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- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 2. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 5. |
- Grecu, Mihaela, et al.
(författare)
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In-hospital and 12-month follow-up outcome from the ESC-EORP EHRA Atrial Fibrillation Ablation Long-Term registry : sex differences
- 2020
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 22:1, s. 66-73
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The purpose of this study was to compare sex differences of atrial fibrillation (AF) catheter ablation (CA) and to analyse the opportunities for improved outcomes.METHODS AND RESULTS: All data were collected from the Atrial Fibrillation Ablation Long-Term registry, a prospective, multinational study conducted by the ESC-EORP European Heart Rhythm Association (EHRA) under the EURObservational Research Programme (ESC-EORP). A total of 104 centres in 27 European countries participated. Of 3593 included patients, 1146 (31.9%) were female. Female patients were older (61.0 vs. 56.4 years; P < 0.001), had more comorbidities (hypertension, diabetes, and obesity), more episodes of arrhythmias per month (6.9 vs. 6.2; P < 0.001), and a higher average EHRA score (2.6 vs. 2.4; P < 0.001). The duration of the procedure was shorter in females (160.1 min vs. 167.9 min; P < 0.001), irrespective of additional ablation lesions added to pulmonary vein isolation. Overall cardiovascular complications were more frequent in women than in men (5.7% vs. 3.4%; P < 0.001). Furthermore, cardiac perforations (3.8% vs. 1.3%; P = 0.011) and neurological complications (2.2% vs. 0.3%; P = 0.004) were found in females in less experienced centres than in experienced ones. On a final note, at 12 months, AF recurrence rate was similar in females and males (34.4% vs. 34.2%; P = 0.897), but more females were still on antiarrhythmic drugs (50.6% vs. 44.1%; P < 0.001) when compared with men.CONCLUSION: Females underwent CA procedures for AF less frequently than males throughout Europe, despite more recurrent symptoms. With the same success rate, severe acute complications remained considerable in females, especially in less experienced centres.
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| 6. |
- Saglietto, Andrea, et al.
(författare)
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AFA-Recur : an ESC EORP AFA-LT registry machine-learning web calculator predicting atrial fibrillation recurrence after ablation
- 2023
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 25:1, s. 92-100
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Atrial fibrillation (AF) recurrence during the first year after catheter ablation remains common. Patient-specific prediction of arrhythmic recurrence would improve patient selection, and, potentially, avoid futile interventions. Available prediction algorithms, however, achieve unsatisfactory performance. Aim of the present study was to derive from ESC-EHRA Atrial Fibrillation Ablation Long-Term Registry (AFA-LT) a machine-learning scoring system based on pre-procedural, easily accessible clinical variables to predict the probability of 1-year arrhythmic recurrence after catheter ablation.Methods and results: Patients were randomly split into a training (80%) and a testing cohort (20%). Four different supervised machine-learning models (decision tree, random forest, AdaBoost, and k-nearest neighbour) were developed on the training cohort and hyperparameters were tuned using 10-fold cross validation. The model with the best discriminative performance on the testing cohort (area under the curve-AUC) was selected and underwent further optimization, including re-calibration. A total of 3128 patients were included. The random forest model showed the best performance on the testing cohort; a 19-variable version achieved good discriminative performance [AUC 0.721, 95% confidence interval (CI) 0.680-0.764], outperforming existing scores (e.g. APPLE score: AUC 0.557, 95% CI 0.506-0.607). Platt scaling was used to calibrate the model. The final calibrated model was implemented in a web calculator, freely available at http://afarec.hpc4ai.unito.ti/.Conclusion: AFA-Recur, a machine-learning-based probability score predicting 1-year risk of recurrent atrial arrhythmia after AF ablation, achieved good predictive performance, significantly better than currently available tools. The calculator, freely available online, allows patient-specific predictions, favouring tailored therapeutic approaches for the individual patient.
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| 7. |
- Tilz, Roland Richard, et al.
(författare)
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Which patients with atrial fibrillation undergo an ablation procedure today in Europe? : A report from the ESC-EHRA-EORP Atrial Fibrillation Ablation Long-Term and Atrial Fibrillation General Pilot Registries
- 2020
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 22:2, s. 250-258
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Tidskriftsartikel (refereegranskat)abstract
- AimsRhythm control management in patients with atrial fibrillation (AF) may be unequal across Europe. The aim of this study was to investigate how selective the patient cohort referred for AF ablation is, as compared to the general AF population in Europe, and to describe the governing mechanisms for such selection.Methods and resultsDescriptive comparative statistical analyses of the baseline characteristics were performed between the cohorts of Atrial Fibrillation Ablation Long-Term (ESC EORP AFA-LT) registry, designed to provide a picture of contemporary real-world AF ablation, and the AF population from the AF-General (ESC EORP AF-Gen) pilot registry. Data collection was performed using a web-based system. In the AFA and in the Atrial Fibrillation General (AFG) pilot registries, 3593 and 3049 patients were enrolled, respectively. Patients who underwent AF ablation were younger, more commonly male, and had significantly less comorbidities. Atrial Fibrillation Ablation patients often presented without comorbidities, resulting in a lower risk of stroke (CHA2DS2-VASc ≥5: 2.9% vs. 24.5%, all P < 0.001) and bleeding (HAS-BLED ≥2: 8.5% vs. 40.5%, P < 0.001) but with European Heart Rhythm Association (EHRA) scores >1 and more prevalent AF-related symptoms such as palpitations, fatigue, and weakness (all P < 0.001) as compared to the general AF patients. Atrial Fibrillation Ablation patients were significantly more often male, had higher left ventricular ejection fraction (59.5% vs. 52.4%) and smaller left atrial size on echocardiogram (P < 0.001 each).ConclusionThe comparison of the patient cohorts in the AFA and AFG registries showed that AF ablation in European clinical practice is mostly performed in relatively young, symptomatic and relatively healthy patients.
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| 8. |
- Vassilikos, Vassilios P., et al.
(författare)
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Impact of centre volume on atrial fibrillation ablation outcomes in Europe : a report from the ESC EHRA EORP Atrial Fibrillation Ablation Long-Term (AFA LT) Registry
- 2021
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 23:1, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The aim of the study was to investigate differences in clinical outcomes and complication rates among European atrial fibrillation (AF) ablation centres related to the volume of AF ablations performed.METHODS AND RESULTS: Data for this analysis were extracted from the ESC EHRA EORP European AF Ablation Long-Term Study Registry. Based on 33rd and 67th percentiles of number of AF ablations performed, the participating centres were classified into high volume (HV) (≥ 180 procedures/year), medium volume (MV) (<180 and ≥74/year), and low volume (LV) (<74/year). A total of 91 centres in 26 European countries enrolled in 3368 patients. There was a significantly higher reporting of cardiovascular complications and stroke incidence in LV centres compared with HV and MV (P = 0.039 and 0.008, respectively) and a lower success rate after AF ablation (55.3% in HV vs. 57.2% in LV vs. 67.4% in MV centres, P < 0.001), despite lower CHA2DS2-VASc score of patients, enrolled in LVs and less complex ablation techniques used. Adjustments of confounding factors (including type of AF ablation) led to elimination of these differences.CONCLUSION: Low-volume centres tended to present slightly higher cardiovascular complications' and stroke incidence and a lower unadjusted success rate after AF ablation, despite the fact that ablation procedures and patients were of lower risk compared with MV and HV centres. On the other hand, adjusted overall complication and recurrence rates were non-significantly different among different volume centres, a fact reflecting the heterogeneity of patient and procedural profiles, and a counterbalance between expertise and risk level among participating centres.
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