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Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.
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Eletrocardiografia , Humanos , Camundongos , Estudos de Casos e Controles , Masculino , Animais , Feminino , Adulto , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/etiologia , Parada Cardíaca/etiologia , Parada Cardíaca/diagnóstico , Cálcio/metabolismo , Cálcio/sangue , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatologia , Taquicardia Supraventricular/etiologia , Pessoa de Meia-Idade , Modelos Animais de Doenças , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Adolescente , Adulto Jovem , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
BACKGROUND: Abnormal ventricular activation at rest is reported in Brugada syndrome (BrS). OBJECTIVES: The aim of this study was to evaluate the usefulness of dynamic changes in ventricular activation during exercise to improve disease phenotyping and diagnosis of BrS. METHODS: Digital 12-lead electrocardiograms during stress testing were analyzed retrospectively at baseline, peak exercise, and recovery in 53 patients with BrS and 52 controls. Biventricular activation was assessed from QRS duration (QRSd), whereas right ventricular activation was assessed from S wave duration in the lateral leads (I and V6) and terminal R wave duration in aVR. Exercise-induced changes in QRS parameters to predict a positive procainamide response were assessed in separate test and validation cohorts with suspected BrS. RESULTS: Baseline electrocardiogram parameters were similar between BrS and controls. QRSd shortened with exercise in all controls but prolonged in all BrS (-6.1 ± 6.0 ms vs 7.1 ± 6.5 ms [P < 0.001] in V6). QRSd in recovery was longer in BrS compared with controls (90 ± 12 ms vs 82 ± 11 ms in V6; P = 0.002). Both groups demonstrated exercise-induced S duration prolongation in V6, with greater prolongation in BrS (8.2 ± 14.3 ms vs 1.2 ± 12.4 ms; P < 0.001). Any exercise-induced QRSd prolongation in V6 differentiated those with a positive vs negative procainamide response with 100% sensitivity and 95% specificity in the test cohort, and 87% sensitivity and 93% specificity in the validation cohort. CONCLUSIONS: Exercise-induced QRSd prolongation is ubiquitous in BrS primarily owing to delayed right ventricular activation. This electrocardiogram phenotype predicts a positive procainamide response and may provide a noninvasive screening tool to aid in the diagnosis of BrS before drug challenge.
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PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.
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Medicina Baseada em Evidências , Humanos , Medicina Baseada em Evidências/métodos , Testes Genéticos/métodos , Achados Incidentais , Sequenciamento Completo do GenomaRESUMO
A major focus of academia, industry, and global governmental agencies is to develop and apply artificial intelligence and other advanced analytical tools to transform health care delivery. The American Heart Association supports the creation of tools and services that would further the science and practice of precision medicine by enabling more precise approaches to cardiovascular and stroke research, prevention, and care of individuals and populations. Nevertheless, several challenges exist, and few artificial intelligence tools have been shown to improve cardiovascular and stroke care sufficiently to be widely adopted. This scientific statement outlines the current state of the art on the use of artificial intelligence algorithms and data science in the diagnosis, classification, and treatment of cardiovascular disease. It also sets out to advance this mission, focusing on how digital tools and, in particular, artificial intelligence may provide clinical and mechanistic insights, address bias in clinical studies, and facilitate education and implementation science to improve cardiovascular and stroke outcomes. Last, a key objective of this scientific statement is to further the field by identifying best practices, gaps, and challenges for interested stakeholders.
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Doenças Cardiovasculares , Cardiopatias , Acidente Vascular Cerebral , Estados Unidos , Humanos , Inteligência Artificial , American Heart Association , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/prevenção & controle , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: Variants in Filamin-C (FLNC) have been associated with various hereditary cardiomyopathies. Recent literature reports a prevalence of sudden cardiac death (SCD) of 13-25% among carriers of truncating-variants, with mean age of 42±15 years for first SCD event. This study reports two familial cases of SCD and the results of cascade screening of their large family. METHODS: Molecular-autopsy of the SCD victims revealed a novel truncating-variant in the FLNC gene (chr 7:128496880 [hg19]; NM_001458.5; c.7467_7474del; p.(Ser2490fs)). We screened thirty-two family members following genetic counseling, and variant carriers underwent a comprehensive workup followed by consultation with a cardiologist with expertise in the genetics of cardiac diseases. RESULTS: Seventeen variant carriers were identified: ages between 9 and 85 (mean 47±26). Fifteen underwent clinical evaluation. To date, none of the identified carriers has had major adverse events. In evaluated patients, ECG showed right-axis deviation in 60% (n = 9). Holter recorded frequent premature ventricular contractions (PVCs) (991±2030 per 24 h) in 33% (n = 5) with 4 patients having polymorphic PVC morphology. Three carriers had echocardiographic evidence of mild left-ventricular (LV) systolic dysfunction and another with mild LV dilatation. Cardiac magnetic-resonance (CMR) exhibited lategadolinium-enhancement in 10 out of 11 exams, mainly in the mid-myocardium and sub-epicardium, frequently involving the septum and the inferior-lateral wall. CONCLUSION: This large FLNC truncating variant carrier family exhibits high cardiomyopathy penetrance, best diagnosed by CMR, with variable clinical expressions. These findings present a challenge in SCD prevention management and underscoring the imperative for better risk stratification measures.
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Cardiomiopatias , Complexos Ventriculares Prematuros , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Mutação/genética , Filaminas/genética , Cardiomiopatias/genética , Miocárdio , Morte Súbita CardíacaRESUMO
PURPOSE: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community. METHODS: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group. RESULTS: We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles. CONCLUSION: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
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Variação Genética , Humanos , Alelos , Variação Genética/genética , Penetrância , Frequência do GeneRESUMO
Cardioneuroablation (CNA) is being increasingly used to treat patients with vasovagal syncope (VVS). Bradycardia, in the cardioinhibitory subtype of VVS, results from transient parasympathetic overactivity leading to sinus bradycardia and/or atrioventricular block. By mitigating parasympathetic overactivity, CNA has been shown to improve VVS symptoms in clinical studies with relatively small sample sizes and short follow-up periods (<5 years) at selected centers. However, CNA may potentially tip the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity. A higher heart rate is associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases. Chronic sympathovagal imbalance may also affect the pathophysiology of spectra of cardiovascular disorders including atrial and ventricular arrhythmias. This review addresses potential long-term pathophysiological consequences of CNA for VVS.
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Bradicardia , Síncope Vasovagal , Humanos , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/cirurgia , Arritmias Cardíacas , Átrios do Coração , Síndrome do Nó SinusalRESUMO
Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.
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Síndrome de Brugada , Parada Cardíaca , Humanos , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/terapia , Eletrocardiografia , Parada Cardíaca/diagnóstico , Parada Cardíaca/terapia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , ConsensoRESUMO
BACKGROUND: It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes. METHODS AND RESULTS: The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of ß-blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482-519 ms] versus 479 ms [IQR, 454-496 ms], P<0.001). Mothers treated with ß-blockers had babies born at term with lower birth weight compared with untreated women (2973±298 g versus 3470±338 g, P=0.002). In addition, the birth weight of babies born at term to treated women with QTc >500 ms was significantly lower compared with women with QTc <500 ms (2783±283 g versus 3084±256 g, P=0.029). CONCLUSIONS: Women with long QT syndrome with more severe phenotypes have a higher incidence of fetal death. Maternal QTc is longer in pregnancies that result in fetal loss, and the birth weight of babies born to patients taking ß-blockers with a QTc >500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.
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Síndrome do QT Longo , Humanos , Feminino , Gravidez , Peso ao Nascer , Estudos Retrospectivos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Morte Fetal/etiologia , Fenótipo , Antagonistas Adrenérgicos beta/uso terapêutico , EletrocardiografiaRESUMO
AIMS: Rare variants in the KCNQ1 gene are found in the healthy population to a much greater extent than the prevalence of Long QT Syndrome type 1 (LQTS1). This observation creates challenges in the interpretation of KCNQ1 rare variants that may be identified as secondary findings in whole exome sequencing.This study sought to identify missense variants within sub-domains of the KCNQ1-encoded Kv7.1 potassium channel that would be highly predictive of disease in the context of secondary findings. METHODS AND RESULTS: We established a set of KCNQ1 variants reported in over 3700 patients with diagnosed or suspected LQTS sent for clinical genetic testing and compared the domain-specific location of identified variants to those observed in an unselected population of 140â 000 individuals. We identified three regions that showed a significant enrichment of KCNQ1 variants associated with LQTS at an odds ratio (OR) >2: the pore region, and the adjacent 5th (S5) and 6th (S6) transmembrane (TM) regions. An additional segment within the carboxyl terminus of Kv7.1, conserved region 2 (CR2), also showed an increased OR of disease association. Furthermore, the TM spanning S5-Pore-S6 region correlated with a significant increase in cardiac events. CONCLUSION: Rare missense variants with a clear phenotype of LQTS have a high likelihood to be present within the pore and adjacent TM segments (S5-Pore-S6) and a greater tendency to be present within CR2. This data will enhance interpretation of secondary findings within the KCNQ1 gene. Further, our data support a more severe phenotype in LQTS patients with variants within the S5-Pore-S6 region.
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Canal de Potássio KCNQ1 , Síndrome do QT Longo , Humanos , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Testes Genéticos , Mutação de Sentido Incorreto , Fenótipo , MutaçãoAssuntos
Exoma , Genética Médica , Humanos , Estados Unidos , Exoma/genética , Genômica , Sequência de Bases , Políticas , Testes Genéticos , Genoma Humano/genética , Achados IncidentaisRESUMO
BACKGROUND: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. METHODS: A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. FINDINGS: In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5-81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. INTERPRETATION: In our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. FUNDING: The current work was supported by the National Natural Science Foundation Project of China (Nos. 82270332 & 81670304), The Fundamental Research Funds for the Central Universities of China - Independent Research Project of Wuhan University (No. 2042022kf1217) from China; the National Institutes of Health of USA [NIH R56 (HL47678), NIH R01 (HL138103), and NIH R01 (HL152201)], the W. W. Smith Charitable Trust and the Wistar and Martha Morris Fund, Sharpe-Strumia Research Foundation, the American Heart Association Postdoctoral Fellowship (20POST35220002) from United States; the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT2) from the Netherlands.
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Síndrome de Brugada , Feminino , Estados Unidos , Humanos , Síndrome de Brugada/etiologia , Síndrome de Brugada/genética , Arritmias Cardíacas/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Mutação de Sentido IncorretoRESUMO
Arrhythmogenic cardiomyopathy is an inherited cardiomyopathy that can involve both ventricles. Several genes have been identified as pathogenic in arrhythmogenic cardiomyopathy, including TMEM43. However, there are limited data on cardiac MRI findings in patients with TMEM43 variants to date. In this case series, cardiac MRI findings and clinical outcomes are described in 14 patients with TMEM43 variants, including eight (57%) with the pathogenic p.Ser358Leu variant (six female patients; mean age, 33 years ± 15 [SD]) and six (43%) with a TMEM43 variant of unknown significance (three female patients; mean age, 38 years ± 11). MRI findings demonstrated left ventricular systolic dysfunction in eight (57%) patients and right ventricular dysfunction in four (29%) patients. Among the nine patients with late gadolinium enhancement imaging, left ventricular late gadolinium enhancement was present in seven (78%; all subepicardial) patients. In summary, TMEM43 variants are associated with high prevalence of subepicardial late gadolinium enhancement and left ventricular dysfunction. Keywords: Arrhythmogenic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, TMEM43, Cardiac MRI, Genetic Variants Supplemental material is available for this article.