.6 mg/L, P<0.001), and there was a modest trend toward increasing CRP levels with increased CAC levels in men (P for trend=0.003) but not in women (P for trend=0.08). Male subjects with aortic plaque also had higher CRP levels than those without (median, 2.3 versus 1.8; P<0.001). In multivariate analysis adjusted for traditional cardiovascular risk factors, body mass index, and estrogen and statin medication use, the associations between CRP levels and CAC and CRP levels and aortic plaque were no longer statistically significant., Conclusions: In a large, population-based sample, subjects with higher CRP levels had a modest increase in the prevalence of subclinical atherosclerosis, but this association was not independent of traditional cardiovascular risk factors. CRP is a poor predictor of atherosclerotic burden.

Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT-pro-BNP, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography-determined coronary artery calcium scores were categorized as none (<10), mild (> or =10 to <100), moderate (> or =100 to <400), and severe (> or =400). NT-pro-BNP levels increased significantly across increasing coronary artery calcium score categories (p <0.0001 for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, beta-blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT-pro-BNP levels (p = 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system.

Objective: The purpose of this study was to evaluate the associations between plasma levels of soluble CD40 ligand (sCD40L), atherosclerosis risk factors, and evidence of subclinical atherosclerosis., Methods and Results: Plasma levels of sCD40L were measured in 2811 subjects from the Dallas Heart Study, a multiethnic population-based cross-sectional study. Electron Beam Computed Tomography measurements of coronary artery calcium (CAC) and MRI measurements of aortic plaque were performed in 2198 and 1965 subjects, respectively. No association was observed between quartiles of sCD40L and age, sex, race, body mass index, diabetes, smoking, creatinine clearance, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or C-reactive protein. In contrast, weak but statistically significant associations were observed between sCD40L and total cholesterol and triglycerides. The prevalence of detectable CAC (CAC score > or =10) and aortic plaque did not differ across sCD40L quartiles, and individuals with CAC scores <10, > or =10 to 100, >100 to 400, and >400 had similar sCD40L levels., Conclusions: In a large and representative multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or with subclinical atherosclerosis. These findings suggest that sCD40L will not be useful as a tool to screen for the presence of subclinical atherosclerosis in the population. Further evaluation of this biomarker should focus on settings in which platelet activation is common, such as following acute coronary syndromes or coronary revascularization procedures.

Sarcoidosis is a common multisystem granulomatous disease that affects 20 per 100,000 people in the world. Although primarily a pulmonary disease, sarcoidosis can affect multiple organ systems. Cardiac involvement of sarcoidosis is most commonly manifested as ventricular ectopy and arrhythmias; atrioventricular conduction disturbances, including complete heart block; congestive heart failure; and even may result in sudden death. Although myocardial infarction is most commonly the result of epicardial coronary artery disease, an infiltrative process such as sarcoidosis may simulate an acute coronary syndrome. Given the high prevalence of sarcoidosis, it is important to be aware of the myriad of cardiac manifestations of this infiltrative process.

Objectives: We sought to compare the prevalence of coronary atherosclerosis in a cohort of middle-age African American (black) and non-Hispanic Caucasian (white) men and women from a population-based probability sample., Background: Blacks have a higher mortality from coronary heart disease (CHD) than whites, particularly among younger individuals, and yet several studies have reported that coronary atherosclerosis is less prevalent in blacks than in whites. Data from population-based samples comparing coronary atherosclerotic burden between blacks and whites are limited., Methods: The prevalence of coronary atherosclerosis in middle-aged blacks and whites was determined using coronary calcium measured by electron beam computed tomography in 1,289 men and women from a population-based probability sample from Dallas, Texas., Results: The population estimates of the frequency of a positive scan for coronary artery calcium were not statistically different between black and white men (37% vs. 41%, p = 0.36) or between black and white women (29% vs. 23%, p = 0.21). Although the prevalence of most of the coronary risk factors varied significantly between blacks and whites, mean Framingham coronary risk factor scores were identical in black and white men (10 +/- 4) but significantly higher in black women (13 +/- 4) than in white women (12 +/- 4)., Conclusions: Blacks in the general population have a prevalence of coronary atherosclerosis similar to whites. Factors other than coronary atherosclerotic burden, which are not reflected in the Framingham risk score, contribute significantly to the higher CHD mortality rate in blacks.

Background: In 1995, the Bypass Angioplasty Revascularization Investigation (BARI) found that patients with diabetes had a survival benefit when treated with surgical revascularization versus balloon angioplasty, prompting a National Heart Lung and Blood Institute (NHLBI) "Clinical Alert." The influence of the BARI findings and of the Clinical Alert on practice patterns is unknown., Methods and Results: The practice patterns of coronary revascularization among patients with diabetes and multivessel coronary artery disease (CAD) were analyzed using data collected in 1994 to 1997 from 13 centers participating in the National Cardiovascular Network. The study population included patients with diabetes and multivessel CAD who underwent elective coronary revascularization (n=9619). Over the 4 years of the study, the Clinical Alert had no significant impact on the proportion of diabetic patients undergoing percutaneous revascularization (28.6% before versus 26.8% after the Clinical Alert; P=0.06). Among individual hospitals, the probability of diabetic patients receiving percutaneous revascularization varied by >13-fold (4.3% to 56.6%). Adjusting for clinical factors and the BARI Clinical Alert did not alter this variability. Among the investigators surveyed, although 91% were aware of the Clinical Alert and 76% felt the findings were valid, >50% felt the Clinical Alert had limited or no impact on their personal or institution's care patterns., Conclusions: Limited consensus exists regarding the most appropriate method of revascularization for diabetic patients with multivessel CAD. The results from a large, randomized, clinical trial and subsequent Clinical Alert had no measurable impact on this practice variability.

For patients undergoing nonurgent coronary stent implantation, blockade of the glycoprotein IIb/IIIa receptor with eptifibatide reduces the incidence of ischemic complications. We evaluated the interaction of eptifibatide with diabetes in patients who underwent this procedure by analyzing the 1-year outcomes of those enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (466 diabetic and 1,595 nondiabetic patients). At 1 year, the composite end point of death, myocardial infarction (MI), or target vessel revascuarlization (TVR) was higher in diabetic patients (24.5% vs 18.4%; p = 0.008). At 1 year, eptifibatide had a similar effect on the composite end point of death, MI, or TVR in diabetic (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.49 to 1.04) and nondiabetic patients (HR 0.80, 95% CI 0.63 to 0.99). A similar treatment effect was also seen on death or MI in both groups. The 1-year mortality rate for diabetic patients assigned to placebo was 3.5% versus 1.3% for patients receiving eptifibatide (HR 0.37, 95% CI 0.10 to 1.41); the latter rate was similar to the mortality rate of 1.4% for nondiabetic patients in the eptifibatide group. However, eptifibatide did not have a significant effect on TVR in diabetic patients (HR 0.90, 95% CI 0.57 to 1.41). Our data suggest that treatment with eptifibatide is associated with a similar relative reduction in adverse ischemic complications in diabetic and nondiabetic patients undergoing coronary stent implantation. There is no evidence of a statistical interaction in the treatment effect of eptifibatide between patients with and without diabetes.