A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Genetic aetiologies should be considered in paediatric cases of acute heart failure presumed to be myocarditis.

There are a variety of causes of acute heart failure in children including myocarditis, genetic/metabolic conditions, and congenital heart defects. In cases with a structurally normal heart and a negative personal and family history, myocarditis is often presumed to be the cause, but we hypothesise that genetic disorders contribute to a significant portion of these cases. We reviewed our cases of children who presented with acute heart failure and underwent genetic testing from 2008 to 2017. Eighty-seven percent of these individuals were found to have either a genetic syndrome or pathogenic or likely pathogenic variant in a cardiac-related gene. None of these individuals had a personal or family history of cardiomyopathy that was suggestive of a genetic aetiology prior to presentation. All of these individuals either passed away or were listed for cardiac transplantation indicating genetic testing may provide important information regarding prognosis in addition to providing information critical to assessment of family members.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterised by ventricular arrhythmias and an increased risk of sudden cardiac death. Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnosis is based on criteria that take into account electrical and structural cardiac abnormalities, as well as mutation analysis. Appropriate pharmacological therapy and the prevention of sudden death with implantable defibrillators are important in the management of these patients. Exercise is considered an important environmental factor for the development and progression of the disease.

Novel and highly lethal NKX2.5 missense mutation in a family with sudden death and ventricular arrhythmia.

To date, several disease-related mutations in NKX2-5, a cardiac-specific homeobox gene, have been documented in patients with a variety of congenital heart diseases (CHDs). The most commonly reported phenotypes are secundum atrial septal defect (ASD) and atrioventricular conduction disease (AVCD). Reports of sudden cardiac death (SCD) have been attributed to progressive conduction disease preventable with pacemaker therapy. A retrospective chart review of individuals from three generations of a family with a novel NKX2-5 mutation associated with CHD, ventricular arrhythmias, and SCD despite pacemaker therapy was conducted. The review documented NKX2-5 Gln181His missense mutation in 11 phenotypically affected members of a single family with a strong family history of SCD, CHD, and AVCD. Before genotyping, four family members died suddenly, two despite pacemaker therapy. The ages at SCD were respectively 23, 29, 44, and 45 years. Observed phenotypic characteristics of genotype-positive patients included ASD, ventricular septal defect, aortic coarctation, tricuspid atresia, supraventricular tachycardia, progressive AVCD, and ventricular tachycardia documented on implantable cardiac defibrillator (ICD) recording. The age at presentation ranged from 5 months to 44 years, and AVCD was seen as early as infancy. Four phenotypically unaffected family members tested negative for the mutation. The findings of this review strongly suggest a new association of this NKX2-5 mutation with SCD from ventricular arrhythmia. This observation has significant implications for the choice of therapy for affected individuals, specifically the use of ICDs, and broadens the observed phenotypic spectrum of NKX2-5 mutations.

Placement of implantable cardioverter-defibrillators in paediatric and congenital heart defect patients: a pipeline for model generation and simulation prediction of optimal configurations.

There is currently no reliable way of predicting the optimal implantable cardioverter-defibrillator (ICD) placement in paediatric and congenital heart defect (CHD) patients. This study aimed to: (1) develop a new image processing pipeline for constructing patient-specific heart-torso models from clinical magnetic resonance images (MRIs); (2) use the pipeline to determine the optimal ICD configuration in a paediatric tricuspid valve atresia patient; (3) establish whether the widely used criterion of shock-induced extracellular potential (Φe) gradients ≥5 V cm(-1) in ≥95% of ventricular volume predicts defibrillation success. A biophysically detailed heart-torso model was generated from patient MRIs. Because transvenous access was impossible, three subcutaneous and three epicardial lead placement sites were identified along with five ICD scan locations. Ventricular fibrillation was induced, and defibrillation shocks were applied from 11 ICD configurations to determine defibrillation thresholds (DFTs). Two configurations with epicardial leads resulted in the lowest DFTs overall and were thus considered optimal. Three configurations shared the lowest DFT among subcutaneous lead ICDs. The Φe gradient criterion was an inadequate predictor of defibrillation success, as defibrillation failed in numerous instances even when 100% of the myocardium experienced such gradients. In conclusion, we have developed a new image processing pipeline and applied it to a CHD patient to construct the first active heart-torso model from clinical MRIs.

Tetralogy of Fallot and aortic root dilation: a long-term outlook.

Dilation of the sinus of Valsalva (SoV) has been increasingly observed after repaired tetralogy of Fallot (TOF). We estimate the prevalence of SoV dilation in adults with repaired TOF and analyze possible factors related to aortic disease. Adults with TOF [n = 109, median age 33.2 years (range 18.1 to 69.5)] evaluated at Johns Hopkins Hospital from 2001 to 2009 were reviewed in an observational retrospective cohort study. Median follow-up was 27.3 (range 0.1-48.8) years. SoV dilation was defined as >95 % confidence interval adjusted for age and body surface area (z-score > 2). The prevalence of SoV dilation was 51 % compared with that of a normal population with a mean z-score of 2.03. Maximal aortic diameters were ≥ 4 cm in 39 % (42 of 109), ≥ 4.5 cm in 21 % (23 of 109), ≥ 5 cm in 8 % (9 of 109), and ≥ 5.5 cm in 2 % (2 of 109). There was no aortic dissection or death due contributable to aortic disease. Aortic valve replacement was performed in 1.8 % and aortic root or ascending aorta (AA) replacement surgery in 2.8 % of patients. By multivariate logistic regression analysis, aortic regurgitation (AR) [odds ratio (OR) = 3.09, p = 0.005], residual ventricular septal defect (VSD) (OR = 4.14, p < 0.02), and TOF with pulmonary atresia (TOF/PA) (OR = 6.75, p = 0.03) were associated with increased odds of dilated aortic root. SoV dilation after TOF repair is common and persists with aging. AR, residual VSD, and TOF/PA are associated with increased odds of dilation. AA evaluation beyond the SoV is important. Indexed values are imperative to avoid bias on the basis of age and body surface area.

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. METHODS: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. RESULTS: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism. CONCLUSIONS: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

Frequency of Ventricular Arrhythmias and Other Rhythm Abnormalities in Children and Young Adults With the Marfan Syndrome.

Patients with the Marfan syndrome (MFS) are at risk for sudden death. The contribution of arrhythmias is unclear. This study examines the prevalence of arrhythmias in children with the MFS and their relation to clinical and/or echocardiographic factors. Data from the Pediatric Heart Network randomized trial of atenolol versus losartan in MFS were analyzed (6 months to 25 years old, aortic root diameter z-score > 3.0, no previous aortic surgery and/or dissection). Baseline 24-hour ambulatory electrocardiographic monitoring was performed. Significant ventricular ectopy (VE) and supraventricular ectopy (SVE) were defined as ≥10 VE or SVE/hour, or the presence of high-grade ectopy. Three-year composite clinical outcome of death, aortic dissection, or aortic root replacement was analyzed. There were 274 analyzable monitors on unique patients from 11 centers. Twenty subjects (7%) had significant VE, 13 (5%) significant SVE; of these, 2 (1%) had both. None had sustained ventricular or supraventricular tachycardia. VE was independently associated with increasing number of major Ghent criteria (odds ratio [OR] = 2.13/each additional criterion, p = 0.03) and greater left ventricular end-diastolic dimension z-score (OR = 1.47/each 1 unit increase in z-score, p = 0.01). SVE was independently associated with greater aortic sinotubular junction diameter z-score (OR = 1.56/each 1 unit increase in z-score, p = 0.03). The composite clinical outcome (14 events) was not related to VE or SVE (p ≥ 0.3), but was independently related to heart rate variability (higher triangular index). In conclusion, in this cohort, VE and SVE were rare. VE was related to larger BSA-adjusted left ventricular size. Routine ambulatory electrocardiographic monitoring may be useful for risk stratification in select MFS patients.

Lightning, sudden cardiac death, simulation and an automated external defibrillator: the perfect storm.

This is a report of an 11-year-old boy who had sudden cardiac death after a lightning strike while playing lacrosse at summer camp. The camp staff had performed weekly drills to prepare for various medical emergencies and quickly activated their "Emergency Activation System". The child received immediate cardiopulmonary resuscitation (CPR) and was defibrillated with an automated defibrillator (AED) within 3 min of becoming pulseless and was ultimately resuscitated after being defibrillated three times. A community ambulance with a defibrillator on board did not arrive until several minutes after the on-site team had achieved return of spontaneous circulation. In this report, we describe the clinical course of this patient; briefly review lightning injuries, other causes of sudden cardiac death in children and use of AEDs. Finally, we review how simulation has been used in this case and others as a mechanism to ensure preparedness for medical emergencies. This child is alive and well today because of these well-trained camp counselors. Their system of using simulation to maintain emergency readiness serves as an example for lay and professional medical providers alike.

Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.

A group of relatively uncommon but important genetic cardiovascular diseases (GCVDs) are associated with increased risk for sudden cardiac death during exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan syndrome, and arrhythmogenic right ventricular cardiomyopathy. These conditions, characterized by diverse phenotypic expression and genetic substrates, account for a substantial proportion of unexpected and usually arrhythmia-based fatal events during adolescence and young adulthood. Guidelines are in place governing eligibility and disqualification criteria for competitive athletes with these GCVDs (eg, Bethesda Conference No. 26 and its update as Bethesda Conference No. 36 in 2005). However, similar systematic recommendations for the much larger population of patients with GCVD who are not trained athletes, but nevertheless wish to participate in any of a variety of recreational physical activities and sports, have not been available. The practicing clinician is frequently confronted with the dilemma of designing noncompetitive exercise programs for athletes with GCVD after disqualification from competition, as well as for those patients with such conditions who do not aspire to organized sports. Indeed, many asymptomatic (or mildly symptomatic) patients with GCVD desire a physically active lifestyle with participation in recreational and leisure-time activities to take advantage of the many documented benefits of exercise. However, to date, no reference document has been available for ascertaining which types of physical activity could be regarded as either prudent or inadvisable in these subgroups of patients. Therefore, given this clear and present need, this American Heart Association consensus document was constituted, based largely on the experience and insights of the expert panel, to offer recommendations governing recreational exercise for patients with known GCVDs.

Brugada syndrome in children.

Brugada syndrome is an inherited arrhythmia associated with characteristic ST elevation in the right precordial leads and sudden cardiac death. The average age of sudden cardiac death is 40 years; reported pediatric cases remain rare. Genetic testing and increased disease awareness may result in many more children being diagnosed with Brugada syndrome.

The relevance of prolonged QTc measurement to pediatric psychopharmacology.

OBJECTIVE: To consider the relevance of prolonged QTc (QT interval corrected for rate) to pediatric psychopharmacology. METHOD: The authors reviewed publications on QTc prolongation and publications on sudden death in Medline from 1968 to November 2002. RESULTS: The search yielded more than 20,000 publications. Review manuscripts with clinical recommendations outnumber the few pediatric studies of QTc duration during treatment. Most reviews have been published in the past 5 years, during a time when the Food and Drug Administration restricted five psychotropic medications because of QTc prolongation (sertindole: not approved; thioridazine, mesoridazine, and droperidol: black-box warning; and ziprasidone: bolded warning) and nine somatic medications because of QTc prolongation. CONCLUSION: Pretreatment screening, careful selection of psychotropic and/or somatic medication combinations, and recognition of QTc prolongation in electrocardiographic tracings during treatment with medications that prolong QTc are important components of clinical practice.

Mutations in Alström protein impair terminal differentiation of cardiomyocytes.

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

Emergency diagnosis and management of pediatric arrhythmias.

True emergencies due to unstable arrhythmias in children are rare, as most rhythm disturbances in this age group are well-tolerated. However, presentation to an emergency department with symptoms of palpitations, fatigue and/or syncope is much more common. Sinus tachycardia is by far the most commonly reported arrhythmia, followed by supraventricular tachycardia. Emergency physicians should be prepared for diagnosis and to acutely manage various types of arrhythmias seen in children, to assess the need for further diagnostic testing, and to determine whether cardiology evaluation and follow-up are needed. This article is intended to provide diagnostic and management guidelines of the most common types of arrhythmias seen in children with structurally normal hearts as well as those associated with congenital heart disease and cardiomyopathies.

Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.

Here we report the first infantile case of restrictive cardiomyopathy caused by a de novo mutation of the cardiac troponin T gene. The patient presented with an apparent life-threatening event. She developed malignant arrhythmias and hemodynamic instability, requiring initial rescue support with extracorporeal membrane oxygenation, and subsequently underwent insertion of a biventricular assist device (VAD). She successfully received an orthotopic heart transplant 172 days after VAD implantation.

Use of a saphenous venous homograft for constructing a conduit from the right ventricle to the pulmonary arteries in the Norwood procedure.

The use of a conduit of polytetrafluoroethylene placed between the right ventricle and the pulmonary arteries as source of pulmonary arterial supply during the first stage of palliation for the hypoplastic left heart syndrome has facilitated post-operative management and resulted in decreased mortality. We describe here the use of a cryopreserved saphenous vein inserted in reversed direction to create the connection between the right ventricle and the pulmonary arteries in a neonate with low birth weight undergoing the modified Norwood procedure.

Pacemaker therapy in isolated congenital complete atrioventricular block.

The aim of this study was to evaluate the effect of pacemaker (PM) therapy in patients with isolated congenital complete atrioventricular block (CCAVB). Patients with CCAVB eventually quality for PM implantation, however, timing remains controversial. Retrospective evaluation of left ventricular end-diastolic diameter (LVEDD), shortening fraction (SF), and cardiothoracic ratio (CTR) in 149 CCAVB patients, before, at, and after PM implantation was carried out. LVEDD shows an average increase of 0.48%/month in non-PM patients, and an average decrease of 0.88%/month in PM patients. SF shows an average increase of 0.10%/month in non-PM, and an average decrease of 0.32%/month in PM patients. CTR shows an average increase of 0.02%/month in non-PM, and an average decrease of 0.19%/month in PM patients. The difference between the non-PM and PM groups is significant (P = 0.05) for all variables. Symptomatic patients show no significant change in LVEDD after PM therapy (from 66.5% before to 68.5% after PM therapy). Asymptomatic patients do show a significant (P < 0.001) decrease in LVEDD after PM therapy (from 78.4% before to 73.3% after PM therapy). CTR does not differ significantly between symptomatic and asymptomatic patients before PM therapy (58% and 57%, respectively). CTR does differ significantly (P < 0.001) between symptomatic and asymptomatic patients after PM therapy (52% and 48%, respectively). Heart size and SF are increased in most patients with isolated CCAVB. PM implantation is associated with a decrease in heart size and normalization of SF in most patients. Indications for PM therapy in children may require reevaluation in asymptomatic patients with increased cardiac size and decreased cardiac function.