148 research outputs found
Prolongation of the QT Interval and Post-Extrasystolic Augmentation of the TU-Wave During Emotional Stress
We present a case of a 25-year-old woman with multiple blackouts and no structural heart disease, with abnormal T-U waves and borderline QT interval on her resting electrocardiogram. During emotional stress she developed frequent monomorphic ventricular premature beats, with characteristic changes of the sinus complexes immediately following the premature beats, namely augmentation and greater degree of merging of the T and U waves and QTc interval prolongation. The changes alert about the possibility of congenital long QT syndrome, specifically genotype 2 or 1
Novel electrocardiographic criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy
Aims: In order to improve the electrocardiographic (ECG) diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC), we evaluated novel quantitative parameters of the QRS complex and the value of bipolar chest leads (CF leads) computed from the standard 12 leads.
Methods and results: We analysed digital 12-lead ECGs in 44 patients with ARVC, 276 healthy subjects including 44 age and sex-matched with the patients and 36 genotyped members of ARVC families. The length and area of the terminal S wave in V1 to V3 were measured automatically using a common for all 12 leads QRS end. T wave negativity was assessed in V1 to V6 and in the bipolar CF leads computed from the standard 12 leads. The length and area of the terminal S wave were significantly shorter, whereas the S wave duration was significantly longer in ARVC patients compared with matched controls. Among members of ARVC families, those with mutations (n = 15) had shorter QRS length in V2 and V3 and smaller QRS area in lead V2 compared with those without mutations (n = 20). In ARVC patients, the CF leads were diagnostically superior to the standard unipolar precordial leads. Terminal S wave duration in V1 >48 ms or major T wave negativity in CF leads separated ARVC patients from matched controls with 90% sensitivity and 86% specificity.
Conclusion: The terminal S wave length and area in the right precordial leads are diagnostically useful and suitable for automatic analysis in ARVC. The CF leads are diagnostically superior to the unipolar precordial leads
Low Prevalence of Risk Markers in Cases of Sudden Death Due to Brugada Syndrome Relevance to Risk Stratification in Brugada Syndrome
ObjectivesThe objective of this study was to determine the prevalence of conventional risk factors in sudden arrhythmic death syndrome (SADS) probands with Brugada syndrome (BrS).BackgroundPatients with BrS and previous aborted sudden cardiac death (SCD) are at high risk of recurrent events. Other universally accepted clinical features associated with higher risk include unheralded syncope and the presence of a spontaneous type 1 electrocardiogram (ECG).MethodsWe analyzed reported symptoms and reviewed ECGs from SADS probands with familial diagnoses of BrS, established by cardiological evaluation, including ECG, 2-dimensional echocardiography, Holter monitoring, exercise tolerance testing, and ajmaline provocation. These cases underwent familial evaluation between 2003 and 2010.ResultsA total of 49 consecutive families with a confirmed SADS death and a diagnosis of BrS were evaluated, comprising assessment of 202 family members in total. One family had 2 members with SADS, resulting in a total of 50 probands included. Mean age of death of probands was 29.1 ± 10.6 years, with 41 males (82%) (p < 0.05). Antemortem ECGs were available for 5 SADS probands, 1 of which demonstrated a spontaneous type 1 pattern. In 45 probands, symptoms before death were reported reliably by family members. Of these, 9 (20%) had experienced at least 1 syncopal episode before the fatal event. Importantly, 68% of probands would not have fulfilled any current criteria for consideration of implantable cardioverter-defibrillator.ConclusionsThe “low-risk” asymptomatic BrS group comprises the majority of SCD in this cohort. Current risk stratification would appear to be inadequate, and new markers of risk are vital
Sudden death and cardiac arrest without phenotype: the utility of genetic testing.
Approximately 4% of sudden cardiac deaths are unexplained [the sudden arrhythmic death syndrome (SADS)], and up to 6-10% of survivors of cardiac arrest do not have an identifiable cardiac abnormality after comprehensive clinical evaluation [idiopathic ventricular fibrillation (IVF)]. Genetic testing may be able to play a role in diagnostics and can be targeted to an underlying phenotype present in family members following clinical evaluation. Alternatively, post-mortem genetic testing (the "molecular autopsy") may diagnose the underlying cause if a clearly pathogenic rare variant is found. Limitations include a modest yield, and the high probability of finding a variant of unknown significance (VUS) leading to a low signal-to-noise ratio. Next generation sequencing enables cost-efficient high throughput screening of a larger number of genes but at the expense of increased genetic noise. The yield from genetic testing is even lower in IVF in the absence of any suggestion of another phenotype in the index case or his/her family, and should be actively discouraged at this time. Future improvements in diagnostic utility include optimization of the use of variant-calling pipelines and shared databases as well as patient-specific models of disease to more accurately assign pathogenicity of variants. Studying "trios" of parents and the index case may better assess the yield of sporadic and recessive disease
Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database
Background: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk
Next generation diagnostics in inherited arrhythmia syndromes : a comparison of two approaches.
Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology
Next Generation Diagnostics in Inherited Arrhythmia Syndromes A Comparison of Two Approaches
Abstract Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology
Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics
This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information
MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.
Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort
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