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Background: Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease., Methods: Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction., Results: A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 ( P =0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort-4 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with MYH6 - FLNC synergistic heterozygosity., Conclusions: Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation. more...

Background: In athletes, ECG changes from physiological cardiac remodelling are common but can overlap with findings from a pathological disorder. We compared ECG findings in a group of elite high school athletes to a cohort of adolescents with hypertrophic cardiomyopathy (HCM)., Methods/results: We prospectively performed 15-lead ECGs and echocardiograms in 147 elite high school athletes. Student-athlete ECGs were compared in blinded fashion to ECGs of 148 adolescents with HCM of similar age and ethnicity. Standard ECG hypertrophy criteria and established expert opinion guidelines (European Society of Cardiology, ESC and Seattle criteria) were analysed. All student-athletes had normal echocardiograms. Overall, 77/147 (52%) of student-athletes met standard ECG criteria for ventricular hypertrophy compared to 126/148 (85%) adolescents with HCM (p<0.0001). There were 112/148 (76%) adolescents with HCM who had pathological Q-waves, T-wave inversion and/or ST-segment depression compared to 1/147 (1%) athletes (p<0.0001). Most patients with HCM (84%, 124/148) had ≥1 abnormal ECG finding(s) according to Seattle criteria, compared to 1% of student-athletes (2/147). Similarly, 130/148 (88%) patients with HCM met group-2 ESC criteria (abnormal), compared to 36/147 (24%) student-athletes (p<0.0001)., Conclusions: Over 50% of elite high school athletes with echocardiographically confirmed normal hearts satisfied standard voltage criteria for ventricular hypertrophy. Pathological Q-waves, T-wave inversion or ST-segment depression were most helpful in distinguishing adolescents with HCM from normals. Both ESC and Seattle criteria successfully stratified the student-athlete and HCM cohorts, however each had a false-negative rate >10% for the HCM cohort. The Seattle criteria demonstrated a significantly lower false-positive rate (1%) than the ESC criteria (24%)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/) more...

In adults, the left atrial (LA) volume has been shown to reflect diastolic function and is a powerful predictor of cardiac morbidity and mortality. Normative LA volume values in children and the effect of loading conditions on the LA volume in those with congenital heart disease are lacking. The purposes of the present study were to (1) establish normal LA volume values for children, (2) assess the effect of left ventricular volume loading conditions on LA volume, and (3) describe the effect of abnormal myocardial relaxation on the LA volume. We retrospectively reviewed the echocardiograms from 3 pediatric cohorts: group N (n = 522), children with normal echocardiographic findings; group VSD/PDA (n = 71), children with ventricular septal defect (VSD; n = 50) or patent ductus arteriosus (PDA; n = 21); and group HC (n = 63), children with hypertrophic cardiomyopathy (HC). In group N, we identified the LA volume indexed to the body surface area (LA volume index) as a consistent measure of the LA volume in children 3 to 23 months old (mean 16 ± 3 ml/m(2)) and 2 to 17 years old (mean 22 ± 4 ml/m(2)). LA dilation was more common in group VSD/PDA than in group N (27% vs 2%, p <0.0001) and in children with moderate or large shunts than in those with smaller shunts (61% vs 5%, p <0.0001). In group HC, the LA volume index correlated with the mitral valve E/e' ratio (p <0.0001). In conclusion, this is the first study to establish normal pediatric LA volume values. The LA volume index is a reproducible measure of LA size in children ≥ 3 months old. The LA volume index reflects a chronically increased left ventricular volume load in children with VSD or PDA and chronically elevated left ventricular filling pressures in children with HC., (Copyright © 2010 Elsevier Inc. All rights reserved.) more...

Left atrial (LA) enlargement is an indicator of chronic elevation in left ventricular (LV) end-diastolic pressure as well as diastolic dysfunction. There is a lack of data on the significance of LA volume in the pediatric population. The objective of this study was to elucidate the relation between LA volume and diastolic dysfunction, clinical symptoms, and exercise capacity in young patients with hypertrophic cardiomyopathy. All patients aged <20 years with obstructive hypertrophic cardiomyopathy who underwent evaluation at the Mayo Clinic from 2002 to 2006 were retrospectively identified. Reviews of the LA volume index and other traditional diastolic Doppler echocardiographic parameters, as well as clinical data, were performed. A total of 88 patients (66 male) were studied. The median age at evaluation was 14 years. The mean LA volume index was 39 +/- 19 ml/m(2). Additional echocardiographic parameters included a mean LV outflow gradient of 55 +/- 51 mm Hg, a mean E/E' ratio of 14.0 +/- 7.6, and a mean maximal septal wall thickness of 23 +/- 9 mm. On univariate linear regression analysis, LA volume index had an excellent correlation with diastolic dysfunction grade (p <0.001, r(2) = 0.6), LV outflow tract gradient, mitral E/E', and the degree of mitral regurgitation. LA volume index was also positively associated with symptom score (p = 0.005) and maximal oxygen consumption on exercise test (n = 22; p = 0.01). On multivariate analysis, LA volume index was related to diastolic dysfunction grade (p <0.001) and mean mitral regurgitation grade (p = 0.05). In conclusion, this study demonstrates the potential clinical importance of LA volume index in pediatric hypertrophic cardiomyopathy as a marker of the severity of underlying diastolic dysfunction, symptom score, and decreased exercise capacity. LA volume index has significant diagnostic and prognostic value in these patients. more...

Background: Septal myectomy in young patients with obstructive hypertrophic cardiomyopathy (HCM) can be performed with low mortality, and leads to excellent improvement in symptoms. Left atrial (LA) enlargement has been associated with exercise intolerance, severity of mitral regurgitation (MR), and left ventricular (LV) outflow tract (LVOT) obstruction in adults with HCM., Methods: Young patients (1-22 years of age) who had a septal myectomy for obstructive HCM between 2002 and 2005 were identified. Retrospective analyses of premyectomy and postmyectomy echocardiograms were performed., Results: In this cohort of 32 patients (25 male), the average maximal LV wall thickness was 25 +/- 9 mm and LVOT maximal instantaneous gradient was 106 +/- 44 mm Hg. MR was present in all patients with a mean grade of 3 +/- 1. All patients had successful myectomy and there were no early deaths. After myectomy, LVOT maximal instantaneous gradient decreased to 17 +/- 13 mm Hg (P < .0001). Mean LA volume (LAV) index decreased from 52.1 +/- 2.2 to 33.2 +/- 11.9 mL/m(2) (P < .0001). Mean MR grade decreased to 2 +/- 1. Early mitral medial annular tissue Doppler velocity (E') increased from 6.2 +/- 1.9 to 13 +/- 2.6 cm/s (P < .043). A postmyectomy decrease in LAV index correlated with decrease in LVOT obstruction (P = .001) and change in degree of MR (P = .04)., Conclusion: Septal myectomy not only reduces LVOT maximal instantaneous gradient and MR in young patients, but also results in decreased LAV index, and E/A and E/E' ratios. These hemodynamic improvements may contribute to the observed survival benefit and increased exercise tolerance observed after myectomy. This is the first series to demonstrate that LAV correlates closely with hemodynamic status in children with obstructive HCM and may be a significant predictor of clinical outcome in these patients. more...

Background: Symptomatic pediatric patients with obstructive hypertrophic cardiomyopathy (HCM) have a higher death rate (6% annually) compared with adults. Transaortic left ventricular septal myectomy provides excellent outcomes for adults with obstructive HCM. We sought to assess the effect of septal myectomy on late survival and outcome in pediatric patients with obstructive HCM., Methods: From 1975 to 2003, 56 pediatric patients underwent septal myectomy for obstructive HCM. Mean age at diagnosis was 6.3 +/- 5.4 years. Ages at operation ranged from 2 months to 20 years (mean 11 +/- 5.6 years). Concomitant procedures included mitral valve repair (n = 7), closure of atrial septal defect (n = 3), and other (n = 5)., Results: After myectomy, mean left ventricular outflow tract (LVOT) gradient decreased from 103 +/- 34 to 16 +/- 12 mm Hg and mean degree of mitral regurgitation decreased from 2.0 +/- 1.0 to 1.0 +/- 0.3 (both p < 0.0001). There were no early deaths. Four patients underwent elective cardioverter defibrillator implantation and 1 patient received a permanent pacemaker. Follow-up ranged up to 29 years (mean, 8.6 +/- 6.2). Cardiac reoperations were required in 8 patients: heart transplantation (n = 2), repeat myectomy (n = 2), mitral valve repair-replacement (n = 2), Konno-Rastan procedure (n = 1), and aortic valve replacement (n = 1). Age 14 years or less at operation was the only predictor of late reoperation (p = 0.017). Two patients died late; one suddenly without residual LVOT obstruction and one from chronic rejection after heart transplantation. Ninety-six percent of surviving patients were in New York Heart Association functional class I or II. Survival estimates at 5 and 10 years were 97% and 93%, respectively., Conclusions: Septal myectomy is safe and effective in symptomatic pediatric patients with obstructive HCM. Late survivorship compares very favorably with the natural history of this disease. more...

Background: Left ventricular septal myectomy provides excellent outcomes for symptomatic patients with severe obstructive hypertrophic cardiomyopathy. However, in a few patients, left ventricular outflow tract obstruction may recur and require repeat myectomy. We reviewed this subset of patients to assess the mechanisms of recurrence., Methods: From 1975 to July 2003, 610 septal myectomies were performed; 13 of these were repeat myectomies after classic myectomies performed at our institution (n = 6) or elsewhere (n = 7). Ages ranged from 4 to 70 years (mean, 32 +/- 22). The interval between initial myectomy and repeat myectomy ranged from 13 months to 11 years (mean, 5.0 +/- 3.7 years)., Results: Mechanisms for obstruction included limited myectomy at the initial myectomy (n = 11), septal hypertrophy at the midventricular level (n = 8), and anomalous papillary muscles (n = 3). Mean intraoperative pressure gradients decreased from 82 +/- 24 to 6.2 +/- 4.4 mm Hg. No mitral valve replacement was performed, and there were no early deaths. Mean follow-up was 5.8 +/- 5.8 years. There was one late death. All surviving patients were free from recurrence of outflow tract obstruction and were in the New York Heart Association functional class I or II., Conclusions: Mechanisms for recurrent obstruction included limited myectomy at the initial operation, midventricular obstruction, anomalies of papillary muscles, and ventricular remodeling, especially in pediatric patients. Repeat myectomy can be performed with excellent outcomes. Need for reoperation may be reduced with current surgical approaches that include a more extended resection of the midventricular septum, relief of papillary muscle anomalies, and routine use of intraoperative transesophageal echocardiography. more...

Background: Early identification of familial cases of hypertrophic cardiomyopathy (HCM) depends on screening echocardiography, but hypertrophy may not be the most sensitive marker for the disease. We report the echocardiographic findings of a family with HCM and a newly reported mutation in the gene (TPM1) encoding alpha-tropomyosin.Methods and results An 8-year-old girl had sudden cardiac death, and was found to have HCM and a novel L185R-TPM1 mutation on postmortem examination. Screening echocardiograms and DNA analyses were performed on her family. Of the 5 remaining family members, 3 were genetically affected. Those without the TPM1 mutation had normal echocardiographic results. The only echocardiographic finding that identified all 3 of the gene-positive family members was an abnormal left ventricular diastolic filling pattern., Conclusion: Abnormal left ventricular diastolic filling patterns, indicating diastolic dysfunction, may provide an early marker for the diagnosis of familial HCM in children, even in the absence of left ventricular hypertrophy. more...