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We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.A retrospective cohort study was conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.Warfarin treatment.Ischemic stroke, intracranial hemorrhage, and death.In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA2DS2-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA2DS2-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA2DS2-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).These findings indicate that discontinuation of warfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.

Patent foramen ovale (PFO) is present in approximately 25% of the general population. PFO is characterized by intermittent shunting of blood from the right to the left atrium, especially in the context of increased right-sided filling pressures, with risk of paradoxical embolism. We describe a 69-year-old woman presenting with acute chest pain, severe dyspnoea, and acute inferolateral ST-segment elevation on the electrocardiogram. The patient was diagnosed with myocardial infarction and failure of the right cardiac ventricle, which was considered to be secondary to extensive pulmonary embolism leading to increased filling pressures and paradoxical coronary embolism. The patient underwent emergent percutaneous interventions with coronary thrombus extraction and pulmonary thrombus fragmentation and local thrombolysis. The patient was free of symptoms at follow up 6 months later and echocardiography showed substantially improved right ventricular function. We discuss issues related to the diagnosis, treatment, and secondary prevention for patients with concomitant pulmonary and coronary arterial thrombosis.

Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently.Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Background: Increased levels of cardio-enriched microRNAs (miRNAs) have been described in patients with myocardial infarction (MI). We wanted to evaluate the diagnostic and prognostic potential of cardio-enriched miRNAs in patients presenting with a suspected acute coronary syndrome (ACS). Methods: Cardio-enriched miRNAs (miR-1, miR-208b and miR-499-5p) were measured using real time PCR in plasma samples from 424 patients with suspected ACS treated in a coronary care unit. miRNAs were assessed for discrimination of a clinical diagnosis of myocardial infarction and for association with 30-day mortality and diagnosis of heart failure. Correlation with left ventricular systolic dysfunction as measured by the ejection fraction (LVEF) was also assessed. To confirm myocardial origin miRNA was measured during coronary artery bypass surgery. Results: miRNAs were higher in MI patients and correlated with LVEF (p < 0.001). Discrimination of MI was accurate for miR-208b (AUC = 0.82) and miR-499-5p (AUC = 0.79) but considerable lower than for Troponin T (AUC = 0.95). Increased miRNA levels were strongly associated with increased risk of mortality or heart failure within 30 days for miR-208b (OR 1.79, 95% CI = 1.38-2.23, p = 1 × 10 -5 ) and miR-499-5p (OR 1.70, 95% CI = 1.31-2.20, p = 5 × 10 -5 ) but the association was lost when adjusting for Troponin T. During surgery miR-208b and miR-499-5p was released in the coronary sinus after cardioplegia-reperfusion to markedly higher levels than in a peripheral vein. Conclusions: Our findings confirm increased levels of cardio-enriched miRNAs in the blood of MI patients and establish association of increased miRNA levels with reduced systolic function after MI and risk of death or heart failure.

This study sought to study the second-generation everolimus-eluting stent (EES) as compared with first-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in diabetes mellitus (DM) patients.There are limited data available comparing clinical outcomes in this setting with EES and SES, whereas studies comparing EES with PES are not powered for low-frequency endpoints.All DM patients treated with EES, PES, or SES from January 18, 2007, to July 29, 2011, from the SCAAR (Swedish Coronary Angiography and Angioplasty Registery) were included. The EES was compared with SES or PES for the primary composite endpoint of clinically driven detected restenosis, definite stent thrombosis (ST), and all-cause mortality.In 4,751 percutaneous coronary intervention-treated DM patients, 8,134 stents were implanted (EES = 3,928, PES = 2,836, SES = 1,370). The EES was associated with significantly lower event rates compared with SES (SES vs. EES hazard ratio [HR]: 1.99; 95% confidence interval (CI): 1.19 to 3.08). The same was observed when compared with PES (PES vs. EES HR: 1.33; 95% CI: 0.93 to 1.91) but did not reach statistical significance. These results were mainly driven by lower incidence of ST (SES vs. EES HR: 2.87; 95% CI: 1.08 to 7.61; PES vs. EES HR: 1.74, 95% CI: 0.82 to 3.71) and mortality (SES vs. EES HR: 2.02; 95% CI: 1.03 to 3.98; PES vs. EES HR: 1.69; 95% CI: 1.06 to 2.72). No significant differences in restenosis rates were observed between EES and SES or PES (SES vs. EES HR: 1.26; 95% CI: 0.77 to 2.08; PES vs. EES HR: 1.05; 95% CI: 0.71 to 1.55).In all-comer DM patients the use of EES was associated with improved outcomes compared with SES and PES mainly driven by lower rates of ST and mortality. These results suggest better safety rather than efficacy with EES when compared with SES or PES.

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Current guidelines do not advocate implantation of cardioverter-defibrillators (ICD) for survivors of ventricular fibrillation (VF) during the first 48 hours of ST-elevation myocardial infarction (STEMI). However, contemporary studies in a real-life setting with long-term follow-up are lacking. We assessed the prognostic impact of early VF in a non-selected population of STEMI patients treated with primary percutaneous coronary intervention (PCI).Consecutive STEMI patients admitted to a Swedish tertiary care hospital during 2007-2009 were identified from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (n=1718, age 66±12 years, 70% male). Patients with VF were identified from the register, and medical records were reviewed to determine the time point of VF. Patients surviving VF in the first 48 hours after symptom onset were compared with patients without VF for one-year mortality and a combined endpoint of death, resuscitated VF or appropriate ICD therapy. VF within 48 hours occurred in 7% of STEMI patients (n=121). In patients alive at 48 hours (n=1663), VF patients (n=101) had higher in-hospital mortality (12% vs. 2%, p0.001). However, in VF patients discharged alive (n=89), mortality was low (1%) and combined endpoint rate (3%) did not differ compared with patients without VF (n=1538; 4% and 4% respectively).In a large non-selected population of STEMI patients treated with primary PCI, VF during the first 48 hours after STEMI is associated with increased in-hospital mortality but does not influence the long-term prognosis for those discharged alive.

AIMS: Red cell distribution width (RDW) has been associated with cardiovascular disease, but the relation to heart failure (HF) is unclear. We investigated the association between RDW and incidence of first hospitalization due to HF in a population-based cohort. METHODS AND RESULTS: Red cell distribution width was measured in 26 784 subjects (aged 45-73 years, 61% women), without history of myocardial infarction (MI), stroke or HF, who participated in the Malmo Diet and Cancer study during 1991-1996. Incidence of HF was identified from the national Swedish hospital discharge register during a mean follow-up of 15 years and studied in relation to RDW. During follow-up, 773 subjects (55% men) were hospitalized due to HF, of whom 166 had an MI before or concurrent with the HF. After adjustment for potential confounding factors (including history of coronary revascularization, biological, lifestyle, and socio-economic factors), the hazard ratios (HR) for HF were 1.47 (95% CI: 1.14-1.89) in the top compared with the bottom quartile of RDW (P for trend 0.005), censoring subjects with incident MI before HF. The results were similar when all hospitalized HF cases were included (HR: 1.33, 1.07-1.66), (P for trend 0.020). After additional adjustment for N-terminal pro-B-type natriuretic peptide, cystatin C and high-sensitive C-reactive protein in a randomly selected subcohort (n= 4761), HR was 1.64 (CI: 0.90-3.00) comparing the top vs. bottom quartile of RDW. CONCLUSION: Red cell distribution width was found to be associated with long-term incidence of first hospitalization due to HF among middle-aged subjects. (Less)

AIMS Immediate treatment with a loading dose of clopidogrel at diagnosis of ST-segment elevation myocardial infarction (STEMI) is recommended by ESC/AHA/ACC guidelines in patients eligible for primary percutaneous coronary intervention (PCI). However, the evidence for this practice is scarce. METHODS AND RESULTS All patients who underwent PCI for STEMI in Sweden between 2003 and 2008 were identified from the national Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Patients with concomitant warfarin treatment and patients not having received aspirin upstream were excluded, leaving 13 847 patients for the analysis. Groups were compared for death and myocardial infarction (MI) during 1-year of follow-up using Cox regression models with adjustment for differences in baseline characteristics by propensity score methods. The combined primary endpoint of death or MI during 1-year follow-up occurred in 1325 of 9813 patients with upstream clopidogrel and in 364 out of 4034 patients without upstream treatment. After propensity score adjustment, a significant relative risk reduction (HR 0.82, 95% CI 0.73-0.93) in death/MI at 1 year was observed. The secondary endpoint of total 1-year death was significantly reduced (HR 0.76, 95% CI: 0.64-0.90), while the incidence of 1-year MI did not show any significant reduction (HR 0.90, 95% CI 0.77-1.06). Similar results were observed in multivariate analysis on top of propensity scoring and in sensitivity analyses excluding patients without clopidogrel and aspirin at discharge. CONCLUSION This large observational study suggests that upstream clopidogrel treatment prior to arrival at the catheterization lab is associated with a reduction in the combined risk of death or MI as well as death alone in patients with STEMI treated with primary PCI.

Aims Inflammatory markers are established risk factors for atrial fibrillation (AF), but the role of autoimmune diseases is unknown. The aim of the study was to examine the association between coeliac disease (CD) and AF in a large cohort of patients with biopsy-verified CD. Methods and results We identified 28 637 patients with CD through biopsy reports (defined as Marsh 3: villous atrophy) from all pathology departments (n = 28) in Sweden. Biopsies had been performed between 1969 and 2008. Age-and sexmatched reference individuals (n = 141 731) were identified from the Swedish Total Population Register. Data on AF were obtained from the Swedish Hospital Discharge Register, the Hospital Outpatient Register, and the Cause of Death Register. Hazard ratios (HRs) for AF were estimated using Cox regression. In the CD cohort, 941 individuals developed AF (vs. 2918 reference individuals) during a median follow-up of 9 years. The corresponding adjusted HR for AF was 1.34 (95% CI 1.24-1.44). The absolute risk of AF in CD was 321 of 100 000 person-years, with an excess risk of 81 of 100 000. A prior AF diagnosis was also associated with an increased risk of subsequent CD (odds ratio 1.45, 95% CI 1.31-1.62). Conclusions Atrial fibrillation is more common both before and after CD diagnosis in patients with CD though the excess risk is small. Potential explanations for the increased risk of AF in CD include chronic inflammation and shared risk factors, but ascertainment bias may also have contributed. Clinical implications Coeliac disease affects 1-2% of the Western population. Our results indicate that patients with coeliac disease, verified by intestinal biopsy, are at increased risk of atrial fibrillation. This observation is consistent with previous findings that elevation of inflammatory markers predicts atrial fibrillation. Additional studies are needed to clarify the mechanistic link between atrial fibrillation and autoimmune diseases such as coeliac disease. (Less)

Low-grade inflammation has been repeatedly associated with cardiovascular diseases but the relationship with incidence of atrial fibrillation (AF) remains unclear. We explored the association between elevated plasma levels of inflammation-sensitive proteins (ISPs) and incidence of AF in a population-based cohort. Plasma levels of five ISPs (fibrinogen, haptoglobin, ceruloplasmin, α(1)-antitrypsin and orosomucoid) and two complement factors (C3 and C4) were measured in 6,031 men (mean age 46.8 years) without history of myocardial infarction, heart failure, stroke or cancer. Incidence of hospitalizations due to AF during a mean follow-up of 25 years was studied both in relation to individual inflammatory proteins and the number of elevated ISPs. During follow-up, 667 patients were hospitalized with a diagnosis of AF. After adjustment for potential confounding factors, the hazard ratios (HR) for AF were 1.00 (reference), 1.08 (95% CI: 0.88-1.31), 1.07 (CI: 0.84-1.36), and 1.40 (CI: 1.12-1.74), respectively, in men with none, one, two and three or more ISPs in the 4th quartile (P for trend = 0.007). Ceruloplasmin was the only individual ISP significantly associated with incidence of AF after adjustment for confounding factors (HR 1.17 per standard deviation, 95% CI: 1.08-1.26). In conclusion, a score of five ISPs was associated with long-term incidence of hospitalizations due to AF in middle-aged men. Of the individual ISPs, a significant association was observed for ceruloplasmin, a protein previously associated with copper metabolism and oxidative stress.

Background and Purpose— In a genome-wide association study and subsequent case-control studies, the single-nucleotide polymorphism rs12425791 on chromosome 12p13 was reported to be associated with ischemic stroke, but this could not be validated in a recent well-powered study. We therefore investigated whether an association between ischemic stroke and rs12425791 could be detected in 3 different case-control studies from the southwest of Sweden. Methods— We examined 3606 patients with ischemic stroke and 2528 controls from 3 independent case-controls studies. Results— No significant association between ischemic stroke and the single-nucleotide polymorphism rs12425791 was detected in any of the 3 case-control samples or in the samples combined. The odds ratio for ischemic stroke for the minor allele in the combined sample was 1.02 (95% CI, 0.93 to 1.13). Conclusions— The single-nucleotide polymorphism rs12425791 does not confer a substantial risk for ischemic stroke in our population. Our results support a recent large study including other European populations.

Orthostatic hypotension (OH), a common manifestation of autonomic dysfunction, has been identified as an independent risk factor for all-cause mortality and incident cardiovascular disease. However, the role of OH in the development of atrial fibrillation has not been studied.We investigated the incidence of atrial fibrillation in relation to baseline presence of OH according to international consensus criteria in the Swedish population-based prospective cohort of the Malmö Preventive Project. The study sample consisted of 33,346 individuals (67.3% men; mean age, 45.6 ± 7.4 years; range, 26-61 years). The association between OH and incidence of atrial fibrillation during follow-up was assessed using the Kaplan-Meier method and multivariable Cox proportional hazard models, taking into account conventional risk factors for atrial fibrillation.At baseline, 1987 participants (6.1%) met the diagnostic criteria for OH. Over a follow-up period of approximately 24 years, 2312 individuals (3.0 events/1000 person-years) were diagnosed with new-onset atrial fibrillation. Of these, 196 had OH at baseline (4.6 events/1000 person-years amongst all OH-positive individuals). In a multivariable Cox regression analysis, OH predicted incidence of atrial fibrillation independently of other risk factors (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.05-1.61; P = 0.016), and this association was significant in hypertensive (HR: 1.44; 95%CI: 1.10-1.88; P = 0.008), but not in normotensive participants (HR: 1.10; 95%CI: 0.77-1.58; P = 0.60).The presence of OH predicts the incidence of atrial fibrillation in middle-aged hypertensive individuals, independently of conventional risk factors. Further studies of the association of autonomic dysfunction and OH with atrial fibrillation are needed.

Genome-wide association studies have opened a new era in the study of the genetic basis of common, multifactorial diseases and traits. Before the introduction of this approach only a handful of common genetic variants showed consistent association for any phenotype. Using genome-wide association, scores of novel and unsuspected loci have been discovered and later replicated for many complex traits. The principle is to genotype a dense set of common genetic variants across the genomes of individuals with phenotypic differences and examine whether genotype is associated with phenotype. Because the last common human ancestor was relatively recent and recombination events are concentrated in focal hotspots, most common variation in the human genome can be surveyed using a few hundred thousand variants acting as proxies for ungenotyped variants. Here, we describe the different steps of genome-wide association studies and use a recent study as example.

The validity of atrial fibrillation (AF) diagnoses in national registers for use as endpoints in prospective studies has not been evaluated. We studied the validity of AF diagnoses in Swedish national hospital discharge and cause of death registers and the occurrence of and risk factors for AF in a middle-aged Swedish population using these registers. Our study included the 30,447 individuals (age 44-73) who attended baseline visits in 1991-1996 of the Malmo Diet and Cancer study. Individuals with a first AF diagnosis were identified by record linkage with national registers. A subset of cases was randomly selected for validation by examination of electrocardiograms and patient records. Electrocardiograms were available in 98% of the validation sample (95% definitive AF, 3% no AF). The 2% with ECGs unavailable had probable AF. Baseline AF prevalence was 1.3%, higher in men and increased with age. During 11.2 years of follow-up 1430 first AF diagnoses occurred. Risk factors were age, hypertension, BMI, diabetes, history of heart failure, history of myocardial infarction and, in men but not women, current smoking. The strongest risk factors were history of heart failure (hazard ratio men 4.5, women 8.7) and myocardial infarction (hazard ratio men 2.0, women 1.8). The largest population attributable risks were observed for hypertension (men 38%, women 34%) and obesity (men 11%, women 10%). In conclusion, case misclassification of AF in national registers is small, indicating feasibility of use in prospective studies. Hypertension and obesity account for large portions of population risk in middle-aged individuals with low prevalence of manifest cardiac disease.

Adrenomedullin (ADM)1 is a multifunctional peptide hormone expressed in most tissues and in multiple cell types in response to cellular stress, ischemia, and hypoxia. These characteristics indicate that ADM may have a role in protection against cellular injury and therefore is a promising biomarker of disease (1). Increased ADM concentrations have been reported in multiple diseases; however, the results between studies have been inconsistent, perhaps owing to technical difficulties in measuring ADM (2). To overcome these problems a novel assay has been developed. This assay reflects ADM production by measurement of midregional proadrenomedullin (MR-proADM), a separate fragment of the precursor peptide preproadrenomedullin. MR-proADM, which has no known function and is produced in a 1:1 stoichiometry to ADM. The MR-proADM assay has been shown to exhibit low intraassay variability, and concentrations of MR-proADM appear stable in samples that are stored at room temperature for up to 72 h, undergo multiple freeze-thaw cycles, or are drawn from patients in a nonfasting state (2). We used the previously described immunoluminometric sandwich assay (2) (Brahms) to measure MR-proADM in 5258 fasting individuals from the cardiovascular cohort of the population-based Malmo Diet and Cancer Study who attended a baseline visit between 1991 and 1996 (3). We studied the relation of MR-proADM with 23 other baseline variables (Table …

Genome-wide association studies have opened a new era in the study of the genetic basis of common, multifactorial diseases and traits. Before the introduction of this approach only a handful of common genetic variants showed consistent association for any phenotype. Using genome-wide association, scores of novel and unsuspected loci have been discovered and later replicated for many complex traits. The principle is to genotype a dense set of common genetic variants across the genomes of individuals with phenotypic differences and examine whether genotype is associated with phenotype. Because the last common human ancestor was relatively recent and recombination events are concentrated in focal hotspots, most common variation in the human genome can be surveyed using a few hundred thousand variants acting as proxies for ungenotyped variants. Here, we describe the different steps of genome-wide association studies and use a recent study as example.

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment., Starr Foundation, Howard Hughes Medical Institute, Deutsche Forschungsgemeinschaft (DFG Bu2263/1-1), National Institutes of Health (U.S.) (1F32DK070527), National Institutes of Health (U.S.) (5 U54 CA121852), Massachusetts Biomedical Research Corporation (Tosteson Postdoctoral Fellowship), National Institutes of Health (U.S.) (NIH/NIDDK grant (5R01 DK60089))

Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression.To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02).Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

AIM:To gain a better understanding of the impact of chronic obstructive pulmonary disease (COPD) on long-term mortality in patients with myocardial infarction (MI) and identify areas where the clin ...

Atrial fibrillation (AF) is a common cardiac disease and major risk factor for stroke, heart failure and death. Tools for prediction of AF have been developed to identify individuals who might benefit from preventive therapies, incorporating conventional cardiovascular risk factors, and the effects of such risk factors have been evaluated across several cohorts.1,2 Recently, a heritable component to AF has been reported and polymorphisms in three genetic regions have been reproducibly associated with AF: chromosome 4q25, located 150 kb from the closest gene - a transcription factor (PITX2) involved in cardiac development; chromosome 16q22, intronic to another transcription factor of unknown function, expressed in cardiac tissue (ZFHX3); and an amino acid-altering variant in KCNH2, one of the major cardiac voltage-gated potassium channels.3–5 Rare genetic variants segregating with AF are typically exclusive to individual families and unlikely to contribute to AF prediction at the population level but genetic polymorphisms could provide important predictive information.

Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the proteome, and the broad range of abundance levels, as well. Proteome-wide, untargeted profiling can be performed in tissues and cells with tandem mass spectrometry. However, applications to plasma are limited by the need for complex preanalytical sample preparation stages limiting sample throughput. Multiplexing of targeted methods based on capture and detection of specific proteins are therefore receiving increasing attention in plasma proteomics. Immunoaffinity assays are the workhorse for measuring individual proteins but have been limited for proteomic applications by long development times, cross-reactivity preventing multiplexing, specificity issues, and incomplete sensitivity to detect proteins in the lower range of the abundance spectrum (below picograms per milliliter). Emerging technologies to address these issues include nucleotide-labeled immunoassays and aptamer reagents that can be automated for efficient multiplexing of thousands of proteins at high sample throughput, coupling of affinity capture methods to mass spectrometry for improved specificity, and ultrasensitive detection systems to measure low-abundance proteins. In addition, proteomics can now be integrated with modern genomics tools to comprehensively relate proteomic profiles to genetic variants, which may both influence binding of affinity reagents and serve to validate the target specificity of affinity assays. The application of deep quantitative proteomic profiling to large cohorts has thus become increasingly feasible with emerging affinity methods. The aims of this article are to provide the broad readership of Circulation with a timely overview of emerging methods for affinity proteomics and recent progress in cardiovascular medicine based on such methods.

Heart failure (HF) is characterized by myocardial dysfunction resulting in increased venous and capillary pressure, and extravascular fluid accumulation when the capacity of the lymphatic system is insufficient. Vascular endothelial growth factor D (VEGF-D) activates VEGF receptors 2 and 3 and is a

Background: Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI. Methods: A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP). Results: Patients receiving pre-hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of

Acute cellular rejection (ACR), a T-cell–mediated form of organ rejection, remains a common problem after transplantation that compromises long-term allograft survival. Surveillance for ACR has been based on endomyocardial biopsy since the 1970s, which is burdensome due to its invasiveness, risk

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510