Christian Turner

Long-Term Outcomes of Dilated Cardiomyopathy Diagnosed During Childhood: Results from a National Population-Based Study of Childhood Cardiomyopathy

Background— Existing studies of childhood dilated cardiomyopathy deal mainly with early survival. This population-based study examines long-term outcomes for children with dilated cardiomyopathy. Methods and Results— The diagnosis of dilated cardiomyopathy was based on clinical, echocardiographic, and pathological findings. The primary study end point included time to the combined outcome of death or cardiac transplantation. There were 175 patients 0 to <10 years of age at the time of diagnosis. Survival free from death or transplantation was 74% (95% confidence interval, 67–80) 1 year after diagnosis, 62% (95% confidence interval, 55–69) at 10 years, and 56% (95% confidence interval, 46–65) at 20 years. In multivariable analysis, age at diagnosis <4 weeks or >5 years, familial cardiomyopathy, and lower baseline left ventricular fractional shortening Z score were associated with increased risk of death or transplantation, as was lower left ventricular fractional shortening Z score during follow-up. At 15 years after diagnosis, echocardiographic normalization had occurred in 69% of surviving study subjects. Normalization was related to higher baseline left ventricular fractional shortening Z score, higher left ventricular fractional shortening Z score during follow-up, and greater improvement in left ventricular fractional shortening Z score. Children with lymphocytic myocarditis had better survival and a higher rate of echocardiographic normalization. At the latest follow-up, 100 of 104 of survivors (96%) were free of cardiac symptoms, and 83 (80%) were no longer receiving pharmacotherapy. Conclusions— Death or transplantation occurred in 26% of patients with childhood dilated cardiomyopathy within 1 year of diagnosis and ~1% per year thereafter. Risk factors for death or transplantation include age at diagnosis, familial cardiomyopathy, and severity of left ventricular dysfunction. The majority of surviving subjects are well and free of cardiac medication.Background— Existing studies of childhood dilated cardiomyopathy deal mainly with early survival. This population-based study examines long-term outcomes for children with dilated cardiomyopathy. Methods and Results— The diagnosis of dilated cardiomyopathy was based on clinical, echocardiographic, and pathological findings. The primary study end point included time to the combined outcome of death or cardiac transplantation. There were 175 patients 0 to 5 years, familial cardiomyopathy, and lower baseline left ventricular fractional shortening Z score were associated with increased risk of death or transplantation, as was lower left ventricular fractional shortening Z score during follow-up. At 15 years after diagnosis, echocardiographic normalization had occurred in 69% of surviving study subjects. Normalization was related to higher baseline left ventricular fractional shortening Z score, higher left ventricular fractional shortening Z score during follow-up, and greater improvement in left ventricular fractional shortening Z score. Children with lymphocytic myocarditis had better survival and a higher rate of echocardiographic normalization. At the latest follow-up, 100 of 104 of survivors (96%) were free of cardiac symptoms, and 83 (80%) were no longer receiving pharmacotherapy. Conclusions— Death or transplantation occurred in 26% of patients with childhood dilated cardiomyopathy within 1 year of diagnosis and ~1% per year thereafter. Risk factors for death or transplantation include age at diagnosis, familial cardiomyopathy, and severity of left ventricular dysfunction. The majority of surviving subjects are well and free of cardiac medication. # Clinical Perspective {#article-title-45}

Sudden Death in Childhood Cardiomyopathy: Results From a Long-Term National Population-Based Study

BACKGROUND Children with cardiomyopathy (CM) are at risk of sudden cardiac death (SCD), but the incidence and risk factors for this outcome are not clear. OBJECTIVES This study sought to determine the incidence and risk factors for SCD in children with varying CM phenotypes from a long-term population-based study of childhood CM. METHODS The NACCS (National Australian Childhood Cardiomyopathy Study) is an ongoing longitudinal cohort study including all children in Australia with primary CM who were diagnosed between January 1, 1987, and December 31, 1996, and were <10 years of age. The cumulative incidence and risk factors for SCD within individual CM phenotypes were explored using survival analysis. RESULTS Of 289 eligible patients, 16 (5.5%) experienced SCD over a median follow-up of 11.9 years (interquartile range: 1.7 to 15.4). The risk of SCD varied according to CM phenotype (p=0.007). The cumulative incidence of SCD at 15 years was 5% for dilated cardiomyopathy (DCM), 6% for hypertrophic cardiomyopathy (HCM), 12% for restrictive cardiomyopathy, and 23% for left ventricular (LV) noncompaction. Older age at diagnosis, positive family history of CM, and severity of LV dysfunction were related to increased risk of SCD in patients with DCM, and a higher posterior wall thickness Z-score was the sole risk factor identified for patients with HCM. CONCLUSIONS Predictors of SCD include CM phenotype, family history of CM (DCM), severity of systolic dysfunction (DCM), and extent of LV hypertrophy (HCM). Continuing follow-up of this cohort into adulthood is likely to reveal an ongoing risk of SCD.

Interdisciplinary psychosocial care for families with inherited cardiovascular diseases

Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting.

The epidemiology of arrhythmia in infants: A population‐based study

Cardiac arrhythmias are an important cause of morbidity in infants. Although the spectrum of types of arrhythmia has been reported, there has been no previous population‐based study of the incidence of arrhythmias in infancy. Our aim was to define the population incidence of arrhythmia in infants.

A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. OBJECTIVE The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. METHODS Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. RESULTS Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. CONCLUSION We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia.

a Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia b Sydney Medical School, University of Sydney, Sydney, Australia c Royal Childrens Hospital, Melbourne, Victoria, Australia d Genetic Health Queensland, Royal Brisbane & Womens Hospital, Brisbane, Queensland, Australia e The Heart Centre for Children, The Childrens Hospital, Westmead, Sydney, NSW, Australia f Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Outcomes of interventional electrophysiology in children under 2 years of age

BACKGROUND Despite the increasing utilisation of interventional electrophysiology in adults and older children with arrhythmias, there are few data reflecting the safety and efficacy of this procedure in the age group under 2 years. AIM We describe our experience in assessing the efficacy and safety with this group of children. METHODS We undertook a retrospective review of all infants under 2 years of age who underwent an interventional electrophysiology procedure between 1995 and 2009 to determine indications, procedural details, short- and long-term success, and complication rate. RESULTS A total of 23 interventional electrophysiology procedures were performed in 17 patients initially under 2 years of age. Of these, three patients had congenital heart disease. The most common indication was arrhythmia resistant to pharmacological agents (59%), with the remaining cases being arrhythmia complicated by cardiovascular instability (41%). There was initial success in 15 patients after the first procedure, with early recurrence in four. Following six repeat procedures, there was long-term success in 15 patients (88%), with three repeat procedures being performed after 2 years of age. There was one non-procedural death related to persisting arrhythmia. There were three minor complications. In one patient, cryotherapy was used successfully. CONCLUSIONS The interventional electrophysiology procedure is a viable therapeutic option in infants under 2 years with arrhythmia resistant to other conventional medical management.

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy

BACKGROUND Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants. OBJECTIVES This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test. METHODS WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants. RESULTS The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing. CONCLUSIONS WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.

Update on the Use and Outcomes of Implantable Cardioverter Defibrillators in Pediatric Patients

Opinion statementThe vast majority of implantable cardioverter defibrillators (ICDs) continue to be implanted in the adult population. Accordingly, manufacturers develop devices and leads primarily for the adult population. Whilst the number of ICDs implanted in children is small in comparison, the potential benefits are large to this group. It is a common frustration among pediatric cardiologists whom implant devices that impressive technological developments continue to be developed for the adult population; as the population of children with ICDs is small, robust clinical studies often lag behind. By necessity, pediatric cardiologists and cardiothoracic surgeons have developed innovative techniques utilizing adult components in unusual configurations for children with complex congenital heart disease. As in the adult population, inappropriate shocks are one of the most limiting and concerning complications in the use of ICDs. Unfortunately, as will be discussed below, children are at increased risk of inappropriate shocks when compared with adults. The true impact of inappropriate shocks is increasingly being realized, and much of the focus in management of children with ICDs surrounds the prevention of inappropriate shocks.

Long-Term Outcomes of Hypertrophic Cardiomyopathy Diagnosed During Childhood: Results From a National Population-Based Study

Background: Late survival and symptomatic status of children with hypertrophic cardiomyopathy have not been well defined. We examined long-term outcomes for pediatric hypertrophic cardiomyopathy. Methods: The National Australian Childhood Cardiomyopathy Study is a longitudinal population-based cohort study of children (0–10 years of age) diagnosed with cardiomyopathy between 1987 and 1996. The primary study end point was time to death or cardiac transplantation. Results: There were 80 patients with hypertrophic cardiomyopathy, with a median age at diagnosis of 0.48 (interquartile range, 0.1, 2.5) years. Freedom from death/transplantation was 86% (95% confidence interval [CI], 77.0–92.0) 1 year after presentation, 80% (95% CI, 69.0–87.0) at 10 years, and 78% (95% CI, 67.0–86.0) at 20 years. From multivariable analyses, risk factors for death/transplantation included symmetrical left ventricular hypertrophy at the time of diagnosis (hazard ratio, 4.20; 95% CI, 1.60–11.05; P=0.004), Noonan syndrome (hazard ratio, 2.88; 95% CI, 1.02–8.08; P=0.045), higher posterior wall thickness z score (hazard ratio, 1.45; 95% CI, 1.22–1.73; P<0.001), and lower fractional shortening z score (hazard ratio, 0.84; 95% CI, 0.74–0.95; P=0.005) during follow-up. Nineteen (23%) subjects underwent left ventricular myectomy. At a median of 15.7 years of follow-up, 27 (42%) of 63 survivors were treated with &bgr;-blocker, and 13 (21%) had an implantable cardioverter-defibrillator. Conclusions: The highest risk of death or transplantation for children with hypertrophic cardiomyopathy is within 1 year after diagnosis, with low attrition rates thereafter. Many subjects receive medical, surgical, or device therapy.