| 1. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 2. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 3. |
- Chen, H.Y., et al.
(författare)
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Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
- 2023
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:21, s. 1927-1939
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Tidskriftsartikel (refereegranskat)abstract
- Aims Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. Methods and results A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
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| 4. |
- Ragnarsson, Sigurdur, et al.
(författare)
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Pacemaker implantation following tricuspid valve annuloplasty.
- 2023
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Ingår i: JTCVS open. - 2666-2736. ; 16, s. 276-289
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Tidskriftsartikel (refereegranskat)abstract
- Tricuspid annuloplasty is associated with increased risk of atrioventricular block and subsequent implantation of a permanent pacemaker. However, the exact incidence of permanent pacemaker, associated risk factors, and outcomes in this frame remain debated. The aim of the study was to report permanent pacemaker incidence, risk factors, and outcomes after tricuspid annuloplasty from nationwide databases.By using data from multiple Swedish mandatory national registries, all patients (n=1502) who underwent tricuspid annuloplasty in Sweden from 2006 to 2020 were identified. Patients who needed permanent pacemaker within 30days from surgery were compared with those who did not. The cumulative incidence of permanent pacemaker implantation was estimated. A multivariable logistic regression model was fit to identify risk factors of 30-day permanent pacemaker implantation. The association between permanent pacemaker implantation and long-term survival was evaluated with multivariable Cox regression.The 30-day permanent pacemaker rate was 14.2% (214/1502). Patients with permanent pacemakers were older (69.8±10.3years vs 67.5±12.4years, P=.012). Independent risk factors of permanent pacemaker implantation were concomitant mitral valve surgery (odds ratio, 2.07; 95% CI, 1.34-3.27), ablation surgery (odds ratio, 1.59; 95% CI, 1.12-2.23), and surgery performed in a low-volume center (odds ratio, 1.85; 95% CI, 1.17-2.83). Permanent pacemaker implantation was not associated with increased long-term mortality risk (adjusted hazard ratio, 0.74; 95% CI, 0.53-1.03).This nationwide study demonstrated a high risk of permanent pacemaker implantation within 30days of tricuspid annuloplasty. However, patients who needed a permanent pacemaker did not have worse long-term survival, and the cumulative incidence of heart failure and major adverse cardiovascular events was similar to patients who did not receive a permanent pacemaker.
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| 5. |
- Ragnarsson, Sigurdur, et al.
(författare)
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Pacemaker implantation following tricuspid valve annuloplasty: A SWEDEHEART study
- 2023
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - 1097-685X. ; 16, s. 276-289
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTricuspid annuloplasty is associated with increased risk of atrioventricular block and subsequent implantation of a permanent pacemaker. However, the exact incidence of permanent pacemaker, associated risk factors, and outcomes in this frame remain debated. The aim of the study was to report permanent pacemaker incidence, risk factors, and outcomes after tricuspid annuloplasty from nationwide databases.MethodsBy using data from multiple Swedish mandatory national registries, all patients (n = 1502) who underwent tricuspid annuloplasty in Sweden from 2006 to 2020 were identified. Patients who needed permanent pacemaker within 30 days from surgery were compared with those who did not. The cumulative incidence of permanent pacemaker implantation was estimated. A multivariable logistic regression model was fit to identify risk factors of 30-day permanent pacemaker implantation. The association between permanent pacemaker implantation and long-term survival was evaluated with multivariable Cox regression.ResultsThe 30-day permanent pacemaker rate was 14.2% (214/1502). Patients with permanent pacemakers were older (69.8 ± 10.3 years vs 67.5 ± 12.4 years, P = .012). Independent risk factors of permanent pacemaker implantation were concomitant mitral valve surgery (odds ratio, 2.07; 95% CI, 1.34-3.27), ablation surgery (odds ratio, 1.59; 95% CI, 1.12-2.23), and surgery performed in a low-volume center (odds ratio, 1.85; 95% CI, 1.17-2.83). Permanent pacemaker implantation was not associated with increased long-term mortality risk (adjusted hazard ratio, 0.74; 95% CI, 0.53-1.03).ConclusionsThis nationwide study demonstrated a high risk of permanent pacemaker implantation within 30 days of tricuspid annuloplasty. However, patients who needed a permanent pacemaker did not have worse long-term survival, and the cumulative incidence of heart failure and major adverse cardiovascular events was similar to patients who did not receive a permanent pacemaker.
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