From the onset of the COVID-19 pandemic, the demand for SARS-CoV-2 testing has resulted in an explosion of analytical tests with very different approaches and designs. The variability in testing modalities, compounded by the lack of available commercial reference materials for standardization early in the pandemic, has led to several challenges regarding data harmonization for viral quantitation.

Introduction:Long-chain omega-3 polyunsaturated fatty acids (OM3 PUFA) are commonly used for cardiovascular disease prevention. High-dose eicosapentaenoic acid (EPA) is reported to reduce major adverse cardiovascular events (MACE); however, a combined EPA and docosahexaenoic acid (DHA) supplementation has not been proven to do so. This study aimed to evaluate the potential interaction between EPA and DHA levels on long-term MACE.Methods:We studied a cohort of 987 randomly selected subjects enrolled in the INSPIRE biobank registry who underwent coronary angiography. We used rapid throughput liquid chromatography-mass spectrometry to quantify the EPA and DHA plasma levels and examined their impact unadjusted, adjusted for one another, and fully adjusted for comorbidities, EPA + DHA, and the EPA/DHA ratio on long-term (10-year) MACE (all-cause death, myocardial infarction, stroke, heart failure hospitalization).Results:The average subject age was 61.5 ± 12.2 years, 57% were male, 41% were obese, 42% had severe coronary artery disease (CAD), and 311 (31.5%) had a MACE. The 10-year MACE unadjusted hazard ratio (HR) for the highest (fourth) vs. lowest (first) quartile (Q) of EPA was HR = 0.48 (95% CI: 0.35, 0.67). The adjustment for DHA changed the HR to 0.30 (CI: 0.19, 0.49), and an additional adjustment for baseline differences changed the HR to 0.36 (CI: 0.22, 0.58). Conversely, unadjusted DHA did not significantly predict MACE, but adjustment for EPA resulted in a 1.81-fold higher risk of MACE (CI: 1.14, 2.90) for Q4 vs. Q1. However, after the adjustment for baseline differences, the risk of MACE was not significant for DHA (HR = 1.37; CI: 0.85, 2.20). An EPA/DHA ratio ≥1 resulted in a lower rate of 10-year MACE outcomes (27% vs. 37%, adjusted p-value = 0.013).Conclusions:Higher levels of EPA, but not DHA, are associated with a lower risk of MACE. When combined with EPA, higher DHA blunts the benefit of EPA and is associated with a higher risk of MACE in the presence of low EPA. These findings can help explain the discrepant results of EPA-only and EPA/DHA mixed clinical supplementation trials.

Objectives The Intermountain Risk Score (IMRS), composed using published sex-specific weightings of parameters in the complete blood count (CBC) and basic metabolic profile (BMP), is a validated predictor of mortality. We hypothesised that IMRS calculated from prepandemic CBC and BMP predicts COVID-19 outcomes and that IMRS using laboratory results tested at COVID-19 diagnosis is also predictive. Design Prospective observational cohort study. Setting Primary, secondary, urgent and emergent care, and drive-through testing locations across Utah and in sections of adjacent US states. Viral RNA testing for SARS-CoV-2 was conducted from 3 March to 2 November 2020. Participants Patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020. Primary and secondary outcome measures The primary outcome was a composite of hospitalisation or mortality, with secondary outcomes being hospitalisation and mortality separately. Results Among 3883 patients, 8.2% were hospitalised and 1.6% died. Subjects with low, mild, moderate and high-risk IMRS had the composite endpoint in 3.5% (52/1502), 8.6% (108/1256), 15.5% (152/979) and 28.1% (41/146) of patients, respectively. Compared with low-risk, subjects in mild-risk, moderate-risk and high-risk groups had HR=2.33 (95% CI 1.67 to 3.24), HR=4.01 (95% CI 2.93 to 5.50) and HR=8.34 (95% CI 5.54 to 12.57), respectively. Subjects aged <60 years had HR=3.06 (95% CI 2.01 to 4.65) and HR=7.38 (95% CI 3.14 to 17.34) for moderate and high risks versus low risk, respectively; those ≥60 years had HR=1.95 (95% CI 0.99 to 3.86) and HR=3.40 (95% CI 1.63 to 7.07). In multivariable analyses, IMRS was independently predictive and was shown to capture substantial risk variation of comorbidities. Conclusions IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalisation and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection.

Abstract Background Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long‐term risk of dementia in AF patients in observational trials. Methods The cognitive decline and dementia in patients with non‐valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open‐label vanguard clinical study with blinded endpoint assessment involving patients with moderate‐ to high‐risk (CHADS2 or CHA2DS2‐Vasc scores of ≥2) non‐valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. Results A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini‐Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti‐Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Conclusion Use of dabigatran and well‐managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study.

Aims:Low-density lipoprotein cholesterol (LDL-C) predicts heart disease onset and may be reduced by intermittent fasting. Some studies, though, reported that fasting increased LDL-C; however, no study evaluated LDL-C as the primary endpoint. This randomized controlled trial evaluated the effect of low-frequency intermittent fasting on LDL-C and other biomarkers. Methods and results:Adults aged 21-70 years were enrolled who were not taking a statin, had modestly elevated LDL-C, had ≥1 metabolic syndrome feature or type 2 diabetes, and were not taking anti-diabetic medication (N = 103). Water-only 24-h fasting was performed twice weekly for 4 weeks and then once weekly for 22 weeks; controls ate ad libitum. The primary outcome was 26-week LDL-C change score. Secondary outcomes (requiring P ≤ 0.01) were 26-week changes in homeostatic model assessment of insulin resistance (HOMA-IR), Metabolic Syndrome Score (MSS), brain-derived neurotrophic factor (BDNF), and MicroCog general cognitive proficiency index (GCPi). Intermittent fasting (n = 50) and control (n = 53) subjects were, respectively, aged 49.3 ± 12.0 and 47.0 ± 9.8 years, predominantly female (66.0% and 67.9%), and overweight (103 ± 24 and 100 ± 21 kg) and had modest LDL-C elevation (124 ± 19 and 128 ± 20 mg/dL). Drop-outs (n = 12 fasting, n = 20 control) provided an evaluable sample of n = 71 (n = 38 fasting, n = 33 control). Intermittent fasting did not change LDL-C (0.2 ± 16.7 mg/dL) vs. control (2.5 ± 19.4 mg/dL; P = 0.59), but it improved HOMA-IR (-0.75 ± 0.79 vs. -0.10 ± 1.06; P = 0.004) and MSS (-0.34 ± 4.72 vs. 0.31 ± 1.98, P = 0.006). BDNF (P = 0.58), GCPi (P = 0.17), and weight (-1.7 ± 4.7 kg vs. 0.2 ± 3.5 kg, P = 0.06) were unchanged. Conclusions:A low-frequency intermittent fasting regimen did not reduce LDL-C or improve cognitive function but significantly reduced both HOMA-IR and MSS. Trial registration:clinicaltrials.gov, NCT02770313.

Low vitamin D (serum or plasma 25-hydroxyvitamin D (25(OH)D)) is a global pandemic and associates with a greater prevalence in all-cause and cardiovascular mortality and morbidity. Open-heart surgery is a form of acute stress that decreases circulating 25(OH)D concentrations and exacerbates the preponderance of low vitamin D in a patient population already characterized by low levels. Although supplemental vitamin D increases 25(OH)D, it is unknown if supplemental vitamin D can overcome the decreases in circulating 25(OH)D induced by open-heart surgery. We sought to identify if supplemental vitamin D protects against the acute decrease in plasma 25(OH)D propagated by open-heart surgery during perioperative care. Participants undergoing open-heart surgery were randomly assigned (double-blind) to one of two groups: (a) vitamin D (n = 75; cholecalciferol, 50,000 IU/dose) or (b) placebo (n = 75). Participants received supplements on three separate occasions: orally the evening before surgery and either orally or per nasogastric tube on postoperative days 1 and 2. Plasma 25(OH)D concentrations were measured at baseline (the day before surgery and before the first supplement bolus), after surgery on postoperative days 1, 2, 3, and 4, at hospital discharge (5-8 days after surgery), and at an elective outpatient follow-up visit at 6 months. Supplemental vitamin D abolished the acute decrease in 25(OH)D induced by open-heart surgery during postoperative care. Moreover, plasma 25(OH)D gradually increased from baseline to day 3 and remained significantly increased thereafter but plateaued to discharge with supplemental vitamin D. We conclude that perioperative vitamin D supplementation protects against the immediate decrease in plasma 25(OH)D induced by open-heart surgery.

Background: The SARS-CoV-2 B.1.1.7 variant, also known as the UK or alpha variant, carries the spike 69/70 deletion mutation and has been reported to be more contagious and possibly more virulent than other variants. This study examines follow-up cardiovascular outcomes for patients infected with deletion-carrying SARS-CoV-2 alpha variant. Methods: From October 2020 to May 2021, all positive SARS-CoV-2 samples at Intermountain Healthcare were tested for the 69/70 deletion (n=92822). Patient characteristics, COVID-19 treatments, and follow-up outcomes were extracted from Intermountain records. Cox hazard regression analysis with multivariable adjustment was used to determine risk of subsequent major cardiovascular adverse event outcomes (MACE), which included all-cause death, heart failure (HF), and hospitalization for coronary artery disease (CAD) or atrial fibrillation (AF). Results: Overall, 4.2% of patients testing positive for the SARS-CoV-2 virus carried the deletion mutation with prevalence increasing with time, ranging from 1.3% in October to 61.0% in May. Baseline characteristics, treatments, and outcomes stratified by non-mutant and deletion mutation status are shown in the Table. While the mutation did result in higher rates of COVID hospitalization (adjusted OR=1.68, p<0.001), there was no difference in overall MACE after adjustment by baseline characteristics and risk factors. There was a non-significant trend toward an increased rate of all-cause death in patients carrying the mutant variant (adjusted HR=1.90, p=0.12). Conclusions: The SARS-CoV-2 deletion mutant, while resulting in an increased risk of COVID hospitalization and a trend toward increased death, did not increase the risk of subsequent CVD. Because of the recent emergence of the variant the long-term effects are not known. Thus, it remains important to minimize risk of exposure. Moreover, long-term surveillance of subsequent CVD risk is warranted.

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.

Background: As the COVID-19 pandemic evolves, stratifying risk is increasingly important. The Intermountain Risk Score (IMRS) uses the complete blood count (CBC) and basic metabolic profile (BMP) as a first-line predictor of mortality and is widely validated. We hypothesized that IMRS predicts COVID-19 outcomes.Methods: Intermountain Healthcare patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020. Viral RNA testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was conducted March 3 through November 2, 2020. IMRS used published sex-specific weightings and associations were evaluated for the composite of COVID-19 hospitalization or mortality.Findings: Among 3,883 patients, 8.2% were hospitalized, 1.6% died. Subjects with low, mild, moderate, and high-risk IMRS had the composite endpoint in 3.5% (52/1,502), 8.6% (108/1,256), 15.5% (152/979), and 28.1% (41/146), respectively. Versus low-risk, subjects in mild, moderate, and high-risk groups had HR=2.33 (95% CI: 1.67, 3.24), HR=4.01 (CI: 2.93, 5.50), and HR=8.34 (CI: 5.54, 12.57), respectively. Subjects aged <60 years had HR=3.06 (CI: 2.01, 4.65) and HR=7.38 (CI: 3.14, 17.34) for moderate and high versus low-risk, respectively; those ≥60 years had HR=1.95 (CI: 0.99, 3.86) and HR=3.40 (CI: 1.63, 7.07). In multivariable analyses, IMRS was independently predictive but was shown to capture substantial risk variation of comorbidities.Interpretation: IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalization and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection.Funding Statement: This study was funded by internal Intermountain departmental funds.Declaration of Interests: BDH, HTM, BSR, and JLA are inventors of clinical decision tools that are licensed to CareCentra and Alluceo. BDH is the PI of grants related to clinical decision tools that were funded by Intermountain Healthcare's Foundry innovation program, the Intermountain Research and Medical Foundation, CareCentra, GlaxoSmithKline, and AstraZeneca. BDH is a member of the scientific advisory board of Labme.ai. KUK is PI of and BDH a co-investigator of a grant funded by the Patient- Centered Outcomes Research Institute (PCORI). IDP was supported by a grant from the National Institute of General Medical Sciences (K23GM129661). Outside the current work, IDP has received grant support from the National Institutes of Health, Centers for Disease Control, Janssen Pharmaceuticals, and Immunexpress Inc and funding to his institution from Regeneron Pharmaceuticals. The authors have no other potential conflicts of interest to report.Ethics Approval Statement: This study was approved as a data-only historical records review study with a waiver of consent by the Intermountain Healthcare Institutional Review Board.

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is associated with cardiovascular disease (CVD) and mortality. Here we examine, in a high-risk CVD population, the association with prevalent coronary artery disease (CAD) and subsequent major adverse events (MACE) at 1-,5- and 10-year follow-up of mtDNA-CN. Methods: Consecutive subjects (n=2267) consenting to a blood sample drawn for the Intermountain INSPIRE biorepository at the time of a coronary angiogram from July 1994 to Sept 2003 were included. The mtDNA-CN was determined by multiplexed real-time polymerase chain reaction coamplifying a stable site of mt D- Loop and a region of a single copy genomic β-2-microglobulin gene(β2M). MtDNA-CN is given as the ratio of Mt to β2M DNA. The presence of severe CAD (>70% stenosis) was analyzed using multivariate logistic regression. The subsequent MACE (including all-cause mortality and non-fatal MI) outcomes were studied using multivariate Cox proportional hazard regression. Results: The average age of subjects was 62.3 ± 13.8, 35% were female, and 50% had prior CAD. Over half (55%) had severe CAD at the angiogram. As the mtDNA-CN increased, severe CAD decreased (58% for 1 st quartile vs. 51% for 4 th quartile). After adjustment for baseline differences, subjects with mtDNA-CN in the 1 st quartile were 1.31 times more likely to have severe CAD than subjects with mtDNA-CN in the 4 th quartile (95% CI: 1.01, 1.71; p=0.04). A total of 902(39.8%) had a subsequent MACE event within 10-years (193[8.5%] in 1-year and 548[24.2%] in 5-years). There was no association between mtDNA-CN and 1-year MACE. However, mtDNA-CN was associated with 5-year (p=0.006) and 10-year (p=0.003) MACE. After adjustment, subjects with mtDNA-CN in the 1 st quartile were at 1.29 increased risk of 10-year MACE than subjects with mtDNA-CN in the 4 th quartile (95% CI: 1.07, 1.56; p=0.008). Conclusions: In a coronary angiographic population, mtDNA-CN was associated with severe CAD and the risk of subsequent long-term MACE. These findings suggest that mtDNA-CN could be used as a clinical biomarker for risk. Moreover, understanding the factors impacting mtDNA-CN may also help in the prevention of secondary CVD outcomes.

Background: Mitochondrial DNA copy number (Mt CN) is a surrogate marker of mitochondrial function. Variations in Mt CN have been associated with several age-related diseases. Lower Mt CN may indicate impaired cellular energy production whereas higher Mt CN may compensate for energy disbalance but also may lead to cellular damage through oxidative stress. This study evaluated the association of Mt CN and all-cause mortality in older cardiovascular patients (Pt). Methods: The study was approved by the Intermountain Healthcare Institutional Review Board. Consenting subjects (n=2,253) were participants in the INSPIRE registry undergoing cardiac catheterization at the Intermountain Heart Institute. Total DNA was extracted from EDTA stabilized blood with either Puregene (Qiagen) or Reliaprep (Promega) reagents. Relative Mt CN measurements were performed with multiplexed real-time polymerase chain reaction coamplifying a stable site of Mt D- Loop and a region of a single copy nuclear β-2-microglobulin gene(β2M) and calculated as a ratio of Mt to β2M DNA. Cox regression was used to evaluate the association of Mt CN with all-cause mortality, with adjustment considering 32 covariables. Further adjustment entered the Intermountain Risk Score (IMRS), a validated mortality risk predictor. Results: Mean Pt age was age 62.3±13.8 yrs.; 65.2% were male; 1,122 (50%) died during 25.4 years of follow-up. Mt CN was lower for males (539±449 vs 654 ± 1053 for females; p=0.004). Mt CN was 616±917 in decedents and 542±438 in survivors (p=0.014). In univariable Cox regression, Quartile 1 versus Quartile 4 of Mt CN was associated with the highest mortality risk (hazard ratio [HR]=1.45, CI=1.22, 1.71, p<0.001). This association remained significant after multivariable adjustment (HR=1.30, CI=1.10, 1.54, p=0.003). There was minimal correlation between IMRS and Mt CN continuous values (r= -0.09 for males, r= -0.13 for females). In Cox regression, adjustment for IMRS and covariables showed Mt CN remained associated with mortality (HR=1.30, CI=1.08, 1.57, p=0.006). Conclusions: Low Mt CN is independently associated with higher risk of all-cause mortality. Further studies validating this finding and examining potential underlying physiologic protective mechanisms may prove to be of therapeutic and prognostic value.

Introduction: Genetic factors are known to play an important role in NIDC with a large number of pathogenic mutations in multiple genes reported. TTNtv mutations are of interest because of their co...

Background: The Intermountain Risk Sore (IMRS) is a general health clinical decision tool based on the complete blood count (CBC) and basic metabolic profile (BMP). IMRS was developed to predict all-cause mortality. IMRS was validated previously in patients from the US and elsewhere, including in general medical and surgical patients and in diagnosis-specific populations. IMRS has been implemented at Intermountain Healthcare to guide clinical care in hospital settings. IMRS has not been tested as a predictor of major adverse health events after diagnosis of novel coronavirus disease (COVID)-19. Methods: Intermountain patients (ages ≥18 years) with a CBC and BMP measured in 2019 and with a COVID-positive test in 2020 (N=1,025) were evaluated to determine if the pre-2020 IMRS predicted a composite of hospitalization or mortality. All study subjects tested positive for COVID between March 3 and June 8, 2020. IMRS was calculated using original sex-specific variable weightings (see Horne BD et al, Am J Med 2009). Results: Overall, 55 females and 54 males had a composite endpoint, respectively (5 and 10 deaths; 52 and 46 hospitalizations), with c-statistics of c=0.748 for females and c=0.669 for males using IMRS calculations from 2019 (see Table). For n=170 patients, IMRS was also calculated from 2020 CBC/BMP panels obtained at the time of COVID diagnosis, and it also predicted the composite endpoint at that timepoint (for females and males combined, odds ratios= 4.05, 2.46, and 1.53 for high-, moderate-, and mild-risk categories vs. low-risk; see Table for category thresholds). Conclusion: IMRS measured using 2019 CBC and BMP lab results predicted major adverse health events for patients diagnosed with COVID in 2020. Use of IMRS may empower population health with anticipation of COVID outcomes; for higher risk patients, the IMRS result may lead to enhanced preventive measures if the patient is free of COVID and, if COVID is diagnosed, it may lead to earlier, more aggressive care.

Introduction: High-frequency intermittent fasting (IF) diets reduce weight similarly to continuous calorie restriction (CR). In patients with type 2 diabetes, twice-weekly IF and CR equivalently reduced HbA1c. IF may improve chronic disease risk factors, but no controlled trial has evaluated whether IF reduces low-density lipoprotein cholesterol (LDL-C), regardless of weight loss, in patients with elevated LDL-C. Hypothesis: The Weekly ONe-Day watER-only Fasting interventionaL (WONDERFUL) randomized (1:1) controlled trial (NCT02770313) tested whether IF reduced LDL-C compared to ad libitum control over 6 months. Methods: Subjects (N=103) were ages 21-70 years, not taking a statin, had elevated baseline LDL-C (90-189 mg/dL for ages 21-39, 90-159 mg/dL for ages 40-70, ≥90 mg/dL for statin intolerant/contraindicated), and had diet-controlled type 2 diabetes or ≥1 metabolic syndrome feature but no anti-diabetes medication. The water-only IF regimen was 4 weeks of 2/week 24-hour IF followed by 22 weeks of 1/week 24-hour IF. Exclusions included pregnant, lactating, or chronic disease (e.g., CAD, MI, stroke/TIA, CKD, COPD, cancer, PE, PAD, DVT, dementia, type 1 diabetes). Results: At baseline, IF (n=50) and control (n=53) were, respectively, 49.3±12.0 and 47.0±9.8 years of age, 66.0% and 67.9% females, weight 103±24 and 100±21 kg, and LDL-C 124±19 and 128±20 mg/dL. Lost to follow-up (n=5 IF, n=4 control) and withdrawals (n=7 IF, n=16 control) gave a final sample of n=71 (n=38 IF, n=33 control). LDL-C change from baseline to 6 months was not different between IF and control (Table). HOMA-IR, one of 4 pre-specified secondary endpoints, was improved (-0.75 vs. -0.10) at p≤0.01 vs. control (Table). Conclusions: A once-per-week IF regimen did not reduce LDL-C compared to control, but HOMA-IR was significantly reduced. This more sustainable IF regimen may reduce some chronic cardiometabolic disease risks (e.g., HOMA-IR) with minimal effects on cholesterol and weight.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99–1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18–1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04–1.09). Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Riyaz Patel, MD1,2*; Vinicius Tragante, PhD3*; Amand F. Schmidt, PhD1,3*; Raymond O. McCubrey, MS4; Michael V. Holmes, MD, PhD5-7; Laurence J. Howe, PhD1; Kenan Direk, PhD1; Axel Åkerblom, MD, PhD8,9; Karin Leander, PhD10; Salim S. Virani, MD, PhD11,12; Karol A. Kaminski, MD, PhD13,14; Jochen D. Muehlschlegel, MD, MMSc15,16; Hooman Allayee, PhD17; Peter Almgren, MSc18; Maris Alver, MSc19,20; Ekaterina V. Baranova, MSc21; Hassan Behloui, PhD22; Bram Boeckx, PhD23,24; Peter S. Braund, PhD25,26; Lutz P. Breitling, MD27; Graciela Delgado, MSc28; Nubia E. Duarte, PhD29; Marie-Pierre Dubé, PhD30,31; Line Dufresne, MSc22,32; Niclas Eriksson, PhD8; Luisa Foco, PhD33; Markus Scholz, PhD34,35; Crystel M. Gijsberts, MD, PhD36; Charlotte Glinge, MD37,38; Yan Gong, PhD39; Jaana Hartiala, PhD17,40; Mahyar Heydarpour, PhD15,16; Jaroslav A. Hubacek, DSc41; Marcus Kleber, PhD28; Daniel Kofink, PhD3; Salma Kotti, PharmD, PhD42; Pekka Kuukasjärvi, PhD43; Vei-Vei Lee, MS44; Andreas Leiherer, PhD45-47; Petra A. Lenzini, MS48; Daniel Levin, PhD49; Leo-Pekka Lyytikäinen, MD50,51; Nicola Martinelli, MD, PhD52; Ute Mons, PhD27; Christopher P. Nelson, PhD25,26; Kjell Nikus, PhD53,54; Anna P. Pilbrow, PhD55; Rafal Ploski, MD, PhD56; Yan V. Sun, PhD57,58; Michael W.T. Tanck, PhD59; W.H.Wilson Tang, MD60,61; Stella Trompet, PhD62,63; Sander W. van der Laan, PhD64; Jessica Van Setten, PhD65; Ragnar O. Vilmundarson, MSc66,67; Chiara Viviani Anselmi, PhD68; Efthymia Vlachopoulou, PhD69; Lawien Al Ali, MD70; Eric Boerwinkle, PhD71; Carlo Briguori, MD, PhD72; John F. Carlquist, PhD4,73; Kathryn F. Carruthers, MPhil74; Gavino Casu, MD75; John Deanfield, MD1,2; Panos Deloukas, PhD76,77; Frank Dudbridge, PhD78; Thomas Engstrøm, MD, PhD79,80; Natalie Fitzpatrick, MSc81; Kim Fox, MD, PhD82; Bruna Gigante, PhD10; Stefan James, MD, PhD8,83; Marja-Liisa Lokki, PhD69, Paulo A. Lotufo, MD, PhD84; Nicola Marziliano, PhD85; Ify R. Mordi, MD49; Joseph B. Muhlestein MD4,73; Christopher Newton-Cheh, MD86; Jan Pitha, PhD41; Christoph H. Saely, MD45,46,87; Ayman Samman-Tahhan, MD88; Pratik B. Sandesara, MD88; Andrej Teren, MD35,89, Adam Timmis, MD81,90; Frans Van de Werf, PhD91; Els Wauters, PhD92; Arthur A.M. Wilde, MD, PhD93,94; Ian Ford, MD, PhD95; David J. Stott, MD96; Ale Algra, MD97; Maria G. Andreassi, PhD98, Diego Ardissino, MD99, Benoit J. Arsenault, PhD100,101; Christie M. Ballantyne, MD12; Thomas O. Bergmeijer, MD102; Connie R. Bezzina, PhD93; Simon C. Body, MBChB, MPH16,103; Eric H. Boersma, MD, PhD104,105; Peter Bogaty, MD106; Michiel Bots, MD107; Hermann Brenner, MD, PhD27,108; Jasper J. Brugts, MD, PhD104; Ralph Burkhardt, MD35,109; Clara Carpeggiani, MD98; Gianluigi Condorelli, MD, PhD68,110; Rhonda M. Cooper-DeHoff, PharmD39,111; Sharon Cresci, MD48,112; Nicolas Danchin, MD, PhD113,114; Ulf de Faire, PhD10; Robert N. Doughty, MD115; Heinz Drexel, MD45,46,116; James C. Engert, PhD32,117,118; Keith A.A. Fox, MD, PhD119; Domenico Girelli, MD, PhD52; Diederick E. Grobbee, MD, PhD107; Emil Hagström, MD, PhD9,120; Stanley L. Hazen, MD, PhD60,121; Claes Held, MD, PhD8,9; Harry Hemingway, MD, PhD81; Imo E. Hoefer, MD, PhD122; G. Kees Hovingh, MD, PhD123; Reza Jabbari, MD, PhD124; Julie A. Johnson, PharmD39,125; J. Wouter Jukema, MD, PhD63,126,127; Marcin P. Kaczor, MD, PhD128; Mika Kähönen, PhD129,130; Jiri Kettner, PhD131; Marek Kiliszek, MD, PhD132; Olaf H. Klungel, PharmD, PhD21; Bo Lagerqvist, MD, PhD8,83; Diether Lambrechts, PhD23,24; Jari O. Laurikka, PhD133,134; Terho Lehtimäki, PhD50,51; Daniel Lindholm, MD, PhD8,9; B. K. Mahmoodi, MD, PhD102; Anke H. Maitland-van der Zee, PharmD, PhD21,135; Ruth McPherson, MD, PhD66,136; Olle Melander, MD, PhD18,137; Andres Metspalu, MD, PhD19,20; Anna Niemcunowicz-Janica, MD, PhD138; Oliviero Olivieri, MD52; Grzegorz Opolski, MD, PhD139; Colin N. Palmer, PhD140; Gerard Pasterkamp, MD, PhD141; Carl J. Pepine, MD125; Alexandre C. Pereira, MD, PhD29; Louise Pilote, MD22,142; Arshed A. Quyyumi, MD88; A. Mark Richards, MD, PhD55,143; Marek Sanak, MD, PhD128; Agneta Siegbahn, MD, PhD8,144; Tabassome Simon, MD, PhD145,146; Juha Sinisalo, MD, PhD147; J. Gustav Smith, MD, PhD148-150; John A. Spertus, MD, MPH151,152; Steen Stender, MD, DSc153; Alexandre F.R. Stewart, PhD66,67; Wojciech Szczeklik, MD, PhD128; Anna Szpakowicz, MD, PhD14; Jean-Claude Tardif, MD30,31; Jurriën M. ten Berg, MD, PhD102; Jacob Tfelt-Hansen, MD, DMSc154; George Thanassoulis, MD32,22,118; Joachim Thiery, MD35,155; Christian Torp-Pedrsen, MD, DSc156,157; Yolanda van der Graaf, MD107; Frank L.J. Visseren, MD158; Johannes Waltenberger159; Peter E. Weeke, MD, PhD160; Pim Van der Harst, MD, PhD70; Chim C. Lang MD49; Naveed Sattar, PhD96; Vicky A. Cameron, PhD55; Jeffrey L. Anderson, MD4,73; James M. Brophy, MD22,142; Guillaume Pare, MD161,162; Benjamin D. Horne, PhD, MPH4,163; Winfried März, MD28,164,165; Lars Wallentin, MD, PhD8,83; Nilesh J. Samani, MD, PhD25,26†; Aroon D. Hingorani, MD, PhD1†; Folkert W. Asselbergs, MD, PhD1,3,166†