Publications by authors named "Sharon Cresci"

58 Publications

Syndrome of Reversible Cardiogenic Shock and Left Ventricular Ballooning in Obstructive Hypertrophic Cardiomyopathy.

J Am Heart Assoc 2021 10 12;10(20):e021141. Epub 2021 Oct 12.

Mount Sinai West New York NY.

Background Cardiogenic shock from most causes has unfavorable prognosis. Hypertrophic cardiomyopathy (HCM) can uncommonly present with apical ballooning and shock in association with sudden development of severe and unrelenting left ventricular (LV) outflow obstruction. Typical HCM phenotypic features of mild septal thickening, outflow gradients, and distinctive mitral abnormalities differentiate these patients from others with Takotsubo syndrome, who have normal mitral valves and no outflow obstruction. Methods and Results We analyzed 8 patients from our 4 HCM centers with obstructive HCM and abrupt presentation of cardiogenic shock with LV ballooning, and 6 cases reported in literature. Of 14 patients, 10 (71%) were women, aged 66±9 years, presenting with acute symptoms: LV ballooning; depressed ejection fraction (25±5%); refractory systemic hypotension; marked LV outflow tract obstruction (peak gradient, 94±28 mm Hg); and elevated troponin, but absence of atherosclerotic coronary disease. Shock was managed with intravenous administration of phenylephrine (n=6), norepinephrine (n=6), β-blocker (n=7), and vasopressin (n=1). Mechanical circulatory support was required in 8, including intra-aortic balloon pump (n=4), venoarterial extracorporeal membrane oxygenation (n=3), and Impella and Tandem Heart in 1 each. In refractory shock, urgent relief of obstruction by myectomy was performed in 5, and alcohol ablation in 1. All patients survived their critical illness, with full recovery of systolic function. Conclusions When cardiogenic shock and LV ballooning occur in obstructive HCM, they are marked by distinctive anatomic and physiologic features. Relief of obstruction with targeted pharmacotherapy, mechanical circulatory support, and myectomy, when necessary for refractory shock, may lead to survival and normalization of systolic function.
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http://dx.doi.org/10.1161/JAHA.121.021141DOI Listing
October 2021

Recurrent Takotsubo Cardiomyopathy in a Patient With Hypertrophic Cardiomyopathy Leading to Cardiogenic Shock Requiring VA-ECMO.

JACC Case Rep 2020 Jun 17;2(7):1014-1018. Epub 2020 Jun 17.

Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.

Providing hemodynamic support for patients with hypertrophic cardiomyopathy and cardiogenic shock can be challenging because inotropic medications worsen intraventricular obstruction, and the effect of appropriate mechanical support remains undefined. We report a patient with hypertrophic cardiomyopathy in shock because of takotsubo cardiomyopathy requiring venoarterial extracorporeal membrane oxygenation and septal reduction for full recovery. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302101PMC
June 2020

Exploring experiences of hypertrophic cardiomyopathy diagnosis, treatment, and impacts on quality of life among middle-aged and older adults: An interview study.

Heart Lung 2021 Nov-Dec;50(6):788-793. Epub 2021 Jul 2.

Center for Health Metrics and Evaluation, American Heart Association, 7272 Greenville Ave, Dallas, TX 75213, USA.

Background: Limited studies exist that describe diagnosis, treatment, and management experiences of patients with hypertrophic cardiomyopathy (HCM). This study's purpose is to characterize patient experiences related to symptom onset, diagnosis, symptom management, support from healthcare professionals, and impacts on daily living.

Methods: Semi-structured interviews were conducted using open-ended questions and question probes were conducted with adults aged ≥18 years diagnosed with HCM ≥1 year prior. Interview recordings were transcribed verbatim and inductive and deductive thematic analyses were performed.

Results: A total of 32 interviews were conducted. The majority of participants were female (53.1%), aged ≥45 years (90.6%), white (96.9%), and non-Hispanic (96.9%). Participants with longer time to HCM diagnosis described having atypical HCM symptoms, denial of their own symptoms, and experiences of misdiagnoses. For HCM information and support, participants utilized personal healthcare professionals as well as non-medical resources. Participants described experiences of anxiety, denial, and upset feelings about their diagnosis, but also gratitude, acceptance, and increased mindfulness toward healthy habits. Individuals reported making changes in daily activities because of reduced physical capacity and making changes in lifestyle choices because of desire to be close to HCM specialists. Over time, participants also described becoming less fearful through utilization of available resources and treatment options.

Conclusions: The diverse but often challenging experiences of individuals with HCM suggest that increasing availability and utilization of HCM patient resources may be effective at reducing the unfavorable physical and psychological impacts of HCM. Common reports of misdiagnoses resulting in delayed HCM diagnosis also indicate a need for HCM-related educational opportunities for healthcare professionals.
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http://dx.doi.org/10.1016/j.hrtlng.2021.06.004DOI Listing
July 2021

Phenylephrine Provocation to Evaluate the Cause of Mitral Regurgitation in Patients With Obstructive Hypertrophic Cardiomyopathy.

Circ Cardiovasc Imaging 2021 05 4;14(5):e012656. Epub 2021 May 4.

Division of Cardiology, Department of Medicine (J.D.M., R.G.B., S.C.M., S.C.), Washington University, St Louis, MO.

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http://dx.doi.org/10.1161/CIRCIMAGING.121.012656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394282PMC
May 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021

COVID-19: Understanding Inter-Individual Variability and Implications for Precision Medicine.

Mayo Clin Proc 2021 02 3;96(2):446-463. Epub 2020 Dec 3.

Department of Medicine and Genetics, Washington University, St Louis, MO.

Coronavirus disease 2019 (COVID-19) is characterized by heterogeneity in susceptibility to the disease and severity of illness. Understanding inter-individual variation has important implications for not only allocation of resources but also targeting patients for escalation of care, inclusion in clinical trials, and individualized medical therapy including vaccination. In addition to geographic location and social vulnerability, there are clear biological differences such as age, sex, race, presence of comorbidities, underlying genetic variation, and differential immune response that contribute to variability in disease manifestation. These differences may have implications for precision medicine. Specific examples include the observation that androgens regulate the expression of the enzyme transmembrane protease, serine 2 which facilitates severe acute respiratory syndrome coronavirus 2 viral entry into the cell; therefore, androgen deprivation therapy is being explored as a treatment option in males infected with COVID-19. An immunophenotyping study of COVID-19 patients has shown that a subset develop T cytopenia which has prompted a clinical trial that is testing the efficacy of interleukin-7 in these patients. Predicting which COVID-19 patients will develop progressive disease that will require hospitalization has important implications for clinical trials that target outpatients. Enrollment of patients at low risk for progression of disease and hospitalization would likely not result in such therapy demonstrating efficacy. There are efforts to use artificial intelligence to integrate digital data from smartwatch applications or digital monitoring systems and biological data to enable identification of the high risk COVID-19 patient. The ultimate goal of precision medicine using such modern technology is to recognize individual differences to improve health for all.
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http://dx.doi.org/10.1016/j.mayocp.2020.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713605PMC
February 2021

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 08 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020

Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations.

J Lipid Atheroscler 2020 3;9(1):172-183. Epub 2020 Jan 3.

Diabetic Cardiovascular Disease Center, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Objective: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.

Methods: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.

Results: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; =1.8E-9) and 0.25 (SE, 0.08; =0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was . The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (=2.83E-11). Nine SNPs, all on chromosome 20 and close to , were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (=9.94E-09).

Conclusion: SNPs near the gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.
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http://dx.doi.org/10.12997/jla.2020.9.1.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266332PMC
January 2020

Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.

Diabetes 2020 04 23;69(4):771-783. Epub 2020 Jan 23.

Research Division, Joslin Diabetes Center, Boston, MA

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes ( = 3.7 × 10). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD ( = 585, = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total = 3059, = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin ( for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on expression in many tissues. In summary, we have found a common regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
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http://dx.doi.org/10.2337/db19-0973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085251PMC
April 2020

Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2019 10 12;12(10):458-485. Epub 2019 Sep 12.

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.
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http://dx.doi.org/10.1161/HCG.0000000000000058DOI Listing
October 2019

A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies.

Diabetes 2019 08 24;68(8):1649-1662. Epub 2019 May 24.

Research Division, Joslin Diabetes Center, Boston, MA

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance ( < 5 × 10) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55-0.74, = 1.9 × 10). This effect was not influenced by ACCORD treatment assignments ( for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42-0.80, = 9 × 10; summary = 7.9 × 10). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene () coding for human voltage-gated sodium channel NaV1.2 ( = 9 × 10). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions.
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http://dx.doi.org/10.2337/db19-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692816PMC
August 2019

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

Circ Genom Precis Med 2019 04 21;12(4):e002471. Epub 2019 Mar 21.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).

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.
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http://dx.doi.org/10.1161/CIRCGEN.119.002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625876PMC
April 2019

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

Circ Genom Precis Med 2019 04 21;12(4):e002470. Epub 2019 Mar 21.

Department of Pharmacotherapy and Translational Research, Centre for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.), University of Florida, Gainesville.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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http://dx.doi.org/10.1161/CIRCGEN.119.002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629546PMC
April 2019

A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction.

Basic Res Cardiol 2018 08 10;113(5):38. Epub 2018 Aug 10.

Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus, Box 8086, Saint Louis, MO, 63110, USA.

The CHRNA5 gene encodes a neurotransmitter receptor subunit involved in multiple processes, including cholinergic autonomic nerve activity and inflammation. Common variants in CHRNA5 have been linked with atherosclerotic cardiovascular disease. Association of variation in CHRNA5 and specific haplotypes with cardiovascular outcomes has not been described. The aim of this study was to examine the association of CHRNA5 haplotypes with gene expression and mortality among patients with acute myocardial infarction (AMI) and explore potential mechanisms of this association. Patients (N = 2054) hospitalized with AMI were genotyped for two common variants in CHRNA5. Proportional hazard models were used to estimate independent association of CHRNA5 haplotype with 1-year mortality. Both individual variants were associated with mortality (p = 0.0096 and 0.0004, respectively) and were in tight LD (D' = 0.99). One haplotype, HAP3, was associated with decreased mortality one year after AMI (adjusted HR = 0.42, 95% CI 0.26, 0.68; p = 0.0004). This association was validated in an independent cohort (N = 637) of post-MI patients (adjusted HR = 0.23, 95% CI 0.07, 0.79; p = 0.019). Differences in CHRNA5 expression by haplotype were investigated in human heart samples (n = 28). Compared with non-carriers, HAP3 carriers had threefold lower cardiac CHRNA5 mRNA expression (p = 0.023). Circulating levels of the inflammatory marker hsCRP were significantly lower in HAP3 carriers versus non-carriers (3.43 ± 4.2 versus 3.91 ± 5.1; p = 0.0379). Activation of the inflammasome, an important inflammatory complex involved in cardiovascular disease that is necessary for release of the pro-inflammatory cytokine IL-1 β, was assessed in bone marrow-derived macrophages (BMDM) from CHRNA5 knockout mice and wild-type controls. In BMDM from CHRNA5 knockout mice, IL-1β secretion was reduced by 50% compared to wild-type controls (p = 0.004). Therefore, a common haplotype of CHRNA5 that results in reduced cardiac expression of CHRNA5 and attenuated macrophage inflammasome activation is associated with lower mortality after AMI. These results implicate CHRNA5 and the cholinergic anti-inflammatory pathway in survival following AMI.
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http://dx.doi.org/10.1007/s00395-018-0697-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292447PMC
August 2018

Association between the EPHX2 p.Lys55Arg polymorphism and prognosis following an acute coronary syndrome.

Prostaglandins Other Lipid Mediat 2018 09 7;138:15-22. Epub 2018 Aug 7.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01-2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70-1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09-6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted.
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http://dx.doi.org/10.1016/j.prostaglandins.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162147PMC
September 2018

Smoking Interacts With CHRNA5, a Nicotinic Acetylcholine Receptor Subunit Gene, to Influence the Risk of IBD-Related Surgery.

Inflamm Bowel Dis 2018 04;24(5):1057-1064

Division of Gastroenterology, Washington University in St. Louis, St. Louis, Missouri.

Background: Inflammatory bowel disease (IBD) is a chronic luminal disease with genetic and environmental factors affecting phenotype. This study evaluated the relationship between CHRNA5, a nicotinic receptor subunit gene, and smoking in predicting IBD-related surgery as well as the relationship between CHRNA5 and nicotine dependence.

Methods: Participants completed a smoking questionnaire and were genotyped for CHRNA5 rs16969968. Demographic and clinical data were obtained from medical records. Wilcoxon, ANOVA, Chi square, and Fisher's exact tests were used for comparisons. Logistic regression was used to evaluate the effect of clinical and genetic predictors on surgery, stratified by disease subtype given paradoxical effects of smoking. Kaplan-Meier curves were used to examine the effect of smoking and genotype on time to surgery. (Significance: P < 0.05 for main effects; P < 0.2 for interaction terms).

Results: 400 (65.8%) patients had Crohn's disease (CD) and 208 (34.2%) had ulcerative colitis (UC). 298 (49%) underwent an IBD-related surgery. There was a trend towards significance between rs16969968 and smoking behavior (smoking status [P = 0.05], nicotine dependence [AA > AG > GG; P = 0.08]). Smoking and genotype were not independently associated with surgery in UC or CD. However, interaction between rs16969968 and smoking in predicting surgery was observed for both UC (OR = 2.72; P = 0.05) and CD (OR = 2.88; P = 0.1). CHRNA5 genotype, but not smoking, predicted time to surgery in patients with UC (P = 0.007) but not in patients with CD. The interaction between smoking and genotype was not significantly associated with time to surgery in UC or CD.

Conclusions: The CHRNA5 rs16969968 A variant interacts with smoking to influence IBD-related surgery. 10.1093/ibd/izx094_video1izx094.video15775248538001.
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http://dx.doi.org/10.1093/ibd/izx094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994591PMC
April 2018

Slow Gait Speed and Cardiac Rehabilitation Participation in Older Adults After Acute Myocardial Infarction.

J Am Heart Assoc 2018 02 24;7(5). Epub 2018 Feb 24.

Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

Background: Lack of participation in cardiac rehabilitation (CR) and slow gait speed have both been associated with poor long-term outcomes in older adults after acute myocardial infarction (AMI). Whether the effect of CR participation on outcomes after AMI differs by gait speed is unknown.

Methods And Results: We examined the association between gait speed and CR participation at 1 month after discharge after AMI, and death and disability at 1 year, in 329 patients aged ≥65 years enrolled in the TRIUMPH (Translational Research Investigating Underlying Disparities in Recovery From Acute Myocardial Infarction: Patients' Health Status) registry. Among these patients, 177 (53.7%) had slow gait speed (<0.8 m/s) and 109 (33.1%) participated in CR. Patients with slow gait speed were less likely to participate in CR compared with patients with normal gait speed (27.1% versus 40.1%; =0.012). In unadjusted analysis, CR participants with normal gait speed had the lowest rate of death or disability at 1 year (9.3%), compared with those with slow gait speed and no CR participation (43.2%). After adjustment for cardiovascular risk factors and cognitive impairment, both slow gait speed (odds ratio, 2.30; 95% confidence interval, 1.30-4.06) and non-CR participation (odds ratio, 2.34; 95 confidence interval, 1.22-4.48) were independently associated with death or disability at 1 year. The effect of CR on the primary outcome did not differ by gait speed (=0.70).

Conclusions: CR participation is associated with reduced risk for death or disability after AMI. The beneficial effect of CR participation does not differ by gait speed, suggesting that slow gait speed alone should not preclude referral to CR for older adults after AMI.
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http://dx.doi.org/10.1161/JAHA.117.008296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866339PMC
February 2018

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

Lancet Diabetes Endocrinol 2017 07 26;5(7):534-543. Epub 2017 May 26.

Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.

Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.

Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.

Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.

Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.
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http://dx.doi.org/10.1016/S2213-8587(17)30096-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651679PMC
July 2017

Change in Angina Symptom Status After Acute Myocardial Infarction and Its Association With Readmission Risk: An Analysis of the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) Registry.

J Am Heart Assoc 2016 06 13;5(6). Epub 2016 Jun 13.

Duke Clinical Research Institute, Durham, NC Department of Medicine, Duke University, Durham, NC.

Background: Angina is common both before and after myocardial infarction (MI). Whether the change in angina status within the first 30 days after MI is associated with subsequent readmission and angina persistence is unknown.

Methods And Results: We studied 2915 MI patients enrolled at 24 hospitals in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) registry. Angina before and 30 days after MI was assessed with the Seattle Angina Questionnaire. Patients were divided into angina-free pre- and post-MI (-/-), resolved angina (+/-), new angina (-/+), and persistent angina (+/+) groups. Multivariable proportional hazards and hierarchical modified Poisson models were performed to assess the association of each group with all-cause readmission, readmission for MI or unplanned revascularization, and angina persistence at 1 year. Overall, 1293 patients (44%) had angina before their MI and 849 (29%) reported angina within 30 days of discharge. Patients with post-MI angina were more likely to be younger, nonwhite, and uninsured. Compared with patients who were angina-free pre- and post-MI, 1-year all-cause readmission risks were significantly higher for patients with persistent angina (hazard ratio [HR], 1.35; 95% CI 1.06-1.71) or new angina (HR, 1.40; 95% CI, 1.08-1.82). At 1 year, angina was present in 22% of patients and was more likely if angina was persistent (HR, 3.55; 95% CI, 3.05-4.13) or new (HR, 3.38; 95% CI, 2.59-4.42) at 30 days compared with patients who were angina-free pre- and post-MI.

Conclusions: Post-MI angina, whether new or persistent, is associated with higher likelihood of readmission. Prioritizing post-MI angina management is a potential means of improving 1-year outcomes.
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http://dx.doi.org/10.1161/JAHA.116.003205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937266PMC
June 2016

Association of Smoking Status With Angina and Health-Related Quality of Life After Acute Myocardial Infarction.

Circ Cardiovasc Qual Outcomes 2015 Sep;8(5):493-500

Background: Smoking cessation after acute myocardial infarction (AMI) decreases the risk of recurrent AMI and mortality by 30% to 50%, but many patients continue to smoke. The association of smoking with angina and health-related quality of life (HRQOL) after AMI is unclear.

Methods And Results: Patients in 2 US multicenter AMI registries (n=4003) were assessed for smoking and HRQOL at admission and 1, 6, and 12 months after AMI. Angina and HRQOL were measured with the Seattle Angina Questionnaire and Short Form-12 Physical and Mental Component Scales. At admission, 29% never had smoked, 34% were former smokers (quit before AMI), and 37% were active smokers, of whom 46% quit by 1 year (recent quitters). In hierarchical, multivariable, regression models that adjusted for sociodemographic, clinical and treatment factors, never and former smokers had similar and the best HRQOL in all domains. Recent quitters had intermediate HRQOL levels, with angina and Short Form-12 Mental Component Scale scores similar to never smokers. Persistent smokers had worse HRQOL in all domains compared with never smokers and worse Short Form-12 Mental Component Scale scores than recent quitters.

Conclusions: Smoking after AMI is associated with more angina and worse HRQOL in all domains, whereas smokers who quit after AMI have similar angina levels and mental health as never smokers. These observations may help encourage patients to stop smoking after AMI.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.114.001545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703446PMC
September 2015

Utility of a genetic risk score to predict recurrent cardiovascular events 1 year after an acute coronary syndrome: A pooled analysis of the RISCA, PRAXY, and TRIUMPH cohorts.

Atherosclerosis 2015 Sep 17;242(1):261-7. Epub 2015 Jul 17.

Department of Medicine, McGill University, Montreal, QC, Canada. Electronic address:

Background: Limited evidence exists regarding the utility of genetic risk scores (GRS) in predicting recurrent cardiovascular events after acute coronary syndrome (ACS). We sought to determine whether a GRS would predict early recurrent cardiovascular events within 1 year of ACS.

Methods & Results: Participants admitted with acute coronary syndromes from the RISCA, PRAXY, and TRIUMPH cohorts, were genotyped for 30 single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) or myocardial infarction (MI) in prior genome wide association studies. A 30 SNP CAD/MI GRS was constructed. The primary endpoint was defined as all-cause mortality, recurrent ACS or cardiac re-hospitalization within 1 year of ACS admission. Results across all cohorts for the 30 SNP CAD/MI GRS were pooled using a random-effects model. There were 1040 patients from the RISCA cohort, 691 patients from the PRAXY cohort, and 1772 patients from the TRIUMPH cohort included in the analysis and 389 occurrences of the primary endpoint of recurrent events at 1-year post-ACS. In unadjusted and fully adjusted analyses, a 30 SNP GRS was not significantly associated with recurrent events (HR per allele 0.97 (95%CI 0.91-1.03) for RISCA, HR 0.99 (95%CI 0.93-1.05) for PRAXY, 0.98 (95%CI 0.94-1.02) for TRIUMPH, and 0.98 (95%CI 0.95-1.01) for the pooled analysis). Addition of this GRS to the GRACE risk model did not significantly improve risk prediction.

Conclusion: The 30 MI SNP GRS was not associated with recurrent events 1-year post ACS in pooled analyses across cohorts and did not improve risk discrimination or reclassification indices. Our results suggest that the genetic etiology of early events post-ACS may differ from later events.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.07.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772857PMC
September 2015

CYP450 pharmacogenomics: a cardiology perspective.

Per Med 2015 Mar;12(2):59-62

Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8086, St. Louis, MO 63110, USA.

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http://dx.doi.org/10.2217/pme.14.76DOI Listing
March 2015

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Nature 2015 Feb 10;518(7537):102-6. Epub 2014 Dec 10.

DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Deutsches Herzzentrum München, Technische Universität München, Berlin 13347, Germany.

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
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http://dx.doi.org/10.1038/nature13917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319990PMC
February 2015

Inactivating mutations in NPC1L1 and protection from coronary heart disease.

N Engl J Med 2014 Nov 12;371(22):2072-82. Epub 2014 Nov 12.

Cardiovascular Division, Department of Medicine, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.

Background: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.

Methods: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease.

Results: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%).

Conclusions: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1405386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335708PMC
November 2014

Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction.

Circ Cardiovasc Genet 2014 Jun 24;7(3):277-86. Epub 2014 Apr 24.

From the Department of Medicine, Cardiovascular Division (S.C., J.P.D., A.Y.L., R.G.B.), Department of Genetics (S.C.), Department of Genetics, Statistical Genomics Division (P.A.L., M.A.P.), Washington University School of Medicine, St. Louis, MO; Heart and Vascular Institute, Department of Medicine, Henry Ford Hospital, Detroit, MI (D.E.L.); Saint Luke's Mid America Heart Institute & the Department of Medicine, University of Missouri-Kansas City (J.A.S.).

Background: Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients.

Methods And Results: Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01-2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95-4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function CYP2C19*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92-4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34-24.10; P<0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85-4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69-14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C19*17 or CYP1A2*1C.

Conclusions: Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104276PMC
June 2014

Association between diabetes mellitus and angina after acute myocardial infarction: analysis of the TRIUMPH prospective cohort study.

Eur J Prev Cardiol 2015 Jun 16;22(6):779-87. Epub 2014 Apr 16.

Saint Luke's Mid America Heart Institute, Kansas City, MO, USA University of Missouri-Kansas City, Kansas City, MO, USA.

Aims: While patients with diabetes mellitus (DM) have more extensive coronary disease and worse survival after acute myocardial infarction (AMI) than patients without DM, data on whether they experience more angina are conflicting.

Methods: We examined angina prevalence over the year following AMI among 3367 patients, including 1080 (32%) with DM, from 24 US hospitals enrolled in the TRIUMPH registry from 2005 to 2008.

Results: Patients with vs. without DM were more likely to be treated with antianginal medications both at discharge and over follow up. Despite more aggressive angina therapy, patients with vs. without DM had higher prevalence and severity of angina prior to AMI (49 vs. 43%, p = 0.001) and at each follow-up assessment, although rates of angina declined in both groups over time. In a hierarchical, multivariable, repeated-measures model that adjusted for multiple demographic and clinical factors including severity of coronary disease and in-hospital revascularization, DM was associated with a greater odds of angina over the 12 months of follow up; this association increased in magnitude over time (12-month OR 1.18, 95% CI 1.01-1.37; DM*time pinteraction = 0.008).

Conclusions: Contrary to conventional wisdom, angina is more prevalent and more severe among patients with DM, both prior to and following AMI. This effect is amplified over time and independent of patient and treatment factors, including the presence of multivessel disease and coronary revascularization. This increased burden of angina may be due to more diffuse nature of coronary disease, more rapid progression of coronary disease over time, or greater myocardial demand among DM patients.
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http://dx.doi.org/10.1177/2047487314533622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199926PMC
June 2015

CHRNA5 variant predicts smoking cessation in patients with acute myocardial infarction.

Nicotine Tob Res 2014 Sep 11;16(9):1224-31. Epub 2014 Apr 11.

Department of Medicine, Washington University School of Medicine, St. Louis, MO; Department of Genetics, Washington University School of Medicine, St. Louis, MO;

Introduction: While smoking is a major modifiable risk factor for secondary prevention of myocardial infarction (MI), active smoking is common among patients hospitalized with acute MI. Recent studies suggest that nicotinic receptor variants, and specifically the high-risk CHRNA5 rs16969968 A allele, are associated with cessation failure among noncardiac patients. This study investigates the association between CHRNA5 rs16969968 and smoking cessation in patients hospitalized with acute MI.

Methods: Using data from the TRIUMPH study, we ascertained smoking status at the time of index hospitalization for acute MI and 1 year after hospitalization. After adjusting for age and sex, we used logistic regression to model the association between smoking cessation and CHRNA5 rs16969968.

Results: At index admission, 752 Caucasian subjects were active smokers and 699 were former smokers. Among these ever-smokers, the A allele was associated with significantly decreased abstinence (45.0% abstinence for A allele carriers vs. 51.7% for GG homozygotes; odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.56-0.88, p = .0027). The A allele was also significantly associated with decreased abstinence at 1 year (69.1% abstinence for A allele carriers vs. 76.0% for GG homozygotes; OR = 0.70, 95% CI = 0.53-0.94, p = .0185).

Conclusions: Among patients who have smoked and who are hospitalized with acute MI, the high-risk CHRNA5 allele was associated with lower likelihood of quitting before hospitalization and significantly less abstinence 1 year after hospitalization with MI. The CHRNA5 rs16969968 genotype may therefore identify patients who would benefit from aggressive, personalized smoking cessation intervention.
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http://dx.doi.org/10.1093/ntr/ntu059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155476PMC
September 2014

Insulin resistance is associated with significant clinical atherosclerosis in nondiabetic patients with acute myocardial infarction.

Arterioscler Thromb Vasc Biol 2013 Sep 18;33(9):2245-51. Epub 2013 Jul 18.

Division of Cardiovascular Diseases, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.

Objective: The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals.

Approach And Results: We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ≥ 2 arteries with ≥ 70% stenosis (or ≥ 50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (P(trend) = 0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07-1.60]) and quartile 4 (1.29 [1.03-1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein).

Conclusions: We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome.
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http://dx.doi.org/10.1161/ATVBAHA.113.301585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855677PMC
September 2013

Detection of rare genomic variants from pooled sequencing using SPLINTER.

J Vis Exp 2012 Jun 23(64). Epub 2012 Jun 23.

Center for Genome Sciences and Systems Biology, Department of Genetics, Washington University School of Medicine.

As DNA sequencing technology has markedly advanced in recent years(2), it has become increasingly evident that the amount of genetic variation between any two individuals is greater than previously thought(3). In contrast, array-based genotyping has failed to identify a significant contribution of common sequence variants to the phenotypic variability of common disease(4,5). Taken together, these observations have led to the evolution of the Common Disease / Rare Variant hypothesis suggesting that the majority of the "missing heritability" in common and complex phenotypes is instead due to an individual's personal profile of rare or private DNA variants(6-8). However, characterizing how rare variation impacts complex phenotypes requires the analysis of many affected individuals at many genomic loci, and is ideally compared to a similar survey in an unaffected cohort. Despite the sequencing power offered by today's platforms, a population-based survey of many genomic loci and the subsequent computational analysis required remains prohibitive for many investigators. To address this need, we have developed a pooled sequencing approach(1,9) and a novel software package(1) for highly accurate rare variant detection from the resulting data. The ability to pool genomes from entire populations of affected individuals and survey the degree of genetic variation at multiple targeted regions in a single sequencing library provides excellent cost and time savings to traditional single-sample sequencing methodology. With a mean sequencing coverage per allele of 25-fold, our custom algorithm, SPLINTER, uses an internal variant calling control strategy to call insertions, deletions and substitutions up to four base pairs in length with high sensitivity and specificity from pools of up to 1 mutant allele in 500 individuals. Here we describe the method for preparing the pooled sequencing library followed by step-by-step instructions on how to use the SPLINTER package for pooled sequencing analysis (http://www.ibridgenetwork.org/wustl/splinter). We show a comparison between pooled sequencing of 947 individuals, all of whom also underwent genome-wide array, at over 20kb of sequencing per person. Concordance between genotyping of tagged and novel variants called in the pooled sample were excellent. This method can be easily scaled up to any number of genomic loci and any number of individuals. By incorporating the internal positive and negative amplicon controls at ratios that mimic the population under study, the algorithm can be calibrated for optimal performance. This strategy can also be modified for use with hybridization capture or individual-specific barcodes and can be applied to the sequencing of naturally heterogeneous samples, such as tumor DNA.
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http://dx.doi.org/10.3791/3943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471313PMC
June 2012
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