The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiomyocyte subtypes is a prerequisite for modeling specific forms of cardiovascular disease ...in vitro and for developing novel therapies to treat them. Here we have investigated the development of the human atrial and ventricular lineages from hPSCs, and we show that retinoic acid signaling at the mesoderm stage of development is required for atrial specification. Analyses of early developmental stages revealed that ventricular and atrial cardiomyocytes derive from different mesoderm populations that can be distinguished based on CD235a and RALDH2 expression, respectively. Molecular and electrophysiological characterization of the derivative cardiomyocytes revealed that optimal specification of ventricular and atrial cells is dependent on induction of the appropriate mesoderm. Together these findings provide new insights into the development of the human atrial and ventricular lineages that enable the generation of highly enriched, functional cardiomyocyte populations for therapeutic applications.
Display omitted
•Human atrial and ventricular cardiomyocytes derive from distinct mesoderm populations•Atrial and ventricular mesoderm are distinguished by RALDH2 and CD235a expression•Atrial cardiomyocytes are specified by autocrine RA signaling•Efficient atrial/ventricular myocyte generation depends on mesoderm patterning
Keller, Protze, and colleagues show that atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Molecular and functional analyses revealed that appropriate mesoderm patterning is required for generating enriched populations of atrial or ventricular cardiomyocytes from hPSCs. These findings provide important new insights for the derivation of populations for future therapeutic applications.
Abstract
Aims
The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous ...reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors.
Methods and results
We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control.
Conclusion
Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.
Graphical Abstract
Short-coupled ventricular fibrillation (SCVF) is a distinct primary electrical disorder accounting for at least 6.6% of otherwise idiopathic VF. Quinidine is highly effective for SCVF.
Splice-site variants in cardiac genes may predispose carriers to potentially lethal arrhythmias. To investigate, we screened 1315 probands and first-degree relatives enrolled in the Canadian Hearts ...in Rhythm Organization (HiRO) registry. 10% (134/1315) of patients in the HiRO registry carry variants within 10 base-pairs of the intron-exon boundary with 78% (104/134) otherwise genotype negative. These 134 probands were carriers of 57 unique variants. For each variant, American College of Medical Genetics and Genomics (ACMG) classification was revisited based on consensus between nine in silico tools. Due in part to the in silico algorithms, seven variants were reclassified from the original report, with the majority (6/7) downgraded. Our analyses predicted 53% (30/57) of variants to be likely/pathogenic. For the 57 variants, an average of 9 tools were able to score variants within splice sites, while 6.5 tools responded for variants outside these sites. With likely/pathogenic classification considered a positive outcome, the ACMG classification was used to calculate sensitivity/specificity of each tool. Among these, Combined Annotation Dependent Depletion (CADD) had good sensitivity (93%) and the highest response rate (131/134, 98%), dbscSNV was also sensitive (97%), and SpliceAI was the most specific (64%) tool. Splice variants remain an important consideration in gene elusive inherited arrhythmia syndromes. Screening for intronic variants, even when restricted to the ±10 positions as performed here may improve genetic testing yield. We compare 9 freely available in silico tools and provide recommendations regarding their predictive capabilities. Moreover, we highlight several novel cardiomyopathy-associated variants which merit further study.
Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield ...and clinical utility of genetic testing in UCA using whole-exome sequencing (WES).
Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest.
Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.
The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts ...to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval QTc), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.
La pandémie de COVID-19 a donné lieu à des initiatives visant à accélérer l’étude et l’utilisation de médicaments susceptibles d’améliorer le pronostic des patients, mais dont l’innocuité et l’efficacité n’ont pas encore été établies. Les auteurs tentent de formuler des lignes directrices raisonnables quant à l’emploi d’agents antimicrobiens, notamment la chloroquine, l’hydroxychloroquine, l’azithromycine et l’association lopinavir-ritonavir, dont les bienfaits demeurent incertains, mais qui sont susceptibles d’accroître le risque d’allongement de l’intervalle QT et de proarythmie ventriculaire. Durant la pandémie, les efforts visant à limiter la propagation de la maladie et à atténuer au minimum les tensions exercées sur les ressources en soins de santé commandent une restriction des interventions médicales et des tests non nécessaires. Pour que le risque de proarythmie médicamenteuse demeure au plus bas, nous recommandons les mesures suivantes : 1) arrêter l’administration de médicaments non nécessaires aussi susceptibles d’allonger l’intervalle QT; 2) déterminer qui sont les patients ambulatoires présentant un risque faible et n’ayant pas besoin de subir d’autres tests (absence d’antécédents d’allongement de l’intervalle QT ou de syncope inexpliquée, d’antécédents familiaux de mort cardiaque subite prématurée ou de traitement médicamenteux susceptible d’allonger l’intervalle QT, et/ou intervalle QT corrigé QTc normal connu); et 3) réaliser des examens initiaux chez les patients hospitalisés ou chez ceux qui sont exposés à un risque plus élevé. Si les examens électrocardiographiques initiaux révèlent un allongement modéré de l’intervalle QTc, un traitement pourrait être administré sous réserve de l’optimisation de la médication et de l’administration d’électrolytes. Si l’allongement de l’intervalle QTc est marqué, il faut éviter d’administrer des médicaments susceptibles d’allonger davantage cet intervalle, ou encore consulter un spécialiste pour pouvoir traiter le patient en prenant les précautions qui s’imposent. Ces recommandations sont formulées à l’heure où il n’existe encore aucun traitement efficace connu contre la COVID-19; il faudra les revoir lorsque d’autres données relatives à l’efficacité et à l’innocuité des agents en cause seront disponibles.
Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with apparently unexplained cardiac arrest (UCA) after varying degrees of evaluation. This is largely due to the lack of a ...standardized approach to UCA.
We sought to develop an evidence-based diagnostic algorithm for IVF by systematically examining the yield of diagnostic testing in UCA probands.
Studies reporting the yield of diagnostic testing in UCA were identified in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and conference abstracts. Their methodological quality was assessed by the National Institutes of Health quality assessment tool. Meta-analyses were performed using the random effects model.
A total of 21 studies were included. The pooled comprehensive diagnostic testing yield was 43% (95% confidence interval 39%-48%). A lower yield was seen when only definite diagnoses based on the prespecified criteria were used (32% vs 47%; P = .15). Epinephrine challenge, Holter monitoring, and family screening were associated with low yield (<5%), whereas cardiac magnetic resonance imaging, exercise treadmill test, and sodium-channel blocker challenge were associated with high yield (≥5%). Coronary spasm provocation, electrophysiology study, and systematic genetic testing were reported to be abnormal in a high proportion of UCA probands (>10%).
We developed a stepwise algorithm for UCA evaluation and criteria to assess the strength of IVF diagnosis on the basis of the diagnostic yield of UCA testing.
Unexplained cardiac arrest may be because of an inherited arrhythmia syndrome. The role of genetic testing in cardiac arrest survivors without a definite clinical phenotype is unclear.
The CASPER ...(Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) is a large registry of cardiac arrest survivors where initial assessment reveals normal coronary arteries, left ventricular function, and resting ECG. Of 375 cardiac arrest survivors in CASPER from 2006 to 2015, 174 underwent genetic testing. Patients were classified as phenotype-positive (n=72) or phenotype-negative (n=102). Genetic testing was performed at treating physicians' discretion in line with contemporary guidelines and availability. All genetic variants identified from original laboratory reports were reassessed by the investigators in line with modern criteria. Pathogenic variants were identified in 29 (17%) patients (60% channelopathy-associated and 40% cardiomyopathy-associated genes) and 70 variants of unknown significance were identified in 32 (18%) patients. Prior syncope (odds ratio, 4.0; 95% confidence interval, 1.6-9.7) and a family history of sudden death (odds ratio, 3.2; 95% confidence interval, 1.1-9.4) were independently associated with the presence of a pathogenic variant. In phenotype-negative patients, broad multiphenotype genetic testing led to higher yields (21% versus 8%;
=0.04) but was associated with more variants of unknown significance (55% versus 5%;
<0.01).
Genetic testing identifies a pathogenic variant in a significant proportion of unexplained cardiac arrest survivors. Prior syncope and family history of sudden death are predictors of a positive genetic test. Both arrhythmia and cardiomyopathy genes are implicated. Broad, multiphenotype testing revealed the highest frequency of pathogenic variants in phenotype-negative patients.
https://www.clinicaltrials.gov. Unique Identifier: NCT00292032.
Sudden cardiac death – A Reappraisal Steinberg, Christian, MD; Laksman, Zachary W.M., MD; Krahn, Andrew D., MD
Trends in cardiovascular medicine,
11/2016, Letnik:
26, Številka:
8
Journal Article
Recenzirano
Sudden cardiac death (SCD) is still among the leading causes of death in women and men, accounting for over 50% of all fatal cardiovascular events in the United States. Two arrhythmia mechanisms of ...SCD can be distinguished: shockable rhythms (ventricular fibrillation, pulseless ventricular tachycardia) and non-shockable rhythms including asystole or pulseless electrical activity. The overall prognosis of cardiac arrest due to shockable rhythms is significantly better. While the majority of SCDs is attributed to coronary artery disease or other structural heart disease, no obvious cause can be identified in 5% of all events, and those events are labeled as sudden unexplained deaths (SUD). Those unexplained events are typically caused by rare hereditary electrical disorders or arrhythmogenic cardiomyopathies. A systematic approach to the diagnosis of cardiac arrest followed by tailored therapy based on etiology has emerged in the last 10–15 years, with significant changes of medical practice and risk management of cardiac arrest victims. The aim of this review is to summarize our contemporary understanding of SCD/SUD in adults and to discuss current concepts of management and secondary prevention in cardiac arrest victims. A full discussion of the topic of primary prevention of SCD is beyond the scope of this article.
Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; ...rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.
Background
Pulmonary vein isolation (PVI) using radiofrequency catheter ablation is a widely accepted therapy for drug‐refractory atrial fibrillation patients. Elimination of the negative component ...of the local unipolar electrogram (UEGM) during PVI is a marker of transmural lesion formation. The ablation index (AI) can predict the quality of ablation lesion. Combining these two parameters could make PVI safer and efficient. The purpose of this pilot study was to examine the correlation between UEGM modification characteristics of the different target areas of left atrium and the associated AI values during PVI.
Methods
We analyzed 10 patients who underwent PVI using radiofrequency energy. The local electrophysiological properties and ablation parameters of 15 designated areas of interest in the left atria targeted by radiofrequency catheter ablation were collected.
Results
Out of the 10 patients, six were men (mean age 66 years) and 80% had paroxysmal AF. The mean time to achieve the UEGM modification in the posterior wall was shorter than that of the anterior wall (8.9 seconds vs. 11.1 s, respectively). The UEGM modification for every lesion was achieved at significantly lower AI values than conventional AIs (p < .001).
Conclusion
During PVI, the AIs deduced according to the local UEGM modification are markedly shorter than those generally recommended AIs in contemporary practice. This indicates that conventionally recommended AIs could be safely reduced while ensuring the efficacy and quality of radiofrequency ablation during PVI. This approach would probably reduce to risk of collateral thermal injuries.
PDF
