| 1. |
- Arking, D. E., et al.
(author)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Journal article (peer-reviewed)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. © 2014 Nature America, Inc.
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| 2. |
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| 3. |
- Kato, Norihiro, et al.
(author)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Journal article (peer-reviewed)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.
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| 5. |
- van der Harst, Pim, et al.
(author)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Journal article (peer-reviewed)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.
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| 6. |
- Screever, Elles M., et al.
(author)
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Comorbidities complicating heart failure: changes over the last 15 years
- 2023
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In: Clinical Research in Cardiology. - : Springer Heidelberg. - 1861-0684 .- 1861-0692. ; 112:1, s. 123-133
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Journal article (peer-reviewed)abstract
- Aims Management of comorbidities represents a critical step in optimal treatment of heart failure (HF) patients. However, minimal attention has been paid whether comorbidity burden and their prognostic value changes over time. Therefore, we examined the association between comorbidities and clinical outcomes in HF patients between 2002 and 2017. Methods and results The 2002-HF cohort consisted of patients from The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) trial (n = 1,032). The 2017-HF cohort were outpatient HF patients enrolled after hospitalization for HF in a tertiary referral academic hospital (n = 382). Kaplan meier and cox regression analyses were used to assess the association of comorbidities with HF hospitalization and all-cause mortality. Patients from the 2017-cohort were more likely to be classified as HF with preserved ejection fraction (24 vs 15%, p < 0.001), compared to patients from the 2002-cohort. Comorbidity burden was comparable between both cohorts (mean of 3.9 comorbidities per patient) and substantially increased with age. Higher comorbidity burden was significantly associated with a comparable increased risk for HF hospitalization and all-cause mortality (HR 1.12 [1.02-1.22] and HR 1.18 [1.05-1.32]), in the 2002- and 2017-cohort respectively. When assessing individual comorbidities, obesity yielded a statistically higher prognostic effect on outcome in the 2017-cohort compared to the 2002-HF cohort (p for interaction 0.026). Conclusion Despite major advances in HF treatment over the past decades, comorbidity burden remains high in HF and influences outcome to a large extent. Obesity emerges as a prominent comorbidity, and efforts should be made for prevention and treatment. [GRAPHICS] .
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| 7. |
- Gero, D., et al.
(author)
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Defining Global Benchmarks in Bariatric Surgery A Retrospective Multicenter Analysis of Minimally Invasive Roux-en-Y Gastric Bypass and Sleeve Gastrectomy
- 2019
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In: Annals of Surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0003-4932 .- 1528-1140. ; 270:5, s. 859-867
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Journal article (peer-reviewed)abstract
- Objective: To define "best possible'' outcomes for bariatric surgery (BS)(Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]). Background: Reference values for optimal surgical outcomes in welldefined low-risk bariatric patients have not been established so far. Consequently, outcome comparison across centers and over time is impeded by heterogeneity in case-mix. Methods: Out of 39,424 elective BS performed in 19 high-volume academic centers from 3 continents between June 2012 and May 2017, we identified 4120 RYGB and 1457 SG low-risk cases defined by absence of previous abdominal surgery, concomitant procedures, diabetes mellitus, sleep apnea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, anticoagulation, BMI>50 kg/m(2) and age>65 years. We chose clinically relevant endpoints covering the intra- and postoperative course. Complications were graded by severity using the comprehensive complication index. Benchmark values were defined as the 75th percentile of the participating centers' median values for respective quality indicators. Results: Patients were mainly females (78%), aged 38+/-11 years, with a baseline BMI 40.8 +/- 5.8 kg/m(2). Over 90 days, 7.2% of RYGB and 6.2% of SG patients presented at least 1 complication and no patients died (mortality in nonbenchmark cases: 0.06%). The most frequent reasons for readmission after 90-days following both procedures were symptomatic cholelithiasis and abdominal pain of unknown origin. Benchmark values for both RYGB and SG at 90-days postoperatively were 5.5% Clavien-Dindo grade >= IIIa complication rate, 5.5% readmission rate, and comprehensive complication index <= 33.73 in the subgroup of patients presenting at least 1 grade >= II complication. Conclusion: Benchmark cutoffs targeting perioperative outcomes in BS offer a new tool in surgical quality-metrics and may be implemented in qualityimprovement cycle. ClinicalTrials.gov Identifier NCT03440138
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| 10. |
- Chin, K. L., et al.
(author)
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Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study
- 2016
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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 18:9, s. 1175-1181
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Journal article (peer-reviewed)abstract
- AIMS: It is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5 mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). METHODS AND RESULTS: Patients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value = 0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. CONCLUSION: Aspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.
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| 11. |
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| 12. |
- Gheorghiade, Mihai, et al.
(author)
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Assessing and grading congestion in acute heart failure : a scientific statement from the acute heart failure committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine.
- 2010
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 12:5, s. 423-33
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Journal article (peer-reviewed)abstract
- Patients with acute heart failure (AHF) require urgent in-hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre-discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre-discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.
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| 13. |
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| 14. |
- Hillege, H. L., et al.
(author)
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Renal function as a predictor of outcome in a broad spectrum of patients with heart failure
- 2006
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In: Circulation. - 1524-4539 .- 0009-7322. ; 113:5, s. 671-8
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Journal article (peer-reviewed)abstract
- BACKGROUND: Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. METHODS AND RESULTS: The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (< or =40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 micromol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. CONCLUSIONS: Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.
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| 15. |
- Jonkman, Nini H., et al.
(author)
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Do self-management interventions work in patients with heart failure? An individual patient data meta-analysis
- 2016
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 133:12, s. 1189-1198
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Journal article (peer-reviewed)abstract
- BACKGROUND: -Self-management interventions are widely implemented in care for patients with heart failure (HF). Trials however 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 HF patients and whether subgroups of patients respond differently.METHODS AND RESULTS: -Systematic literature search identified randomized trials of self-management interventions. Data of twenty studies, representing 5624 patients, were included and analyzed using mixed effects models and Cox proportional-hazard models including interaction terms. Self-management interventions reduced risk of time to the combined endpoint HF-related hospitalization or all-cause death (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.71-0.89), time to HF-related hospitalization (HR, 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 number of HF-related hospital days in patients <65 years (mean number of days 0.70 days vs. 5.35 days; interaction p=0.03). Patients without depression did not show an effect of self-management on survival (HR for all-cause mortality, 0.86; 95%CI, 0.69-1.06), while in patients with moderate/severe depression self-management reduced survival (HR, 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, 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 HF patients, but increased mortality in depressed patients warrants caution in applying self-management strategies in these patients.
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| 16. |
- Nymo, S. H., et al.
(author)
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The association between neutrophil gelatinase-associated lipocalin and clinical outcome in chronic heart failure: Results from CORONA
- 2012
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 271, s. 436-443
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Journal article (peer-reviewed)abstract
- Objective. To study the prognostic value of neutrophil gelatinase-associated lipocalin (NGAL) in chronic heart failure (HF) of ischaemic aetiology. Background. Neutrophil gelatinase-associated lipocalin is a marker of kidney injury as well as matrix degradation and inflammation and has previously been shown to be increased in HF. We investigated whether serum NGAL levels could provide prognostic information in chronic HF. Methods. We assessed NGAL as a predictor of primary outcomes (cardiovascular death, nonfatal stroke and nonfatal myocardial infarction, n=307) and all-cause mortality (n=321), cardiovascular mortality (n=259) and hospitalization (n=647) as well as the number of hospitalizations during follow-up for all (n=1934) and CV causes (n=1204) in 1415 patients with chronic HF (≥60years, New York Heart Association class II-IV, ischaemic systolic HF) in the CORONA population, randomly assigned to 10mg rosuvastatin or placebo. Results. Multivariate analysis revealed that NGAL added significant information when adjusting for clinical variables, but was no longer significant when further adjusting for apolipoprotein A-1 (ApoA-1), glomerular filtration rate (GFR), C-reactive protein (CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). However, belonging to the highest NGAL tertile was associated with more frequent hospitalization, even after adjusting for clinical variables, GFR and ApoA-1, but not after adjusting for CRP and NT-proBNP. There was no interaction between rosuvastatin treatment and NGAL. Conclusion. Neutrophil gelatinase-associated lipocalin added no significant information to NT-proBNP and GFR in a multivariate model for primary and secondary end-points. © 2012 The Association for the Publication of the Journal of Internal Medicine.
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| 19. |
- Yeoh, S. E., et al.
(author)
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Effects of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction patients with chronic obstructive pulmonary disease in EMPHASIS-HF and RALES
- 2022
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:3, s. 529-538
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Journal article (peer-reviewed)abstract
- Aims Heart failure with reduced ejection fraction (HFrEF) and chronic obstructive pulmonary disease (COPD) individually cause significant morbidity and mortality. Their coexistence is associated with even worse outcomes, partly due to suboptimal heart failure therapy, especially underutilisation of beta-blockers. Our aim was to investigate outcomes in HFrEF patients with and without COPD, and the effects of mineralocorticoid receptor antagonists (MRAs) on outcomes. Methods and results We studied the effect of MRA therapy in a post-hoc pooled analysis of 4397 HFrEF patients in the RALES and EMPHASIS-HF trials. The primary endpoint was the composite of heart failure hospitalisation or cardiovascular death. A total of 625 (14.2%) of the 4397 patients had COPD. Patients with COPD were older, more often male, and smokers, but less frequently treated with a beta-blocker. In patients with COPD, event rates (per 100 person-years) for the primary endpoint and for all-cause mortality were 25.2 (95% confidence interval 22.1-28.7) and 17.2 (14.9-19.9), respectively, compared with 19.9 (18.8-21.1) and 12.8 (12.0-13.7) in participants without COPD. The risks of all-cause hospitalisation and sudden death were also higher in patients with COPD. The benefit of MRA, compared with placebo, was consistent in patients with or without COPD for all outcomes, e.g. hazard ratio for the primary outcome 0.66 (0.50-0.85) for COPD and 0.65 (0.58-0.73) for no COPD (interaction p = 0.93). MRA-induced hyperkalaemia was less frequent in patients with COPD. Conclusions In RALES and EMPHASIS-HF, one-in-seven patients with HFrEF had coexisting COPD. HFrEF patients with COPD had worse outcomes than those without. The benefits of MRAs were consistent, regardless of COPD status.
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