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.
Aims
Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, ...potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk.
Methods
We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group.
Results
RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B – moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow‐up, as well as therapeutic options within the current standard of clinical practice.
Conclusions
Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.
Abstract The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light ...on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.
Objective We sought to determine the feasibility and assess the clinical outcomes associated with an early extubation strategy for all children undergoing congenital heart surgery, including neonates ...(age, <30 days). Methods We performed a linked database analysis of all patients undergoing congenital heart surgery from July 1, 2010 to December 31, 2012. We collected data on the cardiac diagnoses, preoperative status, procedure, and postoperative course, including the duration of invasive and noninvasive ventilation, failure of extubation, hemodynamic data, length of stay, complications, and mortality. A multivariable model was used to assess the independent factors associated with an inability to extubate within the operating room and with delayed extubation (>24 hours). Results We operated on 613 children, including 97 neonates. Intraoperative extubation was achieved in 71% of the cases and early extubation (≤24 hours) was achieved in 89% of the cases. The overall mortality was 1.5% (9 of 613 patients). Early extubation was associated with lower mortality (1% vs 9%, P < .001) and a lower rate of reintubation (4% vs 23%, P < .001) compared with delayed extubation. Notably, 63% of the neonates were extubated within 24 hours, including 67% of arterial switch operations and 54% of total anomalous pulmonary venous return repairs. Norwood operations were the only procedure in which no patient was extubated within the first 24 hours. Multivariable logistic regression demonstrated that the predictors of delayed extubation included preoperative mechanical ventilation, weight < 5 kg, a longer procedure time, and the need for postoperative inotrope support. Implementation of an early extubation strategy was associated with low rates of complications (5.1 per 10 procedures), short lengths of intensive care unit stay (median, 1 day; interquartile range, 1-3), and short hospital stays (median, 4 days; interquartile range, 3-6). Conclusions Most children undergoing congenital heart surgery can be extubated in the operating room. Most neonates, including many undergoing complex procedures, can be extubated within the first 24 hours after surgery. Early extubation was associated with low morbidity rates and short lengths of intensive care unit and hospital stays.
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.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ...ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes ...of CPVT patients with ≥2 variants.
The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state).
Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign.
This severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.
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