The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Patterns of Electrocardiographic Abnormalities in Children with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Detection of Tachyarrhythmias in a Large Cohort of Infants Using Direct-to-Consumer Heart Rate Monitoring.

OBJECTIVE: Current estimates of the incidence of tachyarrhythmias in infants rely on clinical documentation and may not reflect the true rate in the general population. Our aim was to describe the epidemiology of tachyarrhythmia detected in a large cohort of infants using direct-to-consumer heart rate (HR) monitoring. STUDY DESIGN: Data were collected from Owlet Smart Sock devices used in infants in the US with birthdates between February 2017 and February 2019. We queried the HR data for episodes of tachyarrhythmia (HR of ≥240 bpm for >60 seconds). RESULTS: The study included 100 949 infants (50.8% male) monitored for more than 200 million total hours. We identified 5070 episodes of tachyarrhythmia in 2508 infants. The cumulative incidence of tachyarrhythmia in our cohort was 2.5% over the first year of life. The median age at the time of the first episode of tachyarrhythmia was 36 days (range, 1-358 days). Tachyarrhythmia was more common in infants with congenital heart disease (4.0% vs 2.4%; P = .015) and in females (2.7% vs 2.0%; P < .001). The median length of an episode was 7.3 minutes (range, 60 seconds to 5.4 hours) and the probability of an episode lasting longer than 45 minutes was 16.8% (95% CI, 15.4%-18.3%). CONCLUSIONS: We found the cumulative incidence of tachyarrhythmia among infants using direct-to-consumer HR monitors to be higher than previously reported in studies relying on clinical diagnosis. This finding may represent previously undetected subclinical disease in young infants, the significance of which remains uncertain. Clinicians should be prepared to discuss these events with parents.

Arrhythmias and fasciculoventricular pathways in patients with Danon disease: A single center experience.

BACKGROUND: Danon disease is a rare X-linked storage disorder characterized by hypertrophic cardiomyopathy leading to arrhythmias and heart failure. A preexcitation pattern on electrocardiogram (ECG) has been described in these patients, however, invasive studies to distinguish between Wolff-Parkinson-White syndrome syndrome and fasciculoventricular pathways (FVP) are limited. OBJECTIVES: The purpose of this study was to delineate the electrophysiological cardiac abnormalities in patients with Danon disease and to describe the presence of FVP in this population. METHODS: We performed a retrospective study of all patients with a confirmed diagnosis of Danon disease presenting to a single center from May 2005 to May 2018. Baseline demographics, clinical characteristics, ECG findings, and electrophysiology study (EPS) results were collected. RESULTS: Ten patients with Danon disease (30% male, average age 17.4 years) were identified. Seven patients (70%) had tachyarrhythmias including five with atrial arrhythmias and six with nonsustained ventricular tachycardia. Preexcitation pattern on ECG was found in four (40%) patients. Of these, two underwent an EPS which confirmed the presence of an FVP. One patient underwent an adenosine challenge which supported a FVP. Implantable cardioverter defibrillator was placed in five patients for primary prevention with no patients receiving an appropriate discharge. Over a follow-up of 5.3 years, five underwent heart transplantation. CONCLUSIONS: This study reports a high incidence of FVP in patients with Danon disease and preexcitation. It underscores an alternate etiology of preexcitation in this population which can potentially be diagnosed without invasive EPS testing. Future multicenter studies are needed to expand this experience.

Impact of Obesity on Left Ventricular Thickness in Children with Hypertrophic Cardiomyopathy.

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) ≥ 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean ± SD, 12.5 ± 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 ± 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 ± 4.1). The overall mean IVST was 20.5 ± 9.6 mm and the overall mean PWT was 11.0 ± 8.4 mm. The mean IVST in the obese patients was 21.6 ± 10.0 mm and mean PWT was 13.3 ± 14.7 mm. The mean IVST in the non-obese patients was 20.1 ± 9.5 mm and mean PWT was 10.4 ± 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied.

The Second Annual Think Tank on Prevention of Sudden Cardiac Death in the Young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium.

Sudden cardiac death in the young (SCDY) spans gender, race, ethnicity, and socioeconomic class. The loss of any pediatric patient is a matter of national and international public health concern, and focused efforts should be aimed at preventing these burdensome tragedies. Prepared by members of the Cardiac Safety Research Consortium, this White Paper summarizes and reports the dialogue at the second Think Tank related to the issues and the proposed solutions for the development of a national resource for screening and prevention of SCDY. This Think Tank, sponsored by the Cardiac Safety Research Consortium and the United States Food and Drug Administration, convened on February 18, 2016, in Miami, FL, to identify and resolve the barriers that prevent early identification of patients at risk for SCDY. All potential stakeholders including national and international experts from industry, medicine, academics, engineering, and community advocacy leaders had an opportunity to share ideas and collaborate.

Arrhythmias in congenital heart disease: a position paper of the European Heart Rhythm Association (EHRA), Association for European Paediatric and Congenital Cardiology (AEPC), and the European Society of Cardiology (ESC) Working Group on Grown-up Congenital heart disease, endorsed by HRS, PACES, APHRS, and SOLAECE.

The population of patients with congenital heart disease (CHD) is continuously increasing with more and more patients reaching adulthood. A significant portion of these young adults will suffer from arrhythmias due to the underlying congenital heart defect itself or as a sequela of interventional or surgical treatment. The medical community will encounter an increasing challenge as even most of the individuals with complex congenital heart defects nowadays become young adults. Within the past 20 years, management of patients with arrhythmias has gained remarkable progress including pharmacological treatment, catheter ablation, and device therapy. Catheter ablation in patients with CHD has paralleled the advances of this technology in pediatric and adult patients with structurally normal hearts. Growing experience and introduction of new techniques like the 3D mapping systems into clinical practice have been particularly beneficial for this growing population of patients with abnormal cardiac anatomy and physiology. Finally, device therapies allowing maintanence of chronotropic competence and AV conduction, improving haemodynamics by cardiac resynchronization, and preventing sudden death are increasingly used. For pharmacological therapy, ablation procedures, and device therapy decision making requires a deep understanding of the individual pathological anatomy and physiology as well as detailed knowledge on natural history and long-term prognosis of our patients. Composing expert opinions from cardiology and paediatric cardiology as well as from non-invasive and invasive electrophysiology this position paper was designed to state the art in management of young individuals with congenital heart defects and arrhythmias.

Resynchronization Therapy for Patients with Congenital Heart Disease: Are We Ready for Prime Time?

PURPOSE OF REVIEW: This review aims to summarize and provide an update of evidence for cardiac resynchronization therapy (CRT) in pediatric and adult congenital heart disease (CHD). RECENT FINDINGS: CRT is a valuable tool in the treatment of heart failure in the setting of CHD. Current evidence points toward the ability of this therapy to increase hemodynamic parameters and reduce heart failure-related symptoms. Within the CHD population, patients with systemic left ventricles appear to benefit the most from CRT. Utilization of CRT in CHD has been technically difficult due to the complexity and variety of anatomic substrates. However, lateral thoracotomies and other advances have made implantation more feasible. The most up-to-date evidence continues to support the use of CRT in the heterogeneous population of CHD with careful and individualized patient selection. Further studies are needed to evaluate the utility of CRT for specific anatomic substrates within this population.

Lone Pediatric Atrial Fibrillation in the United States: Analysis of Over 1500 Cases.

Little is known about lone atrial fibrillation (AF) in pediatrics and its risk factors due to low prevalence. We sought to determine risk factors and estimate recurrence rates in children with lone AF using a large clinical database. Using the Explorys clinical database, we retrospectively identified patients who were below 20 years of age at the time of their AF diagnosis. Patients with congenital heart disease, cardiomyopathy, prior open heart surgery, or thyroid disease were excluded. Out of 7,969,230 children identified, 1910 had AF and 1570 met the definition of lone AF. The prevalence of lone AF was 7.5 per 100,000 children. In comparison to young children (0-4 years), risk for lone AF increased with age (adjusted odds ratio (aOR) 1.2 [95% CI 0.9-1.5, P = 0.21] in those 5-9 years, aOR 1.7 [95% CI 1.3-2.1, P < 0.001] in those 10-14 years, and aOR 10.7 [95% CI 8.7-13.2, P < 0.001] in those 15-19 years). Risk of lone AF was also higher in males than females (aOR 1.7 [95% CI 1.5-1.9, P < 0.001]), and was higher in obese children (BMI ≥ 95th percentile) versus children with normal BMI (aOR 1.3 [95% CI 1.1-1.5], P < 0.001), but there was no difference between overweight (BMI = 85th-94th percentile) and normal (P = 0.14). One-month recurrence rate was 15%, and increased with age. In this large pediatric cohort, the prevalence of lone AF was low, but risk was higher in males and increased with age and obesity. Older children with lone AF had higher rates of recurrence.

Sports participation in long QT syndrome.

Untreated congenital long QT syndrome may result in potentially lethal ventricular tachycardia. In the most common type, risk of such an event has been linked to exercise. This originally resulted in very restrictive guidelines for sports participation in affected individuals. Although the complex interactions of a specific genotype, modifying cofactors, and risk are only now being explored, scientific evidence based on clinical experience now suggests that in many instances such restrictive guidelines are unwarranted. In particular, patients with this condition who are compliant with ß-blocker therapy and who have never had symptoms during exertion are now enjoying the benefits of athletic activity.

Syncope with Swallowing.

Swallowing can be a trigger for syncope and can cause significant morbidity and mortality if not recognized. A 13-year-old presented with clusters of transient complete atrioventricular block after repair of a sinus venosus atrial septal defect. Pacemaker implantation was successful in treating these symptoms.

Use of 3D Electroanatomical Navigation (CARTO-3) to Minimize or Eliminate Fluoroscopy Use in the Ablation of Pediatric Supraventricular Tachyarrhythmias.

BACKGROUND: Radiation exposure related to medical procedures carries known medical risk. Electrophysiology (EP) and catheter ablation procedures are traditionally performed under fluoroscopic guidance. Three-dimensional (3D) electroanatomical navigation systems decrease or eliminate fluoroscopy use in EP procedures. OBJECTIVE: The aim of this study was to assess the efficacy and outcome of a minimal or no fluoroscopic electroanatomical mapping approach for catheter ablations for supraventricular tachycardia (SVT) in the pediatric population. METHODS: Patients were identified through our EP database. A retrospective chart review was performed at a single institution. RESULTS: Sixty-three pediatric patients underwent catheter ablations with a minimal fluoroscopic and 3D electroanatomical mapping using CARTO-3 system (Biosense Webster, Diamond Bar, CA, USA) between October 2012 and March 2015. We selected 20 age-matched patients who underwent ablations for SVT by the same operator prior to October 2012 with fluoroscopy use as our control group. The mean age in the study and control group was 13.9 years and 13.7 years, respectively. Mean procedure time was 208.7 minutes and 217.2 minutes in the study and control group (P = NS). Thirty-four (54%) in the study group had no fluoroscopy use. Mean fluoroscopy time was 4.1 minutes versus 35.4 minutes between the study and the control group (P < 0.001). Radiation dose was 6.7 mGy versus 209.3 mGy between the study and the control group (P < 0.001). Acute procedural success was achieved in 95% and 90% of patients in the study and control groups, respectively. On follow-up, the recurrence rate was 5.3% in the study group and 5.6% in the control group. CONCLUSION: Catheter ablation for SVT in children can be successfully performed in patients with normal cardiac anatomy using minimal or no fluoroscopy with favorable outcomes.

Cardiovascular risk factors and cardiac disorders in long-term survivors of pediatric liver transplantation.

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single-center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post-transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty-eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow-up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow-up being significant risk factors. Fifty-three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.

Compound heterozygous mutations in the SCN5A-encoded Nav1.5 cardiac sodium channel resulting in atrial standstill and His-Purkinje system disease.

An 11-year-old girl on evaluation for syncope was found to have progressive sinus node dysfunction and His-Purkinje system disease with atrial standstill. Genetic analysis revealed compound heterozygous mutations of the SCN5A gene in a novel combination.

Do LQTS gene single nucleotide polymorphisms alter QTc intervals at rest and during exercise stress testing?

BACKGROUND: The impact of harboring, genetic variants or single nucleotide polymorphisms (LQT-PM) on the repolarization response during exercise and recovery is unknown. OBJECTIVE: To assess the QTc interval adaptation during exercise stress testing (EST) in children with LQT polymorphisms compared to a group of age and gender matched normal controls. METHODS: One hundred forty-eight patients were age and gender matched into two groups: LQT-PM and control. Each patient underwent a uniform exercise protocol employing a cycle ergometer followed by a 9 minute recovery phase with continuous 12-lead electrocardiogram (ECG) monitoring. Intervals (RR, QT and QTc) at rest (supine), peak exercise and in recovery (1, 3, 5, 7, and 9 minutes) were measured. RESULTS: Forty-three patients were positive for LQT-PM and the control group consisted of 105 patients. A total of 83 SNPs were identified: SCN5A n = 31 (37%), KCNE1 n = 29 (35%), KCNH2 n = 20 (24%), KCNQ1 n = 2 (2%) and KCNE2 n = 1 (1%). The QTc interval measurements of the LQT-PM were longer at rest, peak exercise and all phases of recovery when compared to the control group. Neither group demonstrated abnormal QTc interval adaptation in response to exercise. Patients with homozygous SNPs had longer resting QTc intervals when compared to patients with only heterozygous SNPs (435 ± 23 ms vs. 415 ± 20 ms, respectively, P value <0.006). CONCLUSIONS: Individuals with LQT-PM may have longer QTc intervals at rest as well as at peak exercise and all phases of the recovery period compared to normal controls. Additionally, subjects with homozygous SNPs had longer resting QTc intervals when compared to those with only heterozygous SNPs.

Pattern of recovery for transient complete heart block after open heart surgery for congenital heart disease: duration alone predicts risk of late complete heart block.

Transient complete heart block (TCHB) is defined as complete interruption of atrioventricular conduction (AVC) after cardiac surgery followed by return of conduction. This study aimed to assess the risk for the development of late complete heart block (LCHB) after recovery of TCHB and to examine the electrocardiographic and electrophysiologic properties of the AVC system after TCHB. Of the 44 patients in this study who experienced TCHB, 37 recovered completely. Seven patients progressed from TCHB to intermittent CHB or LCHB requiring pacemaker implantation. Preoperative, early postoperative, and late postoperative electrocardiograms as well as postoperative atrial stimulation were obtained. The results showed that the median duration of TCHB was 5 days in the TCHB group compared with 9 days in the LCHB group (p = 0.01). All 37 subjects with TCHB recovered AVC within 12 days, but only two with LCHB did so (p = 0.02). The risk of LCHB for the patients with 7 days of postoperative TCHB or longer was 13 times greater than for the patients with fewer than 7 days of TCHB (p = 0.01). The median late postoperative PR interval was slightly but significantly longer in the LCHB group than in the TCHB group (p = 0.02). In contrast, the electrophysiologic properties between the two groups did not differ significantly. From those findings, we concluded that delayed recovery of AVC after surgical TCHB (≥7 days), but not electrophysiologic properties of recovered AVC assessed early in the postoperative period strongly, predicts risk of LCHB. Follow-up evaluation of AVC is particularly indicated for the delayed recovery group.

Electrocardiographic QTc as a Surrogate Measure of Cardiac Risk in Children, Adolescents, and Young Adults With Eating Disorders.

The study goal was to investigate electrocardiographic findings, including corrected QT interval (QTc), in patients aged 8 to 23 with eating disorders (EDs) at presentation, compared with an age-and sex-matched control population. We retrospectively reviewed 200 ED patients, and 200 controls. Blinded electrocardiograms (ECGs) were interpreted by an expert reader, and QT intervals corrected using the Bazett formula. Eating disorder patients were 89.5% female, with mean age 16.4 years and median percent median body mass index (BMI)-for-age (%mBMI)a of 91.1%. In ED patients, QTc was significantly shorter than controls (399.6 vs 415.0msec, P < .001). After adjusting for height, %mBMI, sex, magnesium level, and bradycardia, mean QTc duration in patients with anorexia nervosa-restricting subtype (AN-R) was significantly shorter than other ED patients (P = .010). Higher %mBMI was associated with shorter QTc duration (P = .041) after adjusting for height, magnesium, bradycardia, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis. Within the ED group, no significant association was identified between QTc and medications, electrolytes, or inpatient status.