ABSTRACT
Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.
Subject(s)
Genome-Wide Association Study , Proteins , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans , Polymorphism, Single Nucleotide/genetics , Proteins/genetics , Exome SequencingABSTRACT
Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in combination, are the most frequent, but underestimated, causes of SCD. Molecular autopsy is essential for prevention. Several studies have shown an association between genetic cardiomyopathies and viral myocarditis, which is probably underestimated due to insufficient post-mortem investigations. We report on four autopsy cases illustrating the pathogenesis of these combined pathologies. In two cases, a genetic hypertrophic cardiomyopathy was diagnosed in combination with Herpes Virus Type 6 (HHV6) and/or Parvovirus-B19 (PVB19) in the heart. In the third case, autopsy revealed a dilated cardiomyopathy and virological analyses revealed acute myocarditis caused by three viruses: PVB19, HHV6 and Epstein-Barr virus. Genetic analyses revealed a mutation in the gene coding for desmin. The fourth case illustrated a channelopathy and a PVB19/HHV6 coinfection. Our four cases illustrate the highly probable deleterious role of cardiotropic viruses in the occurrence of SCD in subjects with genetic cardiomyopathies. We discuss the pathogenetic link between viral myocarditis and genetic cardiomyopathy. Molecular autopsy is essential in prevention of these SCD, and a close collaboration between cardiologists, pathologists, microbiologists and geneticians is mandatory.
Subject(s)
Autopsy , Death, Sudden, Cardiac , Herpesvirus 6, Human , Myocarditis , Parvovirus B19, Human , Adult , Female , Humans , Male , Middle Aged , Young Adult , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/virology , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/pathology , Cause of Death , Coinfection , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/pathology , Death, Sudden, Cardiac/prevention & control , Epstein-Barr Virus Infections/complications , Fatal Outcome , Genetic Predisposition to Disease , Herpesvirus 4, Human/genetics , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Mutation , Myocarditis/virology , Myocarditis/pathology , Myocarditis/genetics , Parvoviridae Infections/complications , Parvovirus B19, Human/genetics , Roseolovirus Infections/complications , Roseolovirus Infections/virology , Roseolovirus Infections/diagnosis , Roseolovirus Infections/pathologyABSTRACT
The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria. The classical paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces, reflected in the augmented QRS amplitude. However, the low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm. The theoretical background for voltage measured at the body surface is defined by the solid angle theorem, which relates the measured voltage to spatial and non-spatial determinants. The spatial determinants are represented by the extent of the activation front and the distance of the recording electrodes. The non-spatial determinants comprise electrical characteristics of the myocardium, which are comparatively neglected in the interpretation of the QRS patterns. Various clinical conditions are associated with LVH. These conditions produce considerable diversity of electrical properties alterations thereby modifying the resultant QRS patterns. The spectrum of QRS patterns observed in LVH patients is quite broad, including also left axis deviation, left anterior fascicular block, incomplete and complete left bundle branch blocks, Q waves, and fragmented QRS. Importantly, the QRS complex can be within normal limits. The new paradigm stresses the electrophysiological background in interpreting QRS changes, i.e., the effect of the non-spatial determinants. This postulates that the role of ECG is not to estimate LV size in LVH, but to understand and decode the underlying electrical processes, which are crucial in relation to cardiovascular risk assessment.
Subject(s)
Heart Conduction System , Hypertrophy, Left Ventricular , Humans , Hypertrophy, Left Ventricular/diagnosis , Electrocardiography , Arrhythmias, Cardiac , Bundle-Branch BlockABSTRACT
In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.
Subject(s)
Cardiomyopathies , Channelopathies , Humans , Channelopathies/diagnosis , Channelopathies/genetics , Channelopathies/therapy , Genome-Wide Association Study , Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Cardiomyopathies/therapy , Cognition , High-Throughput Nucleotide SequencingABSTRACT
AIMS: Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. METHODS AND RESULTS: The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16-0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. CONCLUSION: Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300.
Subject(s)
Myocardial Infarction , ST Elevation Myocardial Infarction , Humans , Ventricular Fibrillation/diagnosis , Ventricular Fibrillation/genetics , Ventricular Fibrillation/complications , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/genetics , ST Elevation Myocardial Infarction/complications , Connexin 43/genetics , Prospective Studies , Stroke Volume , Ventricular Function, Left , Myocardial Infarction/complications , Myocardial Infarction/diagnosis , Myocardial Infarction/genetics , Risk FactorsABSTRACT
AIMS: Climate change represents the biggest global health threat of the 21st century. Health care system is itself a large contributor to greenhouse gas (GHG) emissions. In cardiology, atrial fibrillation (AF) catheter ablation is an increasing activity using numerous non-reusable materials that could contribute to GHG emission. Determining a detailed carbon footprint analysis of an AF catheter ablation procedure allows the identification of the main polluting sources that give opportunities for reduction of environmental impact. To assess the carbon footprint of AF catheter ablation procedure. To determine priority actions to decrease pollution. METHODS AND RESULTS: An eco-audit method used to predict the GHG emission of an AF catheter ablation procedure was investigated. Two workstations were considered including surgery and anaesthesia. In the operating room, every waste produced by single-use medical devices, pharmaceutical drugs, and energy consumption during intervention were evaluated. All analyses were limited to the operating room. Thirty procedures were analysed over a period of 8 weeks: 18 pulmonary veins isolation RF ablations, 7 complex RF procedures including PVI, roof and mitral isthmus lines, ethanol infusion of the Marshall vein and cavo tricuspid isthmus line, and 5 pulmonary vein isolation with cryoballoon. The mean emission during AF catheter ablation procedures was 76.9 kg of carbon dioxide equivalent (CO2-e). The operating field accounted for 75.4% of the carbon footprint, while only 24.6% for the anaesthesia workstation. On one hand, material production and manufacturing were the most polluting phases of product life cycle which, respectively, represented 71.3% (54.8 kg of CO2-e) and 17.0% (13.1 kg of CO2-e) of total pollution. On the other hand, transport contributed in 10.6% (8.1 kg of CO2-e), while product use resulted in 1.1% (0.9 kg of CO2-e) of GHG production. Electrophysiology catheters were demonstrated to be the main contributors of environmental impact with 29.9 kg of CO2-e (i.e. 38.8%). Three dimensional mapping system and electrocardiogram patches were accounting for 6.8 kg of CO2-e (i.e. 8.8% of total). CONCLUSION: AF catheter ablation involves a mean of 76.9 kg of CO2-e. With an estimated 600 000 annual worldwide procedures, the environmental impact of AF catheter ablation activity is estimated equal to 125 tons of CO2 emission each day. It represents an equivalent of 700 000 km of car ride every day. Electrophysiology catheters and patches are the main contributors of the carbon footprint. The focus must be on reducing, reusing, and recycling these items to limit the impact of AF ablation on the environment. A road map of steps to implement in different time frames is proposed.
Subject(s)
Ablation Techniques , Atrial Fibrillation , Catheter Ablation , Pulmonary Veins , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/surgery , Carbon Footprint , Carbon Dioxide , Pulmonary Veins/surgery , Catheter Ablation/methods , Treatment OutcomeABSTRACT
The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria, i.e. the increased QRS complex amplitude in defined leads. The classical ECG diagnostic paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces. These increased forces are reflected in the augmented QRS amplitude in the corresponding leads. However, the clinical observations document increased QRS amplitude only in the minority of patients with LVH. The low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm.
Subject(s)
Electrocardiography, Ambulatory , Hypertrophy, Left Ventricular , Humans , Hypertrophy, Left Ventricular/diagnosis , Electrocardiography , Heart Conduction SystemABSTRACT
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.
Subject(s)
Arrhythmogenic Right Ventricular Dysplasia , Defibrillators, Implantable , Arrhythmias, Cardiac/etiology , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/therapy , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Defibrillators, Implantable/adverse effects , Humans , Retrospective Studies , Risk FactorsABSTRACT
The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses, which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechanoelectric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here, we demonstrate that the mechanosensitive ion channel PIEZO1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging PIEZO1 activation in zebrafish results in cardiac arrhythmias. indicating that this ion channel plays an important role in mechanoelectric feedback. This also raises the possibility that PIEZO1 gain of function mutations could be linked to heritable cardiac arrhythmias in humans.
Subject(s)
Arrhythmias, Cardiac , Ion Channels , Animals , Humans , Arrhythmias, Cardiac/genetics , Cardiac Conduction System Disease , Ion Channels/genetics , Ion Channels/metabolism , Mechanotransduction, Cellular/physiology , Myocytes, Cardiac/metabolism , Zebrafish/metabolism , Zebrafish Proteins/geneticsABSTRACT
Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.
Subject(s)
Cardiovascular Diseases/genetics , Channelopathies/genetics , Female , Humans , Male , Sex FactorsABSTRACT
MOTIVATION: Cardiomyocytes derived from stem cells are closely followed, notably since the discovery in 2007 of human induced pluripotent stem cells (hiPSC). Cardiomyocytes (hiPSC-CM) derived from hiPSC are indeed more and more used to study specific cardiac diseases as well as for developing novel applications such as drug safety experiments. Robust dedicated tools to characterize hiPSC-CM are now required. The hiPSC-CM morphology constitutes an important parameter since these cells do not demonstrate the expected rod shape, characteristic of native human cardiomyocytes. Similarly, the presence, the density and the organization of contractile structures would be a valuable parameter to study. Precise measurements of such characteristics would be useful in many situations: for describing pathological conditions, for pharmacological screens or even for studies focused on the hiPSC-CM maturation process. RESULTS: For this purpose, we developed a MATLAB based image analysis toolbox, which gives accurate values for cellular morphology parameters as well as for the contractile cell organization. AVAILABILITY AND IMPLEMENTATION: To demonstrate the power of this automated image analysis, we used a commercial maturation medium intended to promote the maturation status of hiPSC-CM, and compare the parameters with the ones obtained with standard culture medium, and with freshly dissociated mouse cardiomyocytes. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Induced Pluripotent Stem Cells , Myocytes, Cardiac , Humans , Animals , Mice , Cells, CulturedABSTRACT
AIMS: We aimed to provide contemporary real-world data on wearable cardioverter-defibrillator (WCD) use, not only in terms of effectiveness and safety but also compliance and acceptability. METHODS AND RESULTS: Across 88 French centres, the WEARIT-France study enrolled retrospectively patients who used the WCD between May 2014 and December 2016, and prospectively all patients equipped for WCD therapy between January 2017 and March 2018. All patients received systematic education session through a standardized programme across France at the time of initiation of WCD therapy and were systematically enrolled in the LifeVest Network remote services. Overall, 1157 patients were included (mean age 60 ± 12 years, 16% women; 46% prospectively): 82.1% with ischaemic cardiomyopathy, 10.3% after implantable cardioverter-defibrillator explant, and 7.6% before heart transplantation. Median WCD usage period was 62 (37-97) days. Median daily wear time of WCD was 23.4 (22.2-23.8) h. In multivariate analysis, younger age was associated with lower compliance [adjusted odds ratio (OR) 0.97, 95% confidence interval (CI) 0.95-0.99, P < 0.01]. A total of 18 participants (1.6%) received at least one appropriate shock, giving an incidence of appropriate therapy of 7.2 per 100 patient-years. Patient-response button allowed the shock to be aborted in 35.7% of well-tolerated sustained ventricular arrhythmias and in 95.4% of inappropriate ventricular arrhythmia detection, finally resulting in an inappropriate therapy in eight patients (0.7%). CONCLUSION: Our real-life findings reinforce previous studies on the efficacy and safety of the WCD in the setting of transient high-risk group in selected patients. Moreover, they emphasize the fact that when prescribed appropriately, in concert with adequate patient education and dedicated follow-up using specific remote monitoring system, compliance with WCD is high and the device well-tolerated by the patient.
Subject(s)
Defibrillators, Implantable , Wearable Electronic Devices , Aged , Cohort Studies , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/prevention & control , Defibrillators , Electric Countershock , Female , France/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. METHODS: The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease's clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. DISCUSSION: After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 ).
Subject(s)
Arrhythmias, Cardiac/genetics , Cardiomyopathies/genetics , Exercise , Quality of Life/psychology , Adolescent , Arrhythmias, Cardiac/psychology , Cardiomyopathies/psychology , Child , Death, Sudden, Cardiac , Exercise/physiology , Exercise/psychology , Female , Humans , Male , Oxygen , Oxygen Consumption , Prospective StudiesABSTRACT
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy-causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , High-Throughput Nucleotide Sequencing , Aged , Alleles , Alternative Splicing , Exons , Female , Gene Expression , Genes, Reporter , Genetic Association Studies , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing/methods , Humans , Introns , Male , Middle Aged , Molecular Diagnostic Techniques , Mutation , Pedigree , RNA Splice SitesABSTRACT
BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.
Subject(s)
Cardiomyopathies/complications , Defibrillators, Implantable/adverse effects , Tachycardia, Ventricular/etiology , Adult , Female , Humans , Male , Tachycardia, Ventricular/pathology , Validation Studies as TopicABSTRACT
OBJECTIVES: To determine the prognostic value of a low T/R ratio, defined as the amplitude ratio between the T waves and the R waves, in patients (pts) with a spontaneous type-1 Brugada pattern (SBT1). BACKGROUND: Abnormalities of myocardial repolarization may play a key role in the initiation of ventricular fibrillation (VF) in Brugada syndrome (BrS). Recent studies have shown that the height of the T waves and the T/R ratio are inversely proportional to sudden cardiac arrest (SCA) risk in early repolarization syndrome and hypertrophic cardiomyopathy. METHODS: In an international retrospective study, we reviewed 115 pts. (105 males, 91.3%). 45 had VF and/or SCA (38.7⯱â¯11.5â¯years old, all males), while 70 (49.3⯱â¯12.0â¯years, 10 women) remained free of ventricular arrhythmia. 6 ECG markers plus the T/R ratio in leads V5 & II were studied. RESULTS: The T/R ratio among leads II & V5 was significantly lower in the VF/SCA group (0.24 [0.14; 0.38]vs. 0.34 [0.24; 0.45]; pâ¯=â¯0.006). 44.4% of pts. in the VF/SCA group had a lowest T/R ratio among leads II & V5â¯≤â¯0.17 compared to 11.4% in the non-VF/SCA group (pâ¯<â¯0.001). In multivariate analysis, a lowest T/R ratio among leads II & V5â¯≤â¯0.17 was independently associated with VF/SCA (OR 6.10, 95% CI 1.92-19.40; pâ¯=â¯0.002). Type 1 Brugada pattern in the peripheral leads (OR 10.78) and early repolarization (OR 3.60) were other independent markers of VF/SCA. CONCLUSION: A low T/R ratio among leads II & V5 is an independent marker for VF/SCA risk in patients with type-1 Brugada pattern.
Subject(s)
Brugada Syndrome , Adult , Brugada Syndrome/diagnosis , Electrocardiography , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Ventricular Fibrillation/diagnosisABSTRACT
AIMS: There is currently no reliable tool to quantify the risks of ventricular fibrillation or sudden cardiac arrest (VF/SCA) in patients with spontaneous Brugada type 1 pattern (BrT1). Previous studies showed that electrocardiographic (ECG) markers of depolarization or repolarization disorders might indicate elevated risk. We aimed to design a VF/SCA risk prediction model based on ECG analyses for adult patients with spontaneous BrT1. METHODS AND RESULTS: This retrospective multicentre international study analysed ECG data from 115 patients (mean age 45.1 ± 12.8 years, 105 males) with spontaneous BrT1. Of these, 45 patients had experienced VF/SCA and 70 patients did not experience VF/SCA. Among 10 ECG markers, a univariate analysis showed significant associations between VF/SCA and maximum corrected Tpeak-Tend intervals ≥100 ms in precordial leads (LMaxTpec) (P < 0.001), BrT1 in a peripheral lead (pT1) (P = 0.004), early repolarization in inferolateral leads (ER) (P < 0.001), and QRS duration ≥120 ms in lead V2 (P = 0.002). The Cox multivariate analysis revealed four predictors of VF/SCA: the LMaxTpec [hazard ratio (HR) 8.3, 95% confidence interval (CI) 2.4-28.5; P < 0.001], LMaxTpec + ER (HR 14.9, 95% CI 4.2-53.1; P < 0.001), LMaxTpec + pT1 (HR 17.2, 95% CI 4.1-72; P < 0.001), and LMaxTpec + pT1 + ER (HR 23.5, 95% CI 6-93; P < 0.001). Our multidimensional penalized spline model predicted the 1-year risk of VF/SCA, based on age and these markers. CONCLUSION: LMaxTpec and its association with pT1 and/or ER indicated elevated VF/SCA risk in adult patients with spontaneous BrT1. We successfully developed a simple risk prediction model based on age and these ECG markers.
Subject(s)
Brugada Syndrome/physiopathology , Death, Sudden, Cardiac/epidemiology , Electrocardiography , Ventricular Fibrillation/epidemiology , Adult , Age Factors , Brugada Syndrome/complications , Death, Sudden, Cardiac/etiology , Female , Humans , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Risk Factors , Ventricular Fibrillation/etiologyABSTRACT
Aims: Cardiac atrial arrhythmias are the most common type of heart rhythm disorders. Its genetic elucidation remains challenging with poor understanding of cellular and molecular processes. These arrhythmias usually affect elderly population but in rare cases, young children may also suffer from such electrical diseases. Severe complications, including stroke, are commonly age related. This study aims to identify a genetic link between electro-mechanic atrial dysfunction and stroke in children. Methods and results: In two unrelated boys of 11 and 14 years with both stroke and atrial arrhythmias, the clinical phenotype was determined through a complete physical examination, electrocardiogram (ECG), Holter ECG, and computed tomography. The genetic testing was performed on a large 95 genes panel implicated in myocardial electrical imbalance, using the next generation sequencing method. The panel also includes the genes usually associated with the development of cardiomyopathies. In one child, a left atrial dilation was observed. The 2nd boy suffered from atrial standstill. Both suffered from atrial bradycardia, flutter, and fibrillation. The complete genetic testing revealed the SCN5A c.3823G>A (p.D1275N) mutation in the first family, c.1141-2A>G and c.3157G>A (p.E1053K) mutations in the second family. Conclusion: Our results strengthen the association between Nav1.5 mutations and the occurrence of stroke in young patients. It emphasizes the need to look for atrial myopathy in the decision process for anticoagulation in young patients with atrial arrhythmic events.
Subject(s)
Atrial Fibrillation/complications , Atrial Flutter/complications , Atrial Function, Left , Bradycardia/complications , Cardiomyopathies/complications , Genetic Diseases, Inborn/complications , Heart Atria/abnormalities , Heart Block/complications , Stroke/etiology , Adolescent , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Atrial Fibrillation/genetics , Atrial Fibrillation/physiopathology , Atrial Flutter/genetics , Atrial Flutter/physiopathology , Bradycardia/genetics , Bradycardia/physiopathology , Cardiomyopathies/genetics , Cardiomyopathies/physiopathology , Child , Electrocardiography , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/physiopathology , Heart Atria/physiopathology , Heart Block/genetics , Heart Block/physiopathology , Humans , Male , Mutation , NAV1.5 Voltage-Gated Sodium Channel/genetics , PhenotypeABSTRACT
BACKGROUND: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. METHODS: A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4). RESULTS: Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current. CONCLUSIONS: This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4-/- mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.