Publications by authors named "Jacob Tfelt-Hansen"

172 Publications

Witnessed and unwitnessed sudden cardiac death: a nationwide study of persons aged 1-35 years.

Europace 2021 Feb 17. Epub 2021 Feb 17.

The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Section 2142, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Aims: The aim of this study is to compare clinical characteristics and causes of death among witnessed and unwitnessed sudden cardiac death (SCD) cases aged 1-35 years.

Methods And Results: In this retrospective nationwide study, all deaths in persons aged 1-35 years in Denmark during 2000-09 were included (23.7 million person-years). Using the in-depth descriptive Danish death certificates and Danish nationwide registries, 860 cases of sudden, unexpected death were identified. Through review of autopsy reports and register data, we identified 635 cases of SCD of which 266 (42%) were witnessed and 326 (51%) were unwitnessed. In 43 cases (7%), witnessed status was missing. Clinical characteristics were overall similar between the two groups. We found a male predominance among unwitnessed SCD compared to witnessed SCD (71% and 62%, respectively, P-value 0.012), as well as more psychiatric comorbidity (20% and 13%, respectively, P-value 0.029). Unwitnessed SCD more often occurred during sleep whereas witnessed SCD more often occurred while the individual was awake and relaxed (P-value < 0.001). The autopsy rate among all SCD cases was 70% with no significant difference in autopsy rate between the two groups. Sudden unexplained death, which was the leading autopsy conclusion in both groups, was more frequent among unwitnessed SCD (P-value 0.001).

Conclusion: Several clinical characteristics and autopsy findings were similar between witnessed and unwitnessed SCD cases. Our data support the inclusion of both witnessed and unwitnessed cases in epidemiological studies of SCD cases aged 1-35 years, although the risk of misclassification is higher among unwitnessed and non-autopsied cases of SCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euab017DOI Listing
February 2021

Familial Evaluation in Idiopathic Ventricular Fibrillation: Diagnostic Yield and Significance of J-Wave Syndromes.

Circ Arrhythm Electrophysiol 2021 Feb 7. Epub 2021 Feb 7.

Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's, University of London & St. George's University Hospitals NHS Foundation Trust, London United Kingdom.

- Familial cascade screening is well established in patients with heritable cardiac disease and in cases of Sudden Arrhythmic Death Syndrome (SADS). The clinical benefit of family screening in idiopathic ventricular fibrillation (IVF) is unknown. - Patients with IVF were identified from national and institutional registries. All underwent systematic and comprehensive clinical evaluation to exclude identifiable causes of cardiac arrest with a minimum requirement of ECG, cardiac (echocardiogram and/or MRI) and coronary imaging, exercise ECG and sodium channel blocker (SCB) provocation. Additional investigations including genetic testing were performed at the physician's discretion. First-degree relatives who were assessed with at least a 12-lead ECG were included in the final cohort. Results of additional investigations, performed at the physician's discretion, were also recorded. Results were coded as normal, abnormal or minor findings. - We identified 201 first-degree relatives of 96 IVF patients. In addition to a 12 lead ECG, echocardiography was performed in 159 (79%) and ≥ 1 additional investigation in 162 (80%) relatives. An inherited arrhythmia syndrome was diagnosed in 5 (3%) individuals from 4 (4%) families. Two relatives hosted the DPP6 risk haplotype identified in a single proband, one of whom received a primary prevention ICD. In three separate families an asymptomatic parent of the IVF proband developed a type 1 Brugada ECG pattern during SCB provocation. All were managed with lifestyle measures only. The Early Repolarisation ECG pattern (ER) was present in 16% probands and was more common in relatives in those families than those where the proband did not have ER (25% vs. 8%, p=0.04). - The yield of family screening in relatives of IVF probands is low when the proband is comprehensively investigated. The significance of J wave syndromes in relatives and the role for systematic SCB provocation are, however, uncertain and require further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.009089DOI Listing
February 2021

Clinical characteristics and risk factors of arrhythmia during follow-up of patients with idiopathic ventricular fibrillation.

J Cardiovasc Electrophysiol 2020 Oct 7;31(10):2677-2686. Epub 2020 Aug 7.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark.

Aims: The current knowledge of idiopathic ventricular fibrillation (IVF) is limited. We aimed to investigate the nature of IVF, including clinical assessment and later diagnosis, and risk factors of implantable cardioverter defibrillator (ICD) therapy in the follow-up period.

Methods: Between 2007 and 2019 we systematically identified all patients from Rigshospitalet, Denmark, with a resuscitated sudden cardiac arrest (SCA) with no identifiable cause. All patients were followed routinely in the ICD outpatient clinic and the majority also in an inherited heart disease outpatient clinic. Outcomes were analysed with Cox regressions models and cumulative incidence curves.

Results: We identified 84 patients with an initial diagnosis of IVF; of these, three (3.6%) patients were later diagnosed with a cardiac disease. The remaining IVF patients (n = 81, median age 45 years; men 71.6%) were followed a median follow-up of 5.2 years (interquartile range, 2.0-7.6). A total of 24 (29.6%) patients had appropriate ICD therapy and 12 (14.8%) patients had inappropriate ICD therapy. No predominant type of ventricular arrhythmia at first appropriate ICD therapy was observed. Early repolarization at baseline was not associated with an increased risk of appropriate ICD therapy (P = .842). Repeated cardiac arrest at index SCA increased the risk of appropriate ICD therapy (hazard ratio, 2.63 [95% CI, 1.08-6.40; P = .033]).

Conclusion: Most patients remained idiopathic throughout the follow-up period and the overall long-term prognosis of IVF was good. Repeated cardiac arrest at index SCA was a risk factor of appropriate ICD therapy and early repolarization was not associated with an increased risk of appropriate ICD therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14696DOI Listing
October 2020

Symptoms Preceding Sports-Related Sudden Cardiac Death in Persons Aged 1-49 Years.

Curr Cardiol Rep 2021 Jan 6;23(2). Epub 2021 Jan 6.

The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Section 2142, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.

Purpose Of Review: Sports-related sudden cardiac death (Sr-SCD) is a leading natural cause of death in young athletes. To prevent Sr-SCD in athletes, it is important to identify individuals at risk. This review sought to summarize the current knowledge of symptoms prior to Sr-SCD in athletes aged 1-49 years.

Recent Findings: Cardiovascular screening of athletes is a subject of interest. However, the cost of ECG screening in a young population is relatively high compared to potential benefits, and systematic screening of athletes is heavily debated. In the background population, both cardiac and non-specific symptoms are often present prior to SCD. Both cardiac and non-specific symptoms are present in up to 74% prior to Sr-SCD. The main symptoms are syncope, chest pain, palpitations and dizziness. Knowledge of symptoms could potentially be used in combination with non-invasive prediction models to prevent Sr-SCD and treat athletes at risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11886-020-01438-3DOI Listing
January 2021

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

Heart Rhythm 2021 Jan 19;18(1):e1-e50. Epub 2020 Oct 19.

The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2020.10.010DOI Listing
January 2021

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Authors:
Roddy Walsh Najim Lahrouchi Rafik Tadros Florence Kyndt Charlotte Glinge Pieter G Postema Ahmad S Amin Eline A Nannenberg James S Ware Nicola Whiffin Francesco Mazzarotto Doris Škorić-Milosavljević Christian Krijger Elena Arbelo Dominique Babuty Hector Barajas-Martinez Britt M Beckmann Stéphane Bézieau J Martijn Bos Jeroen Breckpot Oscar Campuzano Silvia Castelletti Candan Celen Sebastian Clauss Anniek Corveleyn Lia Crotti Federica Dagradi Carlo de Asmundis Isabelle Denjoy Sven Dittmann Patrick T Ellinor Cristina Gil Ortuño Carla Giustetto Jean-Baptiste Gourraud Daisuke Hazeki Minoru Horie Taisuke Ishikawa Hideki Itoh Yoshiaki Kaneko Jørgen K Kanters Hiroki Kimoto Maria-Christina Kotta Ingrid P C Krapels Masahiko Kurabayashi Julieta Lazarte Antoine Leenhardt Bart L Loeys Catarina Lundin Takeru Makiyama Jacques Mansourati Raphaël P Martins Andrea Mazzanti Stellan Mörner Carlo Napolitano Kimie Ohkubo Michael Papadakis Boris Rudic Maria Sabater Molina Frédéric Sacher Hatice Sahin Georgia Sarquella-Brugada Regina Sebastiano Sanjay Sharma Mary N Sheppard Keiko Shimamoto M Benjamin Shoemaker Birgit Stallmeyer Johannes Steinfurt Yuji Tanaka David J Tester Keisuke Usuda Paul A van der Zwaag Sonia Van Dooren Lut Van Laer Annika Winbo Bo G Winkel Kenichiro Yamagata Sven Zumhagen Paul G A Volders Steven A Lubitz Charles Antzelevitch Pyotr G Platonov Katja E Odening Dan M Roden Jason D Roberts Jonathan R Skinner Jacob Tfelt-Hansen Maarten P van den Berg Morten S Olesen Pier D Lambiase Martin Borggrefe Kenshi Hayashi Annika Rydberg Tadashi Nakajima Masao Yoshinaga Johan B Saenen Stefan Kääb Pedro Brugada Tomas Robyns Daniela F Giachino Michael J Ackerman Ramon Brugada Josep Brugada Juan R Gimeno Can Hasdemir Pascale Guicheney Silvia G Priori Eric Schulze-Bahr Naomasa Makita Peter J Schwartz Wataru Shimizu Takeshi Aiba Jean-Jacques Schott Richard Redon Seiko Ohno Vincent Probst Elijah R Behr Julien Barc Connie R Bezzina

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

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 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Diabetes and the Risk of Sudden Cardiac Death.

Curr Cardiol Rep 2020 Aug 8;22(10):112. Epub 2020 Aug 8.

The Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshospitalet, Section 2142, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.

Purpose Of Review: Persons with diabetes mellitus (DM) have increased morbidity and mortality rates compared with persons without DM. Sudden cardiac death (SCD) is a leading cause of death, and multiple studies have found an increased risk of SCD among individuals with DM. This review sought to collect the latest knowledge of the epidemiological and pathophysiological interplay between DM and SCD.

Recent Findings: Persons with DM have a two- to tenfold increased risk of SCD compared with persons without DM. The underlying mechanisms for the increased risk of SCD are complex and multifactorial. The main pathophysiological contributors are DM-induced cardiac autonomic neuropathy (CAN), metabolic changes, silent ischemia, and polypharmacy. Persons with DM have an increased risk of SCD. Future studies should focus on CAN and the combined risk of QT prolongation from the interplay between CAN, hypoglycemia, and polypharmacy. Genes and pathways involved in control of the autonomic nervous system and cardiac ion channels could be a future focal point.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11886-020-01366-2DOI Listing
August 2020

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand.

Heart Rhythm 2020 Dec 30;17(12):2145-2153. Epub 2020 Jun 30.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Pacific Rim Electrophysiology Research Institute, Bumrungrad Hospital, Bangkok, Thailand.

Background: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model.

Objective: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.

Methods: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants.

Results: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3).

Conclusion: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2020.06.027DOI Listing
December 2020

Diagnostic yield and long-term outcome of nonischemic sudden cardiac arrest survivors and their relatives: Results from a tertiary referral center.

Heart Rhythm 2020 Oct 29;17(10):1679-1686. Epub 2020 Jun 29.

Department of Cardiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.

Background: Cardiac arrest may be the first manifestation of most inherited cardiac diseases. International guidelines recommend screening of relatives of sudden cardiac arrest (SCA) survivors if an inherited cardiac disorder is suspected.

Objective: The purpose of this study was to assess the prevalence and spectrum of inherited cardiac diseases and the long-term outcome in a consecutive cohort of nonischemic SCA survivors (probands) and their relatives.

Methods: This retrospective study consecutively included probands and their relatives referred to our tertiary center for family screening between 2005 and 2018. All participants underwent a systematic workup and follow-up protocol. Data were retrieved from medical records.

Results: We included 155 probands (age 41.2 ± 15.5 years; 61% male) and 282 relatives (age 35.7 ± 18.8 years; 51% male). Mean follow-up was 7.1 years for probands and 4.4 years for relatives. We identified an inherited cardiac disease in 76 (49%) probands and 42 (15%) relatives. An implantable cardioverter-defibrillator was inserted in 147 (95%) probands and 9 (3%) relatives. During follow-up, 4 (3%) probands and 3 (1%) relatives died, and 37 probands and 2 relatives received appropriate shock therapy. All relatives received genetic counseling, and 18 (6%) relatives started pharmacologic treatment during follow-up.

Conclusion: Systematic workup of nonischemic SCA survivors and their relatives identified an inherited cardiac disease in 49% of referred probands and 15% of their relatives. The favorable long-term prognosis of diagnosed relatives probably not only reflects lower age but also the effects of early diagnosis, treatment, and follow-up. These findings support systematic workup of SCA survivors and their relatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2020.06.030DOI Listing
October 2020

Diagnostic findings and follow-up outcomes in relatives to young non-autopsied sudden death victims.

Int J Cardiol 2020 Nov 20;318:61-66. Epub 2020 Jun 20.

The Clinic for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark.

Background: Guidelines recommend clinical assessment of relatives to young sudden cardiac death (SCD) victims in case the SCD was due to an inherited cardiac disorder. Work-up of relatives is guided by findings in the SCD victim. If post-mortem examinations have not been performed the work-up of relatives is challenged.

Method: In this retrospective study we included families referred to our tertiary referral centre between 2005 and 2018 due to a possible SCD (pSCD) in the family. Autopsy had not been performed in any of the pSCD victims. The relatives underwent cardiac work-up focusing on putative presence of inherited cardiac disorders and genetic analysis in selected cases. A family diagnosis was only established if≥1 relative was diagnosed. The families were categorised as: 1) definite inherited cardiac diagnosis, 2) borderline diagnosis, or 3) undiagnosed.

Results: We assessed 149 relatives (43 ± 16 years, 48% men) from 84 pSCD non-autopsied cases (44 ± 11 years, 79% men). In 11 (13%) families a definite inherited cardiac diagnosis was established, a borderline diagnosis in 8 (10%) families, and 65 (77%) families remained undiagnosed. One third of the diagnosed relatives were offered pharmaco- or device-based therapy. During follow-up for 4.7 ± 3.6 years no relatives from the families with definite diagnoses died. No events were seen in the groups with borderline or no diagnoses.

Conclusion: The diagnostic yield and need for treatment in diagnosed relatives warrant work-up, also of families with non-autopsied pSCD victims. No or reduced follow-up of relatives without signs or symptoms of heart diseases may be safe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.06.012DOI Listing
November 2020

Detection of atrial fibrillation with implantable loop recorders in horses.

Equine Vet J 2021 Mar 28;53(2):397-403. Epub 2020 Jun 28.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Cardiac arrhythmias in horses are diagnosed by auscultation or electrocardiogram (ECG), which results in a low sensitivity for detecting arrhythmias that occur sporadically. Implantable loop recorders (ILRs) are small ECG devices placed subcutaneously, to automatically detect arrhythmias in human patients.

Objectives: To test ILRs ability to detect atrial fibrillation (AF) in horses. Furthermore, we hypothesised that anatomical location of the implant site might influence signal quality. Signal quality was evaluated both during exercise and over time.

Study Design: Experimental study.

Methods: In five Standardbred mares, eleven ILRs were implanted subcutaneously in up to three different positions (Front: pectoral region, Left-6: sixth left intercostal space and Ventral: xiphoid region) and AF induced. The R- and T-wave amplitudes were measured in all positions over time during AF. AF burden automatically registered by the ILRs over a 2-month period was compared with selected Holter ECG recordings.

Results: All three positions had stable R- and T-wave amplitudes during the study period and were of sufficient quality to allow AF detection at rest. The position Left-6 showed significantly higher R- and T-wave amplitudes compared with the other positions. During submaximal exercise only the Left-6 position was able to record ECG signals of diagnostic quality. No position yielded diagnostic signals at maximum exercise due to artefacts.

Main Limitations: Few horses and ILRs included and no spontaneous AF episodes were studied.

Conclusions: This preliminary study indicates that ILRs can be used for AF detection in horses, but the anatomical location is important for optimal ECG quality. Despite insufficient quality during exercise, ILRs were suitable for AF detection at rest. Therefore, the ILR may be a valuable diagnostic tool for detecting paroxysmal AF in horses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/evj.13301DOI Listing
March 2021

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Authors:
Najim Lahrouchi Rafik Tadros Lia Crotti Yuka Mizusawa Pieter G Postema Leander Beekman Roddy Walsh Kanae Hasegawa Julien Barc Marko Ernsting Kari L Turkowski Andrea Mazzanti Britt M Beckmann Keiko Shimamoto Ulla-Britt Diamant Yanushi D Wijeyeratne Yu Kucho Tomas Robyns Taisuke Ishikawa Elena Arbelo Michael Christiansen Annika Winbo Reza Jabbari Steven A Lubitz Johannes Steinfurt Boris Rudic Bart Loeys M Ben Shoemaker Peter E Weeke Ryan Pfeiffer Brianna Davies Antoine Andorin Nynke Hofman Federica Dagradi Matteo Pedrazzini David J Tester J Martijn Bos Georgia Sarquella-Brugada Óscar Campuzano Pyotr G Platonov Birgit Stallmeyer Sven Zumhagen Eline A Nannenberg Jan H Veldink Leonard H van den Berg Ammar Al-Chalabi Christopher E Shaw Pamela J Shaw Karen E Morrison Peter M Andersen Martina Müller-Nurasyid Daniele Cusi Cristina Barlassina Pilar Galan Mark Lathrop Markus Munter Thomas Werge Marta Ribasés Tin Aung Chiea C Khor Mineo Ozaki Peter Lichtner Thomas Meitinger J Peter van Tintelen Yvonne Hoedemaekers Isabelle Denjoy Antoine Leenhardt Carlo Napolitano Wataru Shimizu Jean-Jacques Schott Jean-Baptiste Gourraud Takeru Makiyama Seiko Ohno Hideki Itoh Andrew D Krahn Charles Antzelevitch Dan M Roden Johan Saenen Martin Borggrefe Katja E Odening Patrick T Ellinor Jacob Tfelt-Hansen Jonathan R Skinner Maarten P van den Berg Morten Salling Olesen Josep Brugada Ramón Brugada Naomasa Makita Jeroen Breckpot Masao Yoshinaga Elijah R Behr Annika Rydberg Takeshi Aiba Stefan Kääb Silvia G Priori Pascale Guicheney Hanno L Tan Christopher Newton-Cheh Michael J Ackerman Peter J Schwartz Eric Schulze-Bahr Vincent Probst Minoru Horie Arthur A Wilde Michael W T Tanck Connie R Bezzina

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.).

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 (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). 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 (<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 (<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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Genome-wide association studies of cardiac electrical phenotypes.

Cardiovasc Res 2020 Jul;116(9):1620-1634

Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

The genetic basis of cardiac electrical phenotypes has in the last 25 years been the subject of intense investigation. While in the first years, such efforts were dominated by the study of familial arrhythmia syndromes, in recent years, large consortia of investigators have successfully pursued genome-wide association studies (GWAS) for the identification of single-nucleotide polymorphisms that govern inter-individual variability in electrocardiographic parameters in the general population. We here provide a review of GWAS conducted on cardiac electrical phenotypes in the last 14 years and discuss the implications of these discoveries for our understanding of the genetic basis of disease susceptibility and variability in disease severity. Furthermore, we review functional follow-up studies that have been conducted on GWAS loci associated with cardiac electrical phenotypes and highlight the challenges and opportunities offered by such studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341169PMC
July 2020

Diagnostic yield in victims of sudden cardiac death and their relatives.

Europace 2020 06;22(6):964-971

Department of Cardiology, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Aims: International guidelines recommend cardiogenetic screening in families with sudden cardiac death (SCD) if the suspected cause is an inherited cardiac disease. The aim was to assess the diagnostic yield of inherited cardiac diseases in consecutively referred SCD families.

Methods And Results: In this single-centre retrospective study, we consecutively included families referred to our tertiary unit between 2005 and 2018 for screening due to SCD. Following evaluation of premortem medical records and postmortem findings for the proband, the families underwent a guideline-based screening protocol. Relatives were followed and cardiovascular events registered. In total, 304 families with 695 relatives were included. In probands, mean age at death was 39 years (75% males) and in relatives mean age at screening was 35 years (47% males). The proband-diagnosis was established through autopsy findings (n = 89), genetic analyses (n = 7), or based on premortem findings (n = 21). In the remaining 187 families with borderline/no diagnosis in the proband, screening of relatives yielded a diagnosis in 26 additional families. In total, an inherited cardiac disease was identified in 143 out of 304 families (47%). In relatives, 73 (11%) were diagnosed. Arrhythmogenic right ventricular cardiomyopathy (n = 16) was the most common diagnosis. During follow-up (mean 5.5 years), a low rate of serious cardiac events was observed (no SCD events).

Conclusion: Forty-seven percent of SCD families were diagnosed. Eleven percent of the screened relatives received a definite diagnosis and were offered treatment according to guidelines. A low rate of serious cardiovascular events was observed among SCD relatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa056DOI Listing
June 2020

Sibling history is associated with heart failure after a first myocardial infarction.

Open Heart 2020 24;7(1):e001143. Epub 2020 Mar 24.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: Morbidity and mortality due to heart failure (HF) as a complication of myocardial infarction (MI) is high, and remains among the leading causes of death and hospitalisation. This study investigated the association between family history of MI with or without HF, and the risk of developing HF after first MI.

Methods: Through nationwide registries, we identified all individuals aged 18-50 years hospitalised with first MI from 1997 to 2016 in Denmark. We identified 13 810 patients with MI, and the cohort was followed until HF diagnosis, second MI, 3 years after index MI, emigration, death or the end of 2016, whichever occurred first. HRs were estimated by Cox hazard regression models adjusted for sex, age, calendar year and comorbidities (reference: patients with no family history of MI).

Results: After adjustment, we observed an increased risk of MI-induced HF for those having a sibling with MI with HF (HR 2.05, 95% CI 1.02 to 4.12). Those having a sibling with MI without HF also had a significant, but lower increased risk of HF (HR 1.39, 95% CI 1.05 to 1.84). Parental history of MI with or without HF was not associated with HF.

Conclusion: In this nationwide cohort, sibling history of MI with or without HF was associated with increased risk of HF after first MI, while a parental family history was not, suggesting that shared environmental factors may predominate in the determination of risk for developing HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2019-001143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103809PMC
June 2020

Defibrillators for prevention from sudden cardiac death: is it that easy?-Authors' reply.

Europace 2020 08;22(8):1298-1299

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa058DOI Listing
August 2020

Effect of the antipsychotic drug haloperidol on arrhythmias during acute myocardial infarction in a porcine model.

Int J Cardiol Heart Vasc 2020 Feb 30;26:100455. Epub 2019 Dec 30.

Department of Cardiology, Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Patients receiving psychiatric medication, like the antipsychotic drug haloperidol, are at an increased risk of sudden cardiac death (SCD). Haloperidol blocks the cardiac rapidly-activating delayed rectifier potassium current, thereby increasing electrical dispersion of repolarization which can potentially lead to arrhythmias. Whether these patients are also at a higher risk to develop SCD during an acute myocardial infarction (AMI) is unknown. AMI locally shortens action potential duration, which might further increase repolarization dispersion and increase the risk of arrhythmia in the presence of haloperidol compared to without. Our aim was to test whether treatment with haloperidol implies an increased risk of SCD when eventually experiencing AMI. Twenty-eight female Danish Landrace pigs were randomized into three groups: low dose haloperidol (0.1 mg/kg), high dose (1.0 mg/kg) or vehicle-control group. One hour after haloperidol/vehicle infusion, AMI was induced by balloon-occlusion of the mid-left anterior descending coronary artery and maintained for 120 min, followed by 60 min of reperfusion. VF occurred during occlusion in 7/11 pigs in the control group, 3/11 in the low dose (p = 0.198) and 2/6 in the high dose group (p = 0.335). High dose haloperidol significantly prolonged QT, and reduced heart rate, vascular resistance and blood pressure before and during AMI. Premature ventricular contractions in phase 1b during AMI were reduced with high dose haloperidol. AMI-induced arrhythmia was not aggravated in pigs with haloperidol treatment. Our results do not suggest that AMI is contributing to the excess mortality in patients treated with antipsychotic drugs seen in epidemiological studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2019.100455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046512PMC
February 2020

Seasonality of ventricular fibrillation at first myocardial infarction and association with viral exposure.

PLoS One 2020 26;15(2):e0226936. Epub 2020 Feb 26.

The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Aims: To investigate seasonality and association of increased enterovirus and influenza activity in the community with ventricular fibrillation (VF) risk during first ST-elevation myocardial infarction (STEMI).

Methods: This study comprised all consecutive patients with first STEMI (n = 4,659; aged 18-80 years) admitted to the invasive catheterization laboratory between 2010-2016, at Copenhagen University Hospital, Rigshospitalet, covering eastern Denmark (2.6 million inhabitants, 45% of the Danish population). Hospital admission, prescription, and vital status data were assessed using Danish nationwide registries. We utilized monthly/weekly surveillance data for enterovirus and influenza from the Danish National Microbiology Database (2010-2016) that receives copies of laboratory tests from all Danish departments of clinical microbiology.

Results: Of the 4,659 consecutively enrolled STEMI patients, 581 (12%) had VF before primary percutaneous coronary intervention. In a subset (n = 807), we found that VF patients experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with the patients without VF (OR 3.39, 95% CI 1.76-6.54). During the study period, 2,704 individuals were diagnosed with enterovirus and 19,742 with influenza. No significant association between enterovirus and VF (OR 1.00, 95% CI 0.99-1.02), influenza and VF (OR 1.00, 95% CI 1.00-1.00), or week number and VF (p-value 0.94 for enterovirus and 0.89 for influenza) was found.

Conclusion: We found no clear seasonality of VF during first STEMI. Even though VF patients had experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with patients without VF, no relationship was found between enterovirus or influenza exposure and occurrence of VF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043782PMC
May 2020

Reply: Plasma Processing Is Critically Important When Measuring miRNA in Plasma.

JACC Clin Electrophysiol 2020 02;6(2):244-245

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2019.12.005DOI Listing
February 2020

Potassium Disturbances and Risk of Ventricular Fibrillation Among Patients With ST-Segment-Elevation Myocardial Infarction.

J Am Heart Assoc 2020 02 12;9(4):e014160. Epub 2020 Feb 12.

Department of Cardiology, Rigshospitalet Copenhagen University Hospital Copenhagen Denmark.

Background Potassium disturbances per se increase the risk of ventricular fibrillation (VF). Whether potassium disturbances in the acute phase of ST-segment-elevation myocardial infarction (STEMI) are associated with VF before primary percutaneous coronary intervention (PPCI) is uncertain. Methods and Results All consecutive STEMI patients were identified in the Eastern Danish Heart Registry from 1999 to 2016. Comorbidities and medication use were assessed from Danish nationwide registries. Potassium levels were collected immediately before PPCI start. Multivariate logistic models were performed to determine the association between potassium and VF. The main analysis included 8624 STEMI patients of whom 822 (9.5%) had VF before PPCI. Compared with 6693 (77.6%) patients with normokalemia (3.5-5.0 mmol/L), 1797 (20.8%) patients with hypokalemia (<3.5 mmol/L) were often women with fewer comorbidities, whereas 134 (1.6%) patients with hyperkalemia (>5.0 mmol/L) were older with more comorbidities. After adjustment, patients with hypokalemia and hyperkalemia had a higher risk of VF before PPCI (odds ratio 1.90, 95% CI 1.57-2.30, <0.001) and (odds ratio 3.36, 95% CI 1.95-5.77, <0.001) compared with normokalemia, respectively. Since the association may reflect a post-resuscitation phenomenon, a sensitivity analysis was performed including 7929 STEMI patients without VF before PPCI of whom 127 (1.6%) had VF during PPCI. Compared with normokalemia, patients with hypokalemia had a significant association with VF during PPCI (odds ratio 1.68, 95% CI 1.01-2.77, =0.045) after adjustment. Conclusions Hypokalemia and hyperkalemia are associated with increased risk of VF before PPCI during STEMI. For hypokalemia, the association may be independent of the measurement of potassium before or after VF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.014160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070188PMC
February 2020

Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e007471. Epub 2020 Feb 16.

Department of Clinical and Experimental Cardiology, Heart Center (K.V.V.L., C.v.d.W., N.H., S.-A.B.C., A.A.M.W.), the Netherlands.

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias.

Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1').

Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (=0.045).

Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.119.007471DOI Listing
March 2020

Sudden Cardiac Death in the Young.

Heart Lung Circ 2020 Apr 12;29(4):498-504. Epub 2019 Dec 12.

The Department of Cardiology, The Heart Centre, Copenhagen University, Rigshospitalet, Copenhagen, Denmark; Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Sudden cardiac death (SCD) of a young person is a devastating and tragic ultimate outcome of a collection of cardiac disorders. The death often occurs in people who were thought to be well, by definition is sudden, can occur without prior warning symptoms, and is often the first presentation of an underlying genetic heart disease. Many of the genetic heart diseases are caused by single genetic variants that have a one-in-two chance of being inherited by each first-degree relative. Therefore, the surviving family not only have to deal with the sudden loss of a young family member but are also left with the compounding uncertainty as to whether SCD could strike again in another family member. In recent years, our ability to identify the causes of SCD in the young has improved. Finding a precise genetic cause of death allows cascade genetic testing of family members to identify those who are at risk and facilitate early intervention to prevent another sudden death. Thus, investigations to define the precise cause of SCD of a young person not only bring a level of closure for the family but are also of vital clinical relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hlc.2019.11.007DOI Listing
April 2020

Non-diagnostic autopsy findings in sudden unexplained death victims.

BMC Cardiovasc Disord 2020 02 4;20(1):58. Epub 2020 Feb 4.

Department of Cardiology The Heart Center, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2142, 2100, Copenhagen, Denmark.

Background: Several inherited cardiac diseases may lead to sudden cardiac death (SCD) a devastating event in the families. It is crucial to establish a post mortem diagnosis to facilitate relevant work-up and treatment of family members. Sudden unexplained death (SUD) victims constitute roughly one third of all SCD cases in Denmark.

Methods: This was a single center, retrospective study investigating SUD cases. Victims who died unexplained due to suspected or confirmed cardiac disease were consecutively referred to a third line referral center established in 2005. All autopsy reports were investigated. Victims were divided into two groups: non-diagnostic cardiac findings and normal cardiac findings. None of the included victims had findings consistent with a diagnosis based on existing criteria.

Results: In total, 99 SUD cases were referred. The mean age of the victims was 37 years (range 0-62 years, 75% males). A total of 14 (14%) victims had a cardiovascular diagnosis pre-mortem. Thirty-seven cases had normal cardiac findings and non-diagnostic cardiac findings were found in 62 cases (63%). The five most common findings included ventricular hypertrophy and/or enlarged heart (n = 35, 35%), coronary atheromatosis (n = 31, 31%), myocardial fibrosis (n = 19, 19%), dilated chambers (n = 7, 7%) and myocardial inflammation (n = 5, 5%).

Conclusion: One third of SUD victims had normal cardiac findings and non-diagnostic cardiac findings were seen in almost two thirds of the SUD victims. These non-diagnostic findings may be precursors or early markers for underlying structural cardiac disorders or may be innocent bystanders in some cases. Further studies and improved post-mortem examination methods are needed for optimization of diagnostics in SUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12872-020-01361-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001247PMC
February 2020

Symptoms and healthcare contact preceding sudden cardiac death in persons aged 1-49 years.

Trends Cardiovasc Med 2021 Feb 15;31(2):119-124. Epub 2020 Jan 15.

The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Section 2142, Blegdamsvej 9, 2100 Copenhagen, Denmark; Department of Medicine and Surgery, University of Copenhagen, Copenhagen, Denmark.

Sudden Cardiac Death (SCD) is a leading cause of death among persons in their youth and early middle-age. To prevent SCD it is crucial to identify persons at high-risk of SCD. Knowledge of symptoms and medical contact prior to SCD could potentially aid in the identification of high-risk persons in the general population who would benefit from further investigation. This review aims to summarize the current knowledge of symptoms and healthcare contact preceding SCD in persons aged 1-49 years, and to explore how the symptoms differ according to SCD cause and age of the deceased. There was a high frequency of both cardiac and non-specific symptoms prior to SCD. Additionally, many SCD victims contacted the healthcare system prior to death on the basis of their symptoms and only a few were diagnosed with cardiovascular disease. This information underlines that young persons reporting potential cardiac symptoms should also be thoroughly examined. Furthermore, such symptoms could be used in combination with other easily accessible information in non-invasive prediction models aiming at identifying persons at high risk of SCD that would benefit from further investigation and possibly treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcm.2020.01.003DOI Listing
February 2021

Circulating miRNAs and Risk of Sudden Death in Patients With Coronary Heart Disease.

JACC Clin Electrophysiol 2020 01 30;6(1):70-79. Epub 2019 Oct 30.

Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study evaluated whether plasma miRNAs were specifically associated with sudden cardiac and/or arrhythmic death (SCD) in a cohort of patients with coronary heart disease (CHD), most of whom were without primary prevention implantable cardioverter-defibrillators.

Background: Novel biomarkers for sudden death risk stratification are needed in patients with CHD to more precisely target preventive therapies, such as implantable cardioverter-defibrillators. miRNAs have been implicated in regulating inflammation and cardiac fibrosis in cells, and plasma miRNAs have been shown to predict cardiovascular death in patients with CHD.

Methods: We performed a nested case control study within a multicenter cohort of 5,956 patients with CHD followed prospectively for SCD. Plasma levels of 18 candidate miRNAs previously associated with cardiac remodeling were measured in 129 SCD cases and 258 control subjects matched on age, sex, race, and left ventricular ejection fraction.

Results: miR-150-5p, miR-29a-3p, and miR-30a-5p were associated with increased SCD risk (odds ratios and 95% confidence intervals: 2.03 [1.12 to 3.67]; p = 0.02; 1.93 [1.07 to 3.50]; p = 0.02; 0.55 [0.31 to 0.97]; p = 0.04, respectively, for third vs. first tertile miRNA level). Unfavorable levels of all 3 miRNAs was associated with a 4.8-fold increased SCD risk (1.59 to 14.51; p = 0.006). A bioinformatics-based approach predicted miR-150-5p, miR-29a-3p, and miR-30a-5p to be involved in apoptosis, fibrosis, and inflammation.

Conclusions: These findings suggest that plasma miRNAs may regulate pathways important for remodeling and may be useful in identifying patients with CHD at increased risk of SCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981228PMC
January 2020

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Circulation 2020 02 16;141(6):429-439. Epub 2020 Jan 16.

Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (M.B., J.R.G., M.J.A.).

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare variants implicated in LQT5 was sought through an international multicenter collaboration.

Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.

Results: A total of 32 distinct rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], =0.590). The cumulative prevalence of the 32 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).

Conclusions: The present study suggests that putative/confirmed loss-of-function variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035205PMC
February 2020