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Coronary Artery Disease: HELP
Articles from University of Pennsylvania
Based on 176 articles published since 2008
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These are the 176 published articles about Coronary Artery Disease that originated from University of Pennsylvania during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
51 Clinical Trial Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial. 2015

Tricoci, Pierluigi / D'Andrea, Denise M / Gurbel, Paul A / Yao, Zhenling / Cuchel, Marina / Winston, Brion / Schott, Robert / Weiss, Robert / Blazing, Michael A / Cannon, Louis / Bailey, Alison / Angiolillo, Dominick J / Gille, Andreas / Shear, Charles L / Wright, Samuel D / Alexander, John H. ·Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.). · CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.). · Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore and Johns Hopkins University School of Medicine, Baltimore, MD (P.A.G.). · University of Pennsylvania, Philadelphia, PA (M.C.). · Black Hills Cardiovascular Research, Rapid City, SD (B.W.). · diaDexus, Inc., San Francisco, CA (R.S.). · Maine Research Associates, Auburn, ME (R.W.). · Cardiac and Vascular Research Center of Northern Michigan, Petoskey, MI (L.C.). · Gill Heart Institute, University of Kentucky, Lexington, KY (A.B.). · University of Florida College of Medicine-Jacksonville, Jacksonville, FL (D.J.A.). · CSL Limited, Parkville, Victoria, Australia (A.G.). ·J Am Heart Assoc · Pubmed #26307570.

ABSTRACT: BACKGROUND: CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. METHODS AND RESULTS: Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001). CONCLUSIONS: CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

52 Clinical Trial Non-cancer endpoints in BRCA1/2 carriers after risk-reducing salpingo-oophorectomy. 2012

Cohen, J V / Chiel, L / Boghossian, L / Jones, M / Stopfer, J E / Powers, J / Rebbeck, T R / Nathanson, K L / Domchek, S M. ·Pennsylvania Hospital, Philadelphia, PA, USA. ·Fam Cancer · Pubmed #21898151.

ABSTRACT: Risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian cancer and breast cancer in pre-menopausal women with BRCA1 and BRCA2 (B1/2) mutations. Despite its clear benefits, little is known about non-cancer endpoints in this population. Medical records were examined in 226 B1/2 mutation carriers, who had previously undergone RRSO with a focus on bone health as well as the frequency of hypertension, hyperlipidemia, coronary artery disease (CAD), myocardial infarction (MI), diabetes, hypothyroidism and depression. From the medical records, DEXA scans, medications and medical conditions were recorded. Of the 226 patient records examined, 16% (36/226) had hypertension, 17% (39/226) hyperlipidemia, 2% (5/226) CAD or MI, 2% (4/226) diabetes, 13% (29/226) hypothyroidism and 14% (31/226) depression. DEXA results were available in 152 women. Of those DEXA scans, 71% (108/152) were abnormal (57% osteopenia and 14% osteoporosis). Among women who underwent RRSO prior to age 50, 71% (62/88) had osteopenia/osteoporosis. Although there was no difference in osteopenia/osteoporosis in women with RRSO prior to age 50 compared to those RRSO > 50, the age at follow up in these two groups differs greatly (mean age 44.7 vs. 60.6), suggesting that both current age and age at RRSO contribute to bone health assessment. In summary, here, we report the prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers and note a particularly high rate of osteopenia and osteoporosis in B1/2 with breast cancer undergoing RRSO prior to 50. Despite the risk reduction RRSO offers, attention should be paid to non-cancer endpoints, particularly bone health, in this population.

53 Clinical Trial The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. 2008

Mohler, Emile R / Ballantyne, Christie M / Davidson, Michael H / Hanefeld, Markolf / Ruilope, Luis M / Johnson, Joel L / Zalewski, Andrew / Anonymous5940597. ·University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mohlere@uphs.upenn.edu ·J Am Coll Cardiol · Pubmed #18436114.

ABSTRACT: OBJECTIVES: This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk. BACKGROUND: Elevated Lp-PLA(2) levels are associated with an increased risk of CV events. METHODS: Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers. RESULTS: Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted. CONCLUSIONS: Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

54 Article The Hostile Thoracic Aorta: Management Considerations for Severe Aortic Atheroma in a Challenging Case of Coronary Artery Bypass Grafting and Mitral Valve Replacement. 2019

Fernando, Rohesh J / Johnson, Sean D / Augoustides, John G / Patel, Prakash A / Gutsche, Jacob T / Ha, Bao / Feinman, Jared W / Weiss, Stuart J / Cheruku, Sreekanth / McCartney, Sharon L / Dave, Nisha / Fabbro, Michael / Morris, Benjamin N. ·Cardiothoracic Section, Department of Anesthesiology, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC. · Cardiovascular and Thoracic Section, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: yiandoc@hotmail.com. · Cardiovascular and Thoracic Section, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. · Divisions of Cardiothoracic and Critical Care Anesthesiology, Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, TX. · Divisions of Cardiothoracic and Critical Care Anesthesiology, Department of Anesthesiology, Duke University, Durham, NC. · Department of Anesthesiology, Perioperative Medicine and Pain Management, Miller School of Medicine, University of Miami, Miami, FL. · Cardiothoracic Anesthesiology, Department of Anesthesiology, Perioperative Medicine and Pain Management, Miller School of Medicine, University of Miami, Miami, FL. · Cardiothoracic and Critical Care Sections, Department of Anesthesiology, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC. ·J Cardiothorac Vasc Anesth · Pubmed #29685800.

ABSTRACT: -- No abstract --

55 Article Single-phase coronary artery CT angiography extracted from stress dynamic myocardial CT perfusion on third-generation dual-source CT: Validation by coronary angiography. 2018

Yi, Yan / Wu, Wei / Lin, Lu / Zhang, Hong-Zhi / Qian, Hao / Shen, Zhu-Jun / Wang, Yun / Jin, Zheng-Yu / Litt, Harold / Wang, Yi-Ning. ·Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Radiology, University of Pennsylvania Medical Center, PA, USA. · Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: wangyining@pumch.cn. ·Int J Cardiol · Pubmed #30224034.

ABSTRACT: BACKGROUND: CT advances allow coronary arterial tree to be entirely covered during one CTP scan. Our aim was to investigate the potential value of single-phase coronary CT angiography (SP-CCTA) extracted from stress dynamic myocardial CT perfusion (CTP) for coronary artery stenosis assessment. METHODS: Consecutive symptomatic patients were prospectively recruited and scanned with an ATP-stress dynamic myocardial CTP and routine CCTA protocol using third-generation DSCT. Noise reduction was applied to optimize image quality (IQ), the CTP phase with the best enhancement of the coronary arteries was selected as the SP-CCTA. IQ was assessed qualitatively. Using coronary angiography (CAG) as the reference standard, the diagnostic performance for stenosis detection was compared for SP-CCTA and routine CCTA. RESULTS: 56 patients underwent the CTP and CCTA examination, among which 39 patients underwent CAG. The qualitative IQ scores of SP-CCTA were similar to that of routine CCTA (p > 0.05). On a per-segment basis, the sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy and area under the receiver-operating-characteristic curve results of SP-CCTA and routine CCTA for diagnosis of stenosis ≥50% exhibited no significant difference (SP-CCTA: 78.1%, 94.9%, 77.4%, 95.1%, 91.6% and 0.935 vs. routine CCTA: 74.7%, 95.3%, 78.0%, 95.3%, 91.6% and 0.937; all p > 0.05). The mean effective radiation dose of CTP and routine CCTA plus CTP were 3.92 ± 1.72 mSv and 5.98 ± 2.01 mSv (p < 0.05), respectively. CONCLUSIONS: The IQ and diagnostic value of SP-CCTA was equivalent to routine CCTA on third-generation DSCT. SP-CCTA images from CTP may potentially replace a separate routine CCTA, allowing the possibility of "one-stop" cardiac examination for high-risk CAD patients who need myocardial ischemia assessment.

56 Article Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci. 2018

Liu, Boxiang / Pjanic, Milos / Wang, Ting / Nguyen, Trieu / Gloudemans, Michael / Rao, Abhiram / Castano, Victor G / Nurnberg, Sylvia / Rader, Daniel J / Elwyn, Susannah / Ingelsson, Erik / Montgomery, Stephen B / Miller, Clint L / Quertermous, Thomas. ·Department of Biology, School of Humanities and Sciences, Stanford University, Stanford, CA 94305, USA; Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. · Biomedical Informatics Training Program, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. · Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. · Center for Public Health Genomics, Department of Public Health Sciences, Biochemistry and Genetics, and Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: tomq1@stanford.edu. ·Am J Hum Genet · Pubmed #30146127.

ABSTRACT: Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWASs) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMCs) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMCs. We assessed the relevance of HCASMCs to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that may modulate CAD risk through HCASMCs, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMCs, while other annotated genes may have multiple cell and tissue targets. Together, these results provide tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

57 Article Quantitative cardiovascular magnetic resonance perfusion imaging identifies reduced flow reserve in microvascular coronary artery disease. 2018

Zorach, Benjamin / Shaw, Peter W / Bourque, Jamieson / Kuruvilla, Sujith / Balfour, Pelbreton C / Yang, Yang / Mathew, Roshin / Pan, Jonathan / Gonzalez, Jorge A / Taylor, Angela M / Meyer, Craig H / Epstein, Frederick H / Kramer, Christopher M / Salerno, Michael. ·Department of Medicine, Cardiology Division, University of Virginia Health System, Charlottesville, VA, USA. · Berkshire Medical Center, Pittsfield, MA, USA. · Department of Radiology, Cardiovascular Imaging Center, University of Virginia Health System, Charlottesville, VA, USA. · Department of Medicine, Philadelphia VA Medical Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. · Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, VA, USA. · Division of Cardiovascular Disease, Scripps Clinic, Division of Cardiology, Cardiovascular Imaging, Division of Radiology, La Jolla, San Diego, CA, USA. · Department of Medicine, Cardiology Division, University of Virginia Health System, Charlottesville, VA, USA. ckramer@virginia.edu. · Department of Radiology, Cardiovascular Imaging Center, University of Virginia Health System, Charlottesville, VA, USA. ckramer@virginia.edu. · Department of Medicine, Cardiology Division, University of Virginia Health System, Charlottesville, VA, USA. ms5pc@virginia.edu. · Department of Radiology, Cardiovascular Imaging Center, University of Virginia Health System, Charlottesville, VA, USA. ms5pc@virginia.edu. · Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, VA, USA. ms5pc@virginia.edu. ·J Cardiovasc Magn Reson · Pubmed #29471856.

ABSTRACT: BACKGROUND: Preliminary semi-quantitative cardiovascular magnetic resonance (CMR) perfusion studies have demonstrated reduced myocardial perfusion reserve (MPR) in patients with angina and risk factors for microvascular disease (MVD), however fully quantitative CMR has not been studied. The purpose of this study is to evaluate whether fully quantitative CMR identifies reduced MPR in this population, and to investigate the relationship between epicardial atherosclerosis, left ventricular hypertrophy (LVH), extracellular volume (ECV), and perfusion. METHODS: Forty-six patients with typical angina and risk factors for MVD (females, or males with diabetes or metabolic syndrome) who had no obstructive coronary artery disease by coronary angiography and 20 healthy control subjects underwent regadenoson stress CMR perfusion imaging using a dual-sequence quantitative spiral pulse sequence to quantify MPR. Subjects also underwent T1 mapping to quantify ECV, and computed tomographic (CT) coronary calcium scoring to assess atherosclerosis burden. RESULTS: In patients with risk factors for MVD, both MPR (2.21 [1.95,2.69] vs. 2.93 [2.763.19], p < 0.001) and stress myocardial perfusion (2.65 ± 0.62 ml/min/g, vs. 3.17 ± 0.49 ml/min/g p < 0.002) were reduced as compared to controls. These differences remained after adjusting for age, left ventricular (LV) mass, body mass index (BMI), and gender. There were no differences in native T1 or ECV between subjects and controls. CONCLUSIONS: Stress myocardial perfusion and MPR as measured by fully quantitative CMR perfusion imaging are reduced in subjects with risk factors for MVD with no obstructive CAD as compared to healthy controls. Neither myocardial hypertrophy nor fibrosis accounts for these differences.

58 Article Risk factors for progression of coronary artery calcification in patients with chronic kidney disease: The CRIC study. 2018

Bundy, Joshua D / Chen, Jing / Yang, Wei / Budoff, Matthew / Go, Alan S / Grunwald, Juan E / Kallem, Radhakrishna R / Post, Wendy S / Reilly, Muredach P / Ricardo, Ana C / Rosas, Sylvia E / Zhang, Xiaoming / He, Jiang / Anonymous1111208. ·Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA. · Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Los Angeles Biomedical Research Institute, Los Angeles County Harbor-UCLA Medical Center, Torrance, CA, USA. · Division of Research, Kaiser Permanente Division of Research, Oakland, CA, USA. · Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Welch Center for Prevention, Epidemiology, and Clinical Research, The Johns Hopkins University, Baltimore, MD, USA. · Department of Medicine, Columbia University Medical Center, New York, NY, USA. · Department of Medicine, University of Illinois, Chicago, IL, USA. · Joslin Diabetes Center, Harvard University, Boston, MA, USA. · Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA. Electronic address: jhe@tulane.edu. ·Atherosclerosis · Pubmed #29459266.

ABSTRACT: BACKGROUND AND AIMS: Coronary artery calcification (CAC) is common among patients with chronic kidney disease (CKD) and predicts the risk for cardiovascular disease (CVD). We examined the associations of novel risk factors with CAC progression among patients with CKD. METHODS: Among 1123 CKD patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, CAC was measured in Agatston units at baseline and a follow-up visit using electron beam computed tomography or multidetector computed tomography. RESULTS: Over an average 3.3-year follow-up, 109 (25.1%) participants without CAC at baseline had incident CAC and 124 (18.0%) participants with CAC at baseline had CAC progression, defined as an annual increase of ≥100 Agatston units. After adjustment for established atherosclerotic risk factors, several novel risk factors were associated with changes in CAC over follow-up. Changes in square root transformed CAC score associated with 1 SD greater level of risk factors were -0.20 (95% confidence interval, -0.31 to -0.10; p < 0.001) for estimated glomerular filtration rate, 0.14 (0.02-0.25; p = 0.02) for 24-h urine albumin, 0.25 (0.15-0.34; p < 0.001) for cystatin C, -0.17 (-0.27 to -0.07; p < 0.001) for serum calcium, 0.14 (0.03-0.24; p = 0.009) for serum phosphate, 0.24 (0.14-0.33; p < 0.001) for fibroblast growth factor-23, 0.13 (0.04-0.23; p = 0.007) for total parathyroid hormone, 0.17 (0.07-0.27; p < 0.001) for interleukin-6, and 0.12 (0.02-0.22; p = 0.02) for tumor necrosis factor-α. CONCLUSIONS: Reduced kidney function, calcium and phosphate metabolism disorders, and inflammation, independent of established CVD risk factors, may progress CAC among CKD patients.

59 Article Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study. 2018

Raffield, Laura M / Ellis, Jaclyn / Olson, Nels C / Duan, Qing / Li, Jin / Durda, Peter / Pankratz, Nathan / Keating, Brendan J / Wassel, Christina L / Cushman, Mary / Wilson, James G / Gross, Myron D / Tracy, Russell P / Rich, Stephen S / Reiner, Alex P / Li, Yun / Willis, Monte S / Lange, Ethan M / Lange, Leslie A. ·Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA. laura_raffield@unc.edu. · Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA. · Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, 05405, USA. · Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. · Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. · Department of Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, 05405, USA. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA. · Department of Biochemistry, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, 05405, USA. · Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA. · Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. · Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. ·J Hum Genet · Pubmed #29321517.

ABSTRACT: Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10

60 Article Hybrid coronary revascularization versus coronary artery bypass grafting in patients with multivessel coronary artery disease: A meta-analysis. 2018

Sardar, Partha / Kundu, Amartya / Bischoff, Michelle / Chatterjee, Saurav / Owan, Theophilus / Nairooz, Ramez / Giri, Jay / Halkos, Michael E / Liberman, Henry / Douglas, John S / Mukherjee, Debabrata. ·Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah. · Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. · Department of Medicine, University of Utah, Salt Lake City, Utah. · Division of Cardiovascular Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania. · Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia. · Clinical Research Unit, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia. · Division of Cardiovascular Medicine, Texas Tech University Health Sciences Center, El Paso, Texas. ·Catheter Cardiovasc Interv · Pubmed #28471093.

ABSTRACT: OBJECTIVES: This meta-analysis evaluated the effectiveness of hybrid coronary revascularization (HCR) compared to coronary artery bypass grafting (CABG) for the treatment of multivessel coronary artery disease (MVCAD). BACKGROUND: HCR involves a combination of surgical and percutaneous techniques, which in selected patients may present an alternative to conventional CABG. METHODS: Databases were searched through June 30, 2016, and studies comparing HCR with CABG for treatment of MVCAD were selected. We calculated summary odds ratios (ORs) and 95% CIs with the random-effects model. The primary outcome of interest was the occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all cause mortality, myocardial infarction, and stroke. RESULTS: The analysis included 2,245 patients from 8 studies (1 randomized controlled trial and 7 observational studies). The risk of MACCE with HCR and CABG were 3.6% and 5.4%, respectively (OR, 0.53; 95% CI, 0.24-1.16). Compared to CABG group, patients in HCR group had similar risk of all cause mortality (OR, 0.85; 95% CI, 0.38-1.88), myocardial infarction (OR, 0.72; 95% CI, 0.31-1.64), stroke (OR, 0.53; 95% CI, 0.23-1.20), and repeat revascularization (OR, 1.28; 95% CI, 0.58-2.83). The need for postoperative blood transfusions (OR, 0.29; 95% CI, 0.14-0.59) and hospital stay (weighted mean difference -1.20 days; 95% CI -1.52 to -0.88 days) was significantly lower in the HCR group. CONCLUSION: HCR appears to be safe, and has similar outcomes when compared with conventional CABG. HCR can be a suitable alternative to conventional CABG in select patients with MVCAD. © 2017 Wiley Periodicals, Inc.

61 Article Exome-wide association study of plasma lipids in >300,000 individuals. 2017

Liu, Dajiang J / Peloso, Gina M / Yu, Haojie / Butterworth, Adam S / Wang, Xiao / Mahajan, Anubha / Saleheen, Danish / Emdin, Connor / Alam, Dewan / Alves, Alexessander Couto / Amouyel, Philippe / Di Angelantonio, Emanuele / Arveiler, Dominique / Assimes, Themistocles L / Auer, Paul L / Baber, Usman / Ballantyne, Christie M / Bang, Lia E / Benn, Marianne / Bis, Joshua C / Boehnke, Michael / Boerwinkle, Eric / Bork-Jensen, Jette / Bottinger, Erwin P / Brandslund, Ivan / Brown, Morris / Busonero, Fabio / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Y Eugene / Chen, Yii-Der Ida / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Connell, John M / Cucca, Francesco / Cupples, L Adrienne / Damrauer, Scott M / Davies, Gail / Deary, Ian J / Dedoussis, George / Denny, Joshua C / Dominiczak, Anna / Dubé, Marie-Pierre / Ebeling, Tapani / Eiriksdottir, Gudny / Esko, Tõnu / Farmaki, Aliki-Eleni / Feitosa, Mary F / Ferrario, Marco / Ferrieres, Jean / Ford, Ian / Fornage, Myriam / Franks, Paul W / Frayling, Timothy M / Frikke-Schmidt, Ruth / Fritsche, Lars G / Frossard, Philippe / Fuster, Valentin / Ganesh, Santhi K / Gao, Wei / Garcia, Melissa E / Gieger, Christian / Giulianini, Franco / Goodarzi, Mark O / Grallert, Harald / Grarup, Niels / Groop, Leif / Grove, Megan L / Gudnason, Vilmundur / Hansen, Torben / Harris, Tamara B / Hayward, Caroline / Hirschhorn, Joel N / Holmen, Oddgeir L / Huffman, Jennifer / Huo, Yong / Hveem, Kristian / Jabeen, Sehrish / Jackson, Anne U / Jakobsdottir, Johanna / Jarvelin, Marjo-Riitta / Jensen, Gorm B / Jørgensen, Marit E / Jukema, J Wouter / Justesen, Johanne M / Kamstrup, Pia R / Kanoni, Stavroula / Karpe, Fredrik / Kee, Frank / Khera, Amit V / Klarin, Derek / Koistinen, Heikki A / Kooner, Jaspal S / Kooperberg, Charles / Kuulasmaa, Kari / Kuusisto, Johanna / Laakso, Markku / Lakka, Timo / Langenberg, Claudia / Langsted, Anne / Launer, Lenore J / Lauritzen, Torsten / Liewald, David C M / Lin, Li An / Linneberg, Allan / Loos, Ruth J F / Lu, Yingchang / Lu, Xiangfeng / Mägi, Reedik / Malarstig, Anders / Manichaikul, Ani / Manning, Alisa K / Mäntyselkä, Pekka / Marouli, Eirini / Masca, Nicholas G D / Maschio, Andrea / Meigs, James B / Melander, Olle / Metspalu, Andres / Morris, Andrew P / Morrison, Alanna C / Mulas, Antonella / Müller-Nurasyid, Martina / Munroe, Patricia B / Neville, Matt J / Nielsen, Jonas B / Nielsen, Sune F / Nordestgaard, Børge G / Ordovas, Jose M / Mehran, Roxana / O'Donnell, Christoper J / Orho-Melander, Marju / Molony, Cliona M / Muntendam, Pieter / Padmanabhan, Sandosh / Palmer, Colin N A / Pasko, Dorota / Patel, Aniruddh P / Pedersen, Oluf / Perola, Markus / Peters, Annette / Pisinger, Charlotta / Pistis, Giorgio / Polasek, Ozren / Poulter, Neil / Psaty, Bruce M / Rader, Daniel J / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Reiner, Alex P / Renström, Frida / Rich, Stephen S / Ridker, Paul M / Rioux, John D / Robertson, Neil R / Roden, Dan M / Rotter, Jerome I / Rudan, Igor / Salomaa, Veikko / Samani, Nilesh J / Sanna, Serena / Sattar, Naveed / Schmidt, Ellen M / Scott, Robert A / Sever, Peter / Sevilla, Raquel S / Shaffer, Christian M / Sim, Xueling / Sivapalaratnam, Suthesh / Small, Kerrin S / Smith, Albert V / Smith, Blair H / Somayajula, Sangeetha / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Stirrups, Kathleen E / Stitziel, Nathan / Strauch, Konstantin / Stringham, Heather M / Surendran, Praveen / Tada, Hayato / Tall, Alan R / Tang, Hua / Tardif, Jean-Claude / Taylor, Kent D / Trompet, Stella / Tsao, Philip S / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / van Zuydam, Natalie R / Varbo, Anette / Varga, Tibor V / Virtamo, Jarmo / Waldenberger, Melanie / Wang, Nan / Wareham, Nick J / Warren, Helen R / Weeke, Peter E / Weinstock, Joshua / Wessel, Jennifer / Wilson, James G / Wilson, Peter W F / Xu, Ming / Yaghootkar, Hanieh / Young, Robin / Zeggini, Eleftheria / Zhang, He / Zheng, Neil S / Zhang, Weihua / Zhang, Yan / Zhou, Wei / Zhou, Yanhua / Zoledziewska, Magdalena / Anonymous7491224 / Anonymous7501224 / Anonymous7511224 / Anonymous7521224 / Anonymous7531224 / Howson, Joanna M M / Danesh, John / McCarthy, Mark I / Cowan, Chad A / Abecasis, Goncalo / Deloukas, Panos / Musunuru, Kiran / Willer, Cristen J / Kathiresan, Sekar. ·Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK. · Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · ICDDR, B, Dhaka, Bangladesh. · Imperial College London, London, UK. · Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France. · VA Palo Alto Health Care System, Palo Alto, California, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. · Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. · Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. · Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. · Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. · Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy. · The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK. · NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. · The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA. · Medical Department, Lillebaelt Hospital, Vejle, Denmark. · NHLBI Framingham Heart Study, Framingham, Massachusetts, USA. · Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. · Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. · Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Psychology, University of Edinburgh, Edinburgh, UK. · Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. · Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Montreal Heart Institute, Montreal, Quebec, Canada. · Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada. · Université de Montréal, Montreal, Quebec, Canada. · Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland. · The Icelandic Heart Association, Kopavogur, Iceland. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. · Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA. · Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK. · Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China. · National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA. · Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway. · St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. · Department of Cardiology, Peking University First Hospital, Beijing, China. · K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. · Department of Health Sciences, University of Iceland, Reykjavik, Iceland. · The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark. · Steno Diabetes Center, Gentofte, Denmark. · National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark. · Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. · The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. · UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Minerva Foundation Institute for Medical Research, Helsinki, Finland. · National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark. · Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark. · Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Research Center for Prevention and Health, Copenhagen, Denmark. · The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. · Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany. · DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA. · Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · G3 Pharmaceuticals, Lexington, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Institute of Molecular Medicine FIMM, University of Helsinki, Finland. · Faculty of Medicine, University of Split, Split, Croatia. · Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · International Centre for Circulatory Health, Imperial College London, London, UK. · Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA. · Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biobank Research, Umeå University, Umeå, Sweden. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. · Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Saw Swee Hock School of Public Health, National University of Singapore, Singapore. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK. · Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK. · Department of Haematology, University of Cambridge, Cambridge, UK. · Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA. · IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. · Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. · Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. · Dasman Diabetes Institute, Dasman, Kuwait. · Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. · Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia. · The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Atlanta VA Medical Center, Decatur, Georgia, USA. · Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA. · Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. · Yale College, Yale University, New Haven, Connecticut, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #29083408.

ABSTRACT: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

62 Article Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia. 2017

Romanelli, Filippo / Corbo, AnthonyMarco / Salehi, Maryam / Yadav, Manisha C / Salman, Soha / Petrosian, David / Rashidbaigi, Omid J / Chait, Jesse / Kuruvilla, Jes / Plummer, Maria / Radichev, Ilian / Margulies, Kenneth B / Gerdes, A Martin / Pinkerton, Anthony B / Millán, José Luis / Savinov, Alexei Y / Savinova, Olga V. ·Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York, United States of America. · Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America. · Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America. · Department of Clinical Specialties, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York, United States of America. · Heart Failure and Transplant Program, Perelman School of Medicine, University of Pennsylvania Translational Research Center, Philadelphia, Pennsylvania, United States of America. · Prebys Center for Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America. ·PLoS One · Pubmed #29023576.

ABSTRACT: OBJECTIVE: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelium leads to arterial calcification in mice. The purpose of this study was to examine the effect of elevated endothelial TNAP on coronary atherosclerosis. In addition, we aimed to examine endogenous TNAP activity in human myocardium. APPROACH AND RESULTS: A vascular pattern of TNAP activity was observed in human non-failing, ischemic, and idiopathic dilated hearts (5 per group); no differences were noted between groups in this study. Endothelial overexpression of TNAP was achieved in mice harboring a homozygous recessive mutation in the low density lipoprotein receptor (whc allele) utilizing a Tie2-cre recombinase (WHC-eTNAP mice). WHC-eTNAP developed significant coronary artery calcification at baseline compared WHC controls (4312 vs 0μm2 alizarin red area, p<0.001). Eight weeks after induction of atherosclerosis, lipid deposition in the coronary arteries of WHC-eTNAP was increased compared to WHC controls (121633 vs 9330μm2 oil red O area, p<0.05). Coronary lesions in WHC-eTNAP mice exhibited intimal thickening, calcifications, foam cells, and necrotic cores. This was accompanied by the reduction in body weight and left ventricular ejection fraction (19.5 vs. 23.6g, p<0.01; 35% vs. 47%, p<0.05). In a placebo-controlled experiment under atherogenic conditions, pharmacological inhibition of TNAP in WHC-eTNAP mice by a specific inhibitor SBI-425 (30mg*kg-1*d-1, for 5 weeks) reduced coronary calcium (78838 vs.144622μm2) and lipids (30754 vs. 77317μm2); improved body weight (22.4 vs.18.8g) and ejection fraction (59 vs. 47%). The effects of SBI-425 were significant in the direct comparisons with placebo but disappeared after TNAP-negative placebo-treated group was included in the models as healthy controls. CONCLUSIONS: Endogenous TNAP activity is present in human cardiac tissues. TNAP overexpression in vascular endothelium in mice leads to an unusual course of coronary atherosclerosis, in which calcification precedes lipid deposition. The prevalence and significance of this mechanism in human atherosclerosis requires further investigations.

63 Article Visit-to-Visit Blood Pressure Variability in Young Adulthood and Hippocampal Volume and Integrity at Middle Age: The CARDIA Study (Coronary Artery Risk Development in Young Adults). 2017

Yano, Yuichiro / Reis, Jared P / Levine, Deborah A / Bryan, R Nick / Viera, Anthony J / Shimbo, Daichi / Tedla, Yacob G / Allen, Norrina B / Schreiner, Pamela J / Bancks, Michael P / Sidney, Stephen / Pletcher, Mark J / Liu, Kiang / Greenland, Philip / Lloyd-Jones, Donald M / Launer, Lenore J. ·From the Department of Preventive Medicine, University of Mississippi Medical Center, Jackson (Y.Y.) · Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.Y., Y.G.T., N.B.A., M.P.B., K.L., P.G., D.M.L.-J.) · Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.P.R.) · Division of General Medicine, University of Michigan, Ann Arbor (D.A.L.) · Department of Radiology, University of Pennsylvania Health System, Philadelphia (R.N.B.) · Department of Family Medicine, Hypertension Research Program, University of North Carolina at Chapel Hill (A.J.V.) · Department of Medicine, Columbia University Medical Center, New York, NY (D.S.) · Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (P.J.S.) · Division of Research, Kaiser Permanente of Northern California, Oakland (S.S.) · Department of Epidemiology and Biostatistics, University of California, San Francisco (M.J.P.) · and Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD (L.J.L.). ·Hypertension · Pubmed #28993449.

ABSTRACT: The aims of this study are to assess the relationships of visit-to-visit blood pressure (BP) variability in young adulthood to hippocampal volume and integrity at middle age. We used data over 8 examinations spanning 25 years collected in the CARDIA study (Coronary Artery Risk Development in Young Adults) of black and white adults (age, 18-30 years) started in 1985 to 1986. Visit-to-visit BP variability was defined as by SD

64 Article In vivo label-free structural and biochemical imaging of coronary arteries using an integrated ultrasound and multispectral fluorescence lifetime catheter system. 2017

Bec, Julien / Phipps, Jennifer E / Gorpas, Dimitris / Ma, Dinglong / Fatakdawala, Hussain / Margulies, Kenneth B / Southard, Jeffrey A / Marcu, Laura. ·Department of Biomedical Engineering, University of California Davis, Davis, 95616, CA, USA. · Institute of Biological and Medical Imaging, Helmholtz Zentrum, München, Germany. · Abbott, Sylmar, CA, USA. · Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA. · UC Davis Health System, Division of Cardiovascular Medicine, University of California Davis, Sacramento, 95817, CA, USA. · Department of Biomedical Engineering, University of California Davis, Davis, 95616, CA, USA. lmarcu@ucdavis.edu. ·Sci Rep · Pubmed #28827758.

ABSTRACT: Existing clinical intravascular imaging modalities are not capable of accurate detection of critical plaque pathophysiology in the coronary arteries. This study reports the first intravascular catheter combining intravascular ultrasound (IVUS) with multispectral fluorescence lifetime imaging (FLIm) that enables label-free simultaneous assessment of morphological and biochemical features of coronary vessels in vivo. A 3.7 Fr catheter with a fiber-optic channel was constructed based on a 40 MHz clinical IVUS catheter. The ability to safely acquire co-registered FLIm-IVUS data in vivo using Dextran40 solution flushing was demonstrated in swine coronary arteries. FLIm parameters from the arterial wall were consistent with the emission of fluorophores present in healthy arterial wall (collagen, elastin). Additionally, structural and biochemical features from atherosclerotic lesions were acquired in ex vivo human coronary samples and corroborated with histological findings. Current results show that FLIm parameters linked to the amount of structural proteins (e.g. collagen, elastin) and lipids (e.g. foam cells, extracellular lipids) in the first 200 μm of the intima provide important biochemical information that can supplement IVUS data for a comprehensive assessment of plaques pathophysiology. The unique FLIm-IVUS system evaluated here has the potential to provide a comprehensive insight into atherosclerotic lesion formation, diagnostics and response to therapy.

65 Article Paradoxical coronary artery disease in humans with hyperalphalipoproteinemia is associated with distinct differences in the high-density lipoprotein phosphosphingolipidome. 2017

Hancock-Cerutti, William / Lhomme, Marie / Dauteuille, Carolane / Lecocq, Sora / Chapman, M John / Rader, Daniel J / Kontush, Anatol / Cuchel, Marina. ·National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · ICANalytics, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France. · National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France. · Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France. Electronic address: anatol.kontush@upmc.fr. · Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mcuchel@mail.med.upenn.edu. ·J Clin Lipidol · Pubmed #28826666.

ABSTRACT: BACKGROUND: Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with risk of coronary artery disease (CAD) in epidemiologic studies. Despite this, the directionality of this relationship and the underlying biology behind it remain to be firmly established, especially at the extremes of HDL-C levels. OBJECTIVE: We investigated differences in the HDL phosphosphingolipidome in a rare population of subjects with premature CAD despite high HDL-C levels to gain insight into the association between the HDL lipidome and CAD disease status in this unusual phenotype. We sought to assess differences in HDL composition that are associated with CAD in subjects with HDL-C >90th percentile. We predicted that quantitative lipidomic analysis of HDL particles would reveal novel differences between CAD patients and healthy subjects with matched HDL-C levels. METHODS: We collected plasma samples from 25 subjects with HDL-C >90th percentile and clinically manifest CAD and healthy controls with HDL-C >90th percentile and without self-reported CAD. More than 140 individual HDL phospholipid and sphingolipid species were analyzed by LC/MS/MS. RESULTS: Significant reductions in HDL phosphatidylcholine (-2.41%, Q value = 0.025) and phosphatidylinositol (-10.7%, Q value = 0.047) content, as well as elevated sphingomyelin (+10.0%, Q value = 0.025) content, and sphingomyelin/phosphatidylcholine ratio (+12.8%, P value = .005) were associated with CAD status in subjects with high HDL-C. CONCLUSIONS: These differences may lay the groundwork for further analysis of the relationship between the HDL lipidome and disease states, as well as for the development of biomarkers of CAD status and HDL function.

66 Article Postoperative outcomes and management strategies for coronary artery disease in patients in need of a lung transplantation. 2017

Khandhar, Sameer J / Althouse, Andrew D / Mulukutla, Suresh / Kormos, Robert / Toma, Catalin / Marroquin, Oscar / Volz, Elizabeth / Tefera, Leben / Bermudez, Christian. ·Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Clin Transplant · Pubmed #28658533.

ABSTRACT: BACKGROUND: Patients requiring lung transplantation (LTx) may also have coronary artery disease (CAD). The peri-operative management and long-term outcomes of these patients are not well established. METHODS: Patients referred for LTx from 2008 to 2014 were included in this study. CAD was defined by angiography as no CAD (stenosis <20%), moderate CAD (20%-69%), and significant CAD (stenosis ≥70%). Revascularization was per recommendations of local heart team. Postoperative cardiovascular outcomes and long-term survival are reported. RESULTS: A total of 1493 patients were screened for LTx during this period and 656 received a transplant. Of the patients that underwent LTx, 51% had no CAD, 33% had moderate non-obstructive CAD, and 16% had obstructive CAD. Forty-three patients underwent revascularization. There was a no increased risk of peri-operative cardiovascular events or for adjusted mortality for patients with obstructive CAD (HR=1.24, 95% CI: 0.83-1.86, P=.290) including those requiring revascularization. CONCLUSIONS: There is a high prevalence of coronary disease in the population of patients with advanced lung disease requiring lung transplantation. Careful evaluation and treatment can allow for patients with all severities of CAD including those requiring revascularization to successfully undergo LTx.

67 Article Text mining applied to electronic cardiovascular procedure reports to identify patients with trileaflet aortic stenosis and coronary artery disease. 2017

Small, Aeron M / Kiss, Daniel H / Zlatsin, Yevgeny / Birtwell, David L / Williams, Heather / Guerraty, Marie A / Han, Yuchi / Anwaruddin, Saif / Holmes, John H / Chirinos, Julio A / Wilensky, Robert L / Giri, Jay / Rader, Daniel J. ·Department of Medicine and Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, PA, USA. · Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA. · Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Department of Medicine and Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, PA, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, PA, USA. Electronic address: rader@mail.med.upenn.edu. ·J Biomed Inform · Pubmed #28624641.

ABSTRACT: BACKGROUND: Interrogation of the electronic health record (EHR) using billing codes as a surrogate for diagnoses of interest has been widely used for clinical research. However, the accuracy of this methodology is variable, as it reflects billing codes rather than severity of disease, and depends on the disease and the accuracy of the coding practitioner. Systematic application of text mining to the EHR has had variable success for the detection of cardiovascular phenotypes. We hypothesize that the application of text mining algorithms to cardiovascular procedure reports may be a superior method to identify patients with cardiovascular conditions of interest. METHODS: We adapted the Oracle product Endeca, which utilizes text mining to identify terms of interest from a NoSQL-like database, for purposes of searching cardiovascular procedure reports and termed the tool "PennSeek". We imported 282,569 echocardiography reports representing 81,164 individuals and 27,205 cardiac catheterization reports representing 14,567 individuals from non-searchable databases into PennSeek. We then applied clinical criteria to these reports in PennSeek to identify patients with trileaflet aortic stenosis (TAS) and coronary artery disease (CAD). Accuracy of patient identification by text mining through PennSeek was compared with ICD-9 billing codes. RESULTS: Text mining identified 7115 patients with TAS and 9247 patients with CAD. ICD-9 codes identified 8272 patients with TAS and 6913 patients with CAD. 4346 patients with AS and 6024 patients with CAD were identified by both approaches. A randomly selected sample of 200-250 patients uniquely identified by text mining was compared with 200-250 patients uniquely identified by billing codes for both diseases. We demonstrate that text mining was superior, with a positive predictive value (PPV) of 0.95 compared to 0.53 by ICD-9 for TAS, and a PPV of 0.97 compared to 0.86 for CAD. CONCLUSION: These results highlight the superiority of text mining algorithms applied to electronic cardiovascular procedure reports in the identification of phenotypes of interest for cardiovascular research.

68 Article Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. 2017

Howson, Joanna M M / Zhao, Wei / Barnes, Daniel R / Ho, Weang-Kee / Young, Robin / Paul, Dirk S / Waite, Lindsay L / Freitag, Daniel F / Fauman, Eric B / Salfati, Elias L / Sun, Benjamin B / Eicher, John D / Johnson, Andrew D / Sheu, Wayne H H / Nielsen, Sune F / Lin, Wei-Yu / Surendran, Praveen / Malarstig, Anders / Wilk, Jemma B / Tybjærg-Hansen, Anne / Rasmussen, Katrine L / Kamstrup, Pia R / Deloukas, Panos / Erdmann, Jeanette / Kathiresan, Sekar / Samani, Nilesh J / Schunkert, Heribert / Watkins, Hugh / Anonymous2140907 / Do, Ron / Rader, Daniel J / Johnson, Julie A / Hazen, Stanley L / Quyyumi, Arshed A / Spertus, John A / Pepine, Carl J / Franceschini, Nora / Justice, Anne / Reiner, Alex P / Buyske, Steven / Hindorff, Lucia A / Carty, Cara L / North, Kari E / Kooperberg, Charles / Boerwinkle, Eric / Young, Kristin / Graff, Mariaelisa / Peters, Ulrike / Absher, Devin / Hsiung, Chao A / Lee, Wen-Jane / Taylor, Kent D / Chen, Ying-Hsiang / Lee, I-Te / Guo, Xiuqing / Chung, Ren-Hua / Hung, Yi-Jen / Rotter, Jerome I / Juang, Jyh-Ming J / Quertermous, Thomas / Wang, Tzung-Dau / Rasheed, Asif / Frossard, Philippe / Alam, Dewan S / Majumder, Abdulla Al Shafi / Di Angelantonio, Emanuele / Chowdhury, Rajiv / Anonymous2150907 / Chen, Yii-Der Ida / Nordestgaard, Børge G / Assimes, Themistocles L / Danesh, John / Butterworth, Adam S / Saleheen, Danish. ·MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Applied Mathematics, University of Nottingham Malaysia Campus, Semenyih, Malaysia. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. · Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA. · National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA. · NHLBI and Boston University's The Framingham Heart Study, Framingham, Massachusetts, USA. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · School of Medicine, National Yang-Ming University, Taipei, Taiwan. · College of Medicine, National Defense Medical Center, Taipei, Taiwan. · Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK. · Pfizer Worldwide Research and Development, Stockholm, Sweden. · Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Centre for Genomic Health, Queen Mary University of London, London, UK. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · University Heart Center Lübeck, Lübeck, Germany. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · University of Florida College of Pharmacy, Gainesville, Florida, USA. · Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA. · Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. · Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA. · Department of Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, Missouri, USA. · College of Medicine, University of Florida, Gainesville, Florida, USA. · Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA. · Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda,Maryland, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Carolina Center for Genome Sciences, Chapel Hill, North Carolina, USA. · Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan. · Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. · Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · School of Medicine, Chung Shan Medical University, Taichung, Taiwan. · Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. · National Taiwan University College of Medicine, Taipei, Taiwan. · Centre for Non-Communicable Disease, Karachi, Pakistan. · School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. · National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh. · National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. · Wellcome Trust Sanger Institute, Hinxton, UK. · British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK. ·Nat Genet · Pubmed #28530674.

ABSTRACT: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10

69 Article Clinical risk factors alone are inadequate for predicting significant coronary artery disease. 2017

Korley, Frederick K / Gatsonis, Constantine / Snyder, Bradley S / George, Richard T / Abd, Thura / Zimmerman, Stefan L / Litt, Harold I / Hollander, Judd E. ·Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, United States. Electronic address: korley@med.umich.edu. · Center for Statistical Sciences and Department of Biostatistics, Brown University School of Public Health, Providence, RI, United States. Electronic address: gatsonis@stat.brown.edu. · Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, United States. Electronic address: bsnyder@stat.brown.edu. · Adjunct Faculty, Division of Cardiology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: rtgeorge3@gmail.com. · Division of Cardiology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: tabd1@jh.edu. · Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: stefan.zimmerman@jhmi.edu. · Department of Radiology and Division of Cardiovascular Medicine, Department of Internal Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, United States. Electronic address: Harold.litt@uphs.upenn.edu. · Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, United States. Electronic address: judd.hollander@jefferson.edu. ·J Cardiovasc Comput Tomogr · Pubmed #28487137.

ABSTRACT: OBJECTIVE: We sought to derive and validate a model for identifying suspected ACS patients harboring undiagnosed significant coronary artery disease (CAD). METHODS: This was a secondary analysis of data from a randomized control trial (RCT). Patients randomized to the CTA arm of an RCT examining a CTA-based strategy for ruling-out acute coronary syndrome (ACS) constitute the derivation cohort, which was randomly divided into a training dataset (2/3, used for model derivation) and a test dataset (1/3, used for internal validation (IV)). ED patients from a different center receiving CTA to evaluate for suspected ACS constitute the external validation (EV) cohort. Primary outcome was CTA-assessed significant CAD (stenosis of ≥50% in a major coronary artery). RESULTS: In the derivation cohort, 11.2% (76/679) of subjects had CTA-assessed significant CAD, and in the EV cohort, 8.2% of subjects (87/1056) had CTA-assessed significant CAD. Age was the strongest predictor of significant CAD among the clinical risk factors examined. Predictor variables included in the derived logistic regression model were: age, sex, tobacco use, diabetes, and race. This model exhibited an area under the receiver operating characteristic curve (ROC AUC) of 0.72 (95% CI: 0.61-0.83) based on IV, and 0.76 (95% CI: 0.70, 0.82) based on EV. The derived random forest model based on clinical risk factors yielded improved but not sufficient discrimination of significant CAD (ROC AUC = 0.76 [95% CI: 0.67-0.85] based on IV). Coronary artery calcium score was a more accurate predictor of significant CAD than any combination of clinical risk factors (ROC AUC = 0.85 [95% CI: 0.76-0.94] based on IV; ROC AUC = 0.92 [95% CI: 0.88-0.95] based on EV). CONCLUSIONS: Clinical risk factors, either individually or in combination, are insufficient for accurately identifying suspected ACS patients harboring undiagnosed significant coronary artery disease.

70 Article Percutaneous revascularization in patients treated with thoracic radiation for cancer. 2017

Fender, Erin A / Liang, Jackson J / Sio, Terence T / Stulak, John M / Lennon, Ryan J / Slusser, Joshua P / Ashman, Jonathan B / Miller, Robert C / Herrmann, Joerg / Prasad, Abhiram / Sandhu, Gurpreet S. ·Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. · Division of Cardiovascular Disease, University of Pennsylvania, Philadelphia, PA, USA. · Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, USA. · Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. · Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. Electronic address: sandhu.gurpreet@mayo.edu. ·Am Heart J · Pubmed #28454813.

ABSTRACT: OBJECTIVES: To assess coronary revascularization outcomes in patients with previous thoracic radiation therapy (XRT). BACKGROUND: Previous chest radiation has been reported to adversely affect long term survival in patients with coronary disease treated with percutaneous coronary interventions (PCI). METHODS: Retrospective, single center cohort study of patients previously treated with thoracic radiation and PCI. Patients were propensity matched against control patients without radiation undergoing revascularization during the same time period. RESULTS: We identified 116 patients with radiation followed by PCI (XRT-PCI group) and 408 controls. Acute procedural complications were similar between groups. There were no differences in all-cause and cardiac mortality between groups (all-cause mortality HR 1.31, P=.078; cardiac mortality 0.78, P=.49). CONCLUSION: Patients with prior thoracic radiation and coronary disease treated with PCI have similar procedural complications and long term mortality when compared to control subjects.

71 Article ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. 2017

Stitziel, Nathan O / Khera, Amit V / Wang, Xiao / Bierhals, Andrew J / Vourakis, A Christina / Sperry, Alexandra E / Natarajan, Pradeep / Klarin, Derek / Emdin, Connor A / Zekavat, Seyedeh M / Nomura, Akihiro / Erdmann, Jeanette / Schunkert, Heribert / Samani, Nilesh J / Kraus, William E / Shah, Svati H / Yu, Bing / Boerwinkle, Eric / Rader, Daniel J / Gupta, Namrata / Frossard, Philippe M / Rasheed, Asif / Danesh, John / Lander, Eric S / Gabriel, Stacey / Saleheen, Danish / Musunuru, Kiran / Kathiresan, Sekar / Anonymous261203. ·Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Electronic address: nstitziel@wustl.edu. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. · Harvard College, Harvard University, Cambridge, Massachusetts. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. · Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina. · Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom. · Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: kmus@mail.med.upenn.edu. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. Electronic address: skathiresan@partners.org. ·J Am Coll Cardiol · Pubmed #28385496.

ABSTRACT: BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

72 Article Coronary Artery Calcification and Risk of Cardiovascular Disease and Death Among Patients With Chronic Kidney Disease. 2017

Chen, Jing / Budoff, Matthew J / Reilly, Muredach P / Yang, Wei / Rosas, Sylvia E / Rahman, Mahboob / Zhang, Xiaoming / Roy, Jason A / Lustigova, Eva / Nessel, Lisa / Ford, Virginia / Raj, Dominic / Porter, Anna C / Soliman, Elsayed Z / Wright, Jackson T / Wolf, Myles / He, Jiang / Anonymous401214. ·Department of Medicine, School of Medicine, Tulane University, New Orleans, Louisiana2Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana. · LA BioMed at Harbor-UCLA Medical Center, Los Angeles, California. · Department of Medicine, Division of Cardiology, Columbia University, New York, New York. · Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia. · Joslyn Diabetic Center, Harvard Medical School, Boston, Massachusetts. · Department of Medicine, University Hospitals of Case Western Reserve University, Cleveland, Ohio. · Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana. · Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia. · Department of Medicine, School of Medicine, George Washington University, Washington, DC. · Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago. · Department of Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina. · Department of Medicine, School of Medicine, Duke University, Durham, North Carolina. ·JAMA Cardiol · Pubmed #28329057.

ABSTRACT: Importance: Coronary artery calcification (CAC) is highly prevalent in dialysis-naive patients with chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease and all-cause mortality in this population. Objective: To study the prospective association of CAC with risk of cardiovascular disease and all-cause mortality among dialysis-naive patients with CKD. Design, Setting, and Participants: The prospective Chronic Renal Insufficiency Cohort study recruited adults with an estimated glomerular filtration rate of 20 to 70 mL/min/1.73 m2 from 7 clinical centers in the United States. There were 1541 participants without cardiovascular disease at baseline who had CAC scores. Exposures: Coronary artery calcification was assessed using electron-beam or multidetector computed tomography. Main Outcomes and Measures: Incidence of cardiovascular disease (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every 6 months and confirmed by medical record adjudication. Results: During an average follow-up of 5.9 years in 1541 participants aged 21 to 74 years, there were 188 cardiovascular disease events (60 cases of myocardial infarction, 120 heart failures, and 27 strokes; patients may have had >1 event) and 137 all-cause deaths. In Cox proportional hazards models adjusted for age, sex, race, clinical site, education level, physical activity, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, use of antihypertensive treatment, current cigarette smoking, diabetes status, body mass index, C-reactive protein level, hemoglobin A1c level, phosphorus level, troponin T level, log N-terminal pro-B-type natriuretic peptide level, fibroblast growth factor 23 level, estimated glomerular filtration rate, and proteinuria, the hazard ratios associated with per 1 SD log of CAC were 1.40 (95% CI, 1.16-1.69; P < .001) for cardiovascular disease, 1.44 (95% CI, 1.02-2.02; P = .04) for myocardial infarction, 1.39 (95% CI, 1.10-1.76; P = .006) for heart failure, and 1.19 (95% CI, 0.94-1.51; P = .15) for all-cause mortality. In addition, inclusion of CAC score led to an increase in the C statistic of 0.02 (95% CI, 0-0.09; P < .001) for predicting cardiovascular disease over use of all the above-mentioned established and novel cardiovascular disease risk factors. Conclusions and Relevance: Coronary artery calcification is independently and significantly related to the risks of cardiovascular disease, myocardial infarction, and heart failure in patients with CKD. In addition, CAC improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel cardiovascular disease risk factors among patients with CKD; however, the changes in the C statistic are small.

73 Article Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease. 2017

Khera, Amit V / Won, Hong-Hee / Peloso, Gina M / O'Dushlaine, Colm / Liu, Dajiang / Stitziel, Nathan O / Natarajan, Pradeep / Nomura, Akihiro / Emdin, Connor A / Gupta, Namrata / Borecki, Ingrid B / Asselta, Rosanna / Duga, Stefano / Merlini, Piera Angelica / Correa, Adolfo / Kessler, Thorsten / Wilson, James G / Bown, Matthew J / Hall, Alistair S / Braund, Peter S / Carey, David J / Murray, Michael F / Kirchner, H Lester / Leader, Joseph B / Lavage, Daniel R / Manus, J Neil / Hartzel, Dustin N / Samani, Nilesh J / Schunkert, Heribert / Marrugat, Jaume / Elosua, Roberto / McPherson, Ruth / Farrall, Martin / Watkins, Hugh / Lander, Eric S / Rader, Daniel J / Danesh, John / Ardissino, Diego / Gabriel, Stacey / Willer, Cristen / Abecasis, Gonçalo R / Saleheen, Danish / Dewey, Frederick E / Kathiresan, Sekar / Anonymous7860898. ·Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston. · Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts5Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. · Regeneron Genetics Center, Tarrytown, New Jersey. · Department of Public Health Sciences, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. · Department of Medicine, Washington University School of Medicine, St Louis, Missouri9Department of Genetics, Washington University School of Medicine, St Louis, Missouri10McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Department of Biomedical Sciences, Humanitas University, Milan, Italy12Humanitas Clinical and Research Center, Milan, Italy. · Ospedale Niguarda, Milano, Italy. · Department of Medicine, University of Mississippi Medical Center, Jackson. · Munich Heart Alliance, München, Germany16Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson. · NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. · Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds University, Leeds, United Kingdom. · Geisinger Health System, Danville, Pennsylvania. · Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. · Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain. · University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom24Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Department of Genetics, University of Pennsylvania, Philadelphia. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom27Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom28NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom29Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy31Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor33Department of Human Genetics, University of Michigan, Ann Arbor34Department of Internal Medicine, University of Michigan, Ann Arbor. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. ·JAMA · Pubmed #28267856.

ABSTRACT: Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

74 Article Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. 2017

Budoff, Matthew J / Ellenberg, Susan S / Lewis, Cora E / Mohler, Emile R / Wenger, Nanette K / Bhasin, Shalender / Barrett-Connor, Elizabeth / Swerdloff, Ronald S / Stephens-Shields, Alisa / Cauley, Jane A / Crandall, Jill P / Cunningham, Glenn R / Ensrud, Kristine E / Gill, Thomas M / Matsumoto, Alvin M / Molitch, Mark E / Nakanishi, Rine / Nezarat, Negin / Matsumoto, Suguru / Hou, Xiaoling / Basaria, Shehzad / Diem, Susan J / Wang, Christina / Cifelli, Denise / Snyder, Peter J. ·Division of Cardiology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Division of Preventive Medicine, University of Alabama at Birmingham. · Section of Vascular Medicine, Division of Cardiovascular Disease, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Division of Cardiology, Department of Medicine, Emory Heart and Vascular Center, Emory University School of Medicine, Atlanta, Georgia. · Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, La Jolla. · Division of Endocrinology, Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. · Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York11Division of Geriatrics, Albert Einstein College of Medicine, Bronx, New York. · Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine and Baylor St. Luke's Medical Center, Houston, Texas13Department of Molecular and Cell Biology, Baylor College of Medicine and Baylor St. Luke's Medical Center, Houston, Texas. · Division of Epidemiology and Community Health, Department of Medicine, University of Minnesota, Minneapolis15Minneapolis VA Health Care System, Minneapolis, Minnesota. · Division of Geriatric Medicine, Yale School of Medicine, New Haven, Connecticut. · Geriatric Research, Education, and Clinical Center, VA Puget Sound Health System, University of Washington School of Medicine, Seattle18Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, University of Washington School of Medicine, Seattle. · Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Division of Epidemiology and Community Health, Department of Medicine, University of Minnesota, Minneapolis. · Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia. ·JAMA · Pubmed #28241355.

ABSTRACT: Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

75 Article Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. 2017

Webb, Thomas R / Erdmann, Jeanette / Stirrups, Kathleen E / Stitziel, Nathan O / Masca, Nicholas G D / Jansen, Henning / Kanoni, Stavroula / Nelson, Christopher P / Ferrario, Paola G / König, Inke R / Eicher, John D / Johnson, Andrew D / Hamby, Stephen E / Betsholtz, Christer / Ruusalepp, Arno / Franzén, Oscar / Schadt, Eric E / Björkegren, Johan L M / Weeke, Peter E / Auer, Paul L / Schick, Ursula M / Lu, Yingchang / Zhang, He / Dube, Marie-Pierre / Goel, Anuj / Farrall, Martin / Peloso, Gina M / Won, Hong-Hee / Do, Ron / van Iperen, Erik / Kruppa, Jochen / Mahajan, Anubha / Scott, Robert A / Willenborg, Christina / Braund, Peter S / van Capelleveen, Julian C / Doney, Alex S F / Donnelly, Louise A / Asselta, Rosanna / Merlini, Pier A / Duga, Stefano / Marziliano, Nicola / Denny, Josh C / Shaffer, Christian / El-Mokhtari, Nour Eddine / Franke, Andre / Heilmann, Stefanie / Hengstenberg, Christian / Hoffmann, Per / Holmen, Oddgeir L / Hveem, Kristian / Jansson, Jan-Håkan / Jöckel, Karl-Heinz / Kessler, Thorsten / Kriebel, Jennifer / Laugwitz, Karl L / Marouli, Eirini / Martinelli, Nicola / McCarthy, Mark I / Van Zuydam, Natalie R / Meisinger, Christa / Esko, Tõnu / Mihailov, Evelin / Escher, Stefan A / Alver, Maris / Moebus, Susanne / Morris, Andrew D / Virtamo, Jarma / Nikpay, Majid / Olivieri, Oliviero / Provost, Sylvie / AlQarawi, Alaa / Robertson, Neil R / Akinsansya, Karen O / Reilly, Dermot F / Vogt, Thomas F / Yin, Wu / Asselbergs, Folkert W / Kooperberg, Charles / Jackson, Rebecca D / Stahl, Eli / Müller-Nurasyid, Martina / Strauch, Konstantin / Varga, Tibor V / Waldenberger, Melanie / Anonymous491201 / Zeng, Lingyao / Chowdhury, Rajiv / Salomaa, Veikko / Ford, Ian / Jukema, J Wouter / Amouyel, Philippe / Kontto, Jukka / Anonymous501201 / Nordestgaard, Børge G / Ferrières, Jean / Saleheen, Danish / Sattar, Naveed / Surendran, Praveen / Wagner, Aline / Young, Robin / Howson, Joanna M M / Butterworth, Adam S / Danesh, John / Ardissino, Diego / Bottinger, Erwin P / Erbel, Raimund / Franks, Paul W / Girelli, Domenico / Hall, Alistair S / Hovingh, G Kees / Kastrati, Adnan / Lieb, Wolfgang / Meitinger, Thomas / Kraus, William E / Shah, Svati H / McPherson, Ruth / Orho-Melander, Marju / Melander, Olle / Metspalu, Andres / Palmer, Colin N A / Peters, Annette / Rader, Daniel J / Reilly, Muredach P / Loos, Ruth J F / Reiner, Alex P / Roden, Dan M / Tardif, Jean-Claude / Thompson, John R / Wareham, Nicholas J / Watkins, Hugh / Willer, Cristen J / Samani, Nilesh J / Schunkert, Heribert / Deloukas, Panos / Kathiresan, Sekar / Anonymous511201. ·Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom. · Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri. · Deutsches Herzzentrum München, Technische Universität München, München, Germany; DZHK, Partner Site Munich Heart Alliance, Munich, Germany. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts. · Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden. · Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · School of Public Heath, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin. · Fred Hutchinson Cancer Research Center, Seattle, Washington; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan. · Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands. · Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. · Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom. · Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy. · Niguarda Hospital, Milan, Italy. · Azienda Sanitaria Locale 3 San Francesco, Nuoro, Italy 3, Nuoro, Italy. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical informatics, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri; Deutsches Herzzentrum München, Technische Universität München, München, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway. · Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Sweden. · Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany. · Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road Headington, Oxford, Oxford, United Kingdom. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia. · School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, Scotland, United Kingdom. · National Institute for Health and Welfare (THL), Helsinki, Finland. · Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Montreal Heart Institute, Montreal, Quebec, Canada. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. · Merck Sharp & Dohme, Rahway, New Jersey. · Department of Cardiology, Division Heart & Lungs, UMC Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom. · Fred Hutchinson Cancer Research Center, Seattle, Washington. · Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Ohio State University, Columbus, Ohio. · Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. · Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom. · Department of Cardiology, Leiden University Medical Center, Leiden and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France. · Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Toulouse University School of Medicine, Toulouse, France. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Noncommunicable Diseases, Karachi, Pakistan. · British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. · Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. · Department of Epîdemiology and Public Health, University of Strasbourg, Strasbourg, France. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. · Parma University Hospital, Parma, Italy. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York. · Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom. · Deutsches Herzzentrum München, Technische Universität München, München, Germany. · Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University Kiel, Kiel, Germany. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany. · Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina. · Department of Clinical Sciences in Malmo, Lund University, Clinical Research Center, Malmo, Sweden. · Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Department of Genetics, Cardiovascular Institute and Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Cardiology, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York. · Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom. · Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan. · Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address: njs@le.ac.uk. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: p.deloukas@qmul.ac.uk. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts. ·J Am Coll Cardiol · Pubmed #28209224.

ABSTRACT: BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

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