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  • Arking, Dan E, et al. (författare)
  • Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
  • 2014
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
  • Tidskriftsartikel (refereegranskat)abstract
    • The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
  • den Hoed, Marcel, et al. (författare)
  • Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
  • 2013
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 45:6, s. 621-
  • Tidskriftsartikel (refereegranskat)abstract
    • Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
  • Kato, Norihiro, et al. (författare)
  • Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
  • 2015
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1546-1718. ; 47:11, s. 93-1282
  • Tidskriftsartikel (refereegranskat)abstract
    • We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
  • van der Harst, Pim, et al. (författare)
  • Seventy-five genetic loci influencing the human red blood cell
  • 2012
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836. ; 492:7429, s. 369-375
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  • Jaarsma, Tiny, et al. (författare)
  • Effect of moderate or intensive disease management program on outcome in patients with heart failure : Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH).
  • 2008
  • Ingår i: Archives of Internal Medicine. - 0003-9926. ; 168:3, s. 316-24
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Heart failure (HF) disease management programs are widely implemented, but data about their effect on outcome have been inconsistent. METHODS: The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) was a multicenter, randomized, controlled trial in which 1023 patients were enrolled after hospitalization because of HF. Patients were assigned to 1 of 3 groups: a control group (follow-up by a cardiologist) and 2 intervention groups with additional basic or intensive support by a nurse specializing in management of patients with HF. Patients were studied for 18 months. Primary end points were time to death or rehospitalization because of HF and the number of days lost to death or hospitalization. RESULTS: Mean patient age was 71 years; 38% were women; and 50% of patients had mild HF and 50% had moderate to severe HF. During the study, 411 patients (40%) were readmitted because of HF or died from any cause: 42% in the control group, and 41% and 38% in the basic and intensive support groups, respectively (hazard ratio, 0.96 and 0.93, respectively; P = .73 and P = .52, respectively). The number of days lost to death or hospitalization was 39 960 in the control group, 33 731 days for the basic intervention group (P = .81), and 34 268 for the intensive support group (P = .49). All-cause mortality occurred in 29% of patients in the control group, and there was a trend toward lower mortality in the intervention groups combined (hazard ratio, 0.85; 95% confidence interval, 0.66-1.08; P = .18). There were slightly more hospitalizations in the 2 intervention groups (basic intervention group, P = .89; and intensive support group, P = .60). CONCLUSIONS: Neither moderate nor intensive disease management by a nurse specializing in management of patients with HF reduced the combined end points of death and hospitalization because of HF compared with standard follow-up. There was a nonsignificant, potentially relevant reduction in mortality, accompanied by a slight increase in the number of short hospitalizations in both intervention groups. Clinical Trial Registry http://trialregister.nl Identifier: NCT 98675639.
  • Jonkman, Nini H., et al. (författare)
  • Do Self-Management Interventions Work in Patients With Heart Failure? An Individual Patient Data Meta-Analysis
  • 2016
  • Ingår i: Circulation. - Lippincott Williams & Wilkins. - 0009-7322. ; 133:12, s. 1189-1198
  • Tidskriftsartikel (refereegranskat)abstract
    • Background- Self-management interventions are widely implemented in the care for patients with heart failure (HF). However, trials show inconsistent results, and whether specific patient groups respond differently is unknown. This individual patient data meta-analysis assessed the effectiveness of self-management interventions in patients with HF and whether subgroups of patients respond differently. Methods and Results- A systematic literature search identified randomized trials of self-management interventions. Data from 20 studies, representing 5624 patients, were included and analyzed with the use of mixed-effects models and Cox proportional-hazard models, including interaction terms. Self-management interventions reduced the risk of time to the combined end point of HF-related hospitalization or all-cause death (hazard ratio, 0.80; 95% confidence interval [CI], 0.71-0.89), time to HF-related hospitalization (hazard ratio, 0.80; 95% CI, 0.69-0.92), and improved 12-month HF-related quality of life (standardized mean difference, 0.15; 95% CI, 0.00-0.30). Subgroup analysis revealed a protective effect of self-management on the number of HF-related hospital days in patients &amp;lt; 65 years of age (mean, 0.70 versus 5.35 days; interaction P=0.03). Patients without depression did not show an effect of self-management on survival (hazard ratio for all-cause mortality, 0.86; 95% CI, 0.69-1.06), whereas in patients with moderate/severe depression, self-management reduced survival (hazard ratio, 1.39; 95% CI, 1.06-1.83, interaction P=0.01). Conclusions- This study shows that self-management interventions had a beneficial effect on time to HF-related hospitalization or all-cause death and HF-related hospitalization alone and elicited a small increase in HF-related quality of life. The findings do not endorse limiting self-management interventions to subgroups of patients with HF, but increased mortality in depressed patients warrants caution in applying self-management strategies in these patients.
  • Wong, Liza S M, et al. (författare)
  • Anaemia is associated with shorter leucocyte telomere length in patients with chronic heart failure.
  • 2010
  • Ingår i: European Journal of Heart Failure. - 1388-9842. ; 12:4, s. 348-53
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Anaemia is highly prevalent and associated with poor prognosis in patients with chronic heart failure (CHF). Reduced erythroid proliferation capacity of haematopoietic progenitor cells is associated with reduced telomere length, a marker of cellular ageing. We hypothesize that short telomere length contributes to the susceptibility to develop anaemia in patients with CHF. METHODS AND RESULTS: We studied 875 CHF patients, of whom 254 (29%) fulfilled the WHO criteria of anaemia. Telomere length in DNA from peripheral leucocytes was measured with real-time quantitative polymerase chain reaction. Age, gender, and baseline differences adjusted telomere length was correlated with haemoglobin levels (partial r = 0.130; P = 0.011). One standard deviation shorter telomere length was associated with an increased risk of having anaemia [odds ratio (OR), 1.31; 95% confidence interval (CI), 1.12-1.53; P = 0.001]. This observation was not affected by adjustment for potential confounders (OR, 1.38; 95% CI, 1.05-1.81; P = 0.021 after adjustment for age, gender, erythropoietin levels, renal function, left ventricular ejection fraction, age of CHF onset, blood pressure, history of stroke, diabetes, and B-type natriuretic peptide levels). CONCLUSION: Shorter telomere length increases the odds of having anaemia in CHF patients. This finding supports the hypothesis that cellular ageing in CHF contributes to the susceptibility to develop anaemia.
  • de Boer, Rudolf A, et al. (författare)
  • Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction
  • 2011
  • Ingår i: Annals of Medicine. - 0785-3890. ; 43:1, s. 60-68
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: galectin-3 is an emerging biomarker which has been studied in relatively small heart failure (HF) cohorts with predominantly systolic HF. We studied the prognostic value of base-line galectin-3 in a large HF cohort, with preserved and reduced left ventricular ejection fraction (LVEF), and compared this to other biomarkers. METHODS: we studied 592 HF patients who had been hospitalized for HF and were followed for 18 months. The primary end-point was a composite of all-cause mortality and HF hospitalization. RESULTS: a doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62-2.42) for the primary outcome (P &lt; 0.001). After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38 (1.07-1.78; P = 0.015). Galectin-3 levels were correlated with higher IL-6 and CRP levels (P &lt; 0.002). Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value (n = 291); however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone (ROC analysis, P &lt; 0.05). The predictive value of galectin-3 was stronger in patients with preserved LVEF (n = 114) compared to patients with reduced LVEF (P &lt; 0.001). CONCLUSIONS: galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF.
  • Huzen, Jardi, et al. (författare)
  • Telomere length and psychological well-being in patients with chronic heart failure.
  • 2010
  • Ingår i: Age and Ageing. - 0002-0729. ; 39:2, s. 223-7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: psychological stress and depressive symptoms have been implicated with accelerated ageing and increased progression of diseases. Shorter telomere length indicates a more advanced biological age. It is unknown whether psychological well-being is associated with telomere length in patients with the somatic condition of chronic heart failure (CHF). DESIGN: a cross-sectional analysis was used. SETTING: patients were admitted to the hospital with signs and symptoms of CHF. OBJECTIVE: the study aimed to assess the association between telomere length and psychological well-being in patients with CHF. METHODS: telomere length was determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association functional class II to IV CHF. We evaluated the perceived mental health by the validated RAND-36 questionnaire. Depressive symptoms were assessed by the Centre for Epidemiologic Studies Depression scale (CES-D), and the presence of type D personality was evaluated by the DS14. RESULTS: a lower perceived mental health on the RAND-36 score was associated with shorter telomere length. Adjustment for age and gender did not change our findings (standardised beta, 0.11; P-value, 0.002). Telomere length was not associated with the CES-D or DS14 score. CONCLUSION: decreased perceived mental health is associated with shorter leukocyte telomere length in patients with CHF. Future work should determine whether psychological stress accelerates biological ageing.
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