Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events.

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.

Utility of Echocardiography in the Assessment of Left Ventricular Diastolic Function and Restrictive Physiology in Children and Young Adults with Restrictive Cardiomyopathy: A Comparative Echocardiography-Catheterization Study.

The aim of the study is to determine the utility of echocardiography in the assessment of diastolic function in children and young adults with restrictive cardiomyopathy (RCM). RCM is a rare disease with high mortality requiring frequent surveillance. Accurate, noninvasive echocardiographic measures of diastolic function may reduce the need for invasive catheterization. Single-center, prospective, observational study of pediatric and young adult RCM patients undergoing assessment of diastolic parameters by simultaneous transthoracic echocardiogram (TTE) and invasive catheterization. Twenty-one studies in 15 subjects [median (IQR) = 13.8 years (7.0-19.2), 60% female] were acquired with median left ventricular end-diastolic pressure (LVEDP) 21 (IQR 18-25) mmHg. TTE parameters of diastolic function, including pulmonary vein A wave duration (r s  = 0.79) and indexed left atrial volume (r s  = 0.49), demonstrated significant positive correlation, while mitral valve A (r s  = -0.44), lateral e' (r s  = -0.61) and lateral a' (r s  = -0.61) velocities showed significant negative correlation with LVEDP. Lateral a' velocity (≤0.042 m/s) and pulmonary vein A wave duration (≥156 m/s) both had sensitivity and specificity ≥80% for LVEDP ≥ 20 mmHg. In pediatric and young adult patients with RCM, lateral a' velocity and pulmonary vein A wave duration predicted elevated LVEDP with high sensitivity and specificity; however, due to technical limitations the latter was reliably measured in 12/21 patients. These noninvasive parameters may have utility in identifying patients that require further assessment with invasive testing. These findings require validation in a multicenter prospective cohort prior to widespread clinical implementation.

Clinical Presentation and Outcomes by Sex in Arrhythmogenic Right Ventricular Cardiomyopathy: Findings from the North American ARVC Registry.

BACKGROUND: Sex differences in clinical presentation and outcomes of hereditary arrhythmias are commonly reported. We aimed to compare clinical presentation and outcomes in men and women with arrhythmogenic right ventricular cardiomyopathy (ARVC) enrolled in the North American ARVC Registry. METHODS: A total of 125 ARVC probands (55 females, mean age 38 ± 12; 70 males, mean age 41 ± 15) diagnosed, as either "affected" or "borderline" were included. Baseline clinical characteristics and time-dependent outcomes including syncope, ventricular tachycardia (VT), fast VT (>240 bpm), ventricular fibrillation (VF), and death were compared between males and females. RESULTS: The percentage of ARVC subjects diagnosed as "affected" (84% vs. 89%; P = 0.424) or "borderline" (16% vs. 11%; P = 0.424) was similar between females and males. Among the baseline characteristics, inverted T-waves in V2 trended to be more common in women (P = 0.09), whereas abnormal signal-averaged ECGs (SAECGs; P < 0.001) and inducible VT/VF (P = 0.026) were more frequent in men. During a mean follow-up of 37 ± 20 months, the probability of ICD-recorded VT/VF or death was not significantly different between men and women (P = 0.456). However, there was a trend toward lower risk of fast VT/VF or death in women compared to men (hazard ratio 0.41, 95% CI 0.151-1.113, P = 0.066). Abnormal SAECG and evidence of intramyocardial fat by cardiac MRI was associated with adverse outcomes in men (P = 0.006 and 0.02 respectively). CONCLUSION: In the North American ARVC Registry, we found similar frequency of "affected" and "borderline" subjects between men and women. Sex-related differences were observed in baseline ECG, SAECG, Holter-recorded ventricular arrhythmias, and VT inducibility. Men showed a trend toward greater risk of fast VT than women.

Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome.

BACKGROUND: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. OBJECTIVE: We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. METHODS: The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). RESULTS: Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥ 500 ms) was associated with a higher risk among women than among men. CONCLUSION: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

Association of left ventricular dilation at listing for heart transplant with postlisting and early posttransplant mortality in children with dilated cardiomyopathy.

BACKGROUND: In patients with dilated cardiomyopathy, the magnitude of cardiac remodeling often correlates with the clinical severity of heart failure. We sought to determine whether measures of left ventricular (LV) dilation and systolic dysfunction in children with dilated cardiomyopathy at the time of listing for cardiac transplantation are associated with survival while waiting for and early after transplant. METHODS AND RESULTS: We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups. CONCLUSIONS: The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

Assessment of the Cylex ImmuKnow cell function assay in pediatric heart transplant patients.

BACKGROUND: The Cylex ImmuKnow (Cylex, Columbia, MD) cell function assay (CICFA) is a commercially available test of immune response that purportedly identifies solid organ transplant patients at risk for either acute rejection (AR) or infection. Data on the utility of this test in pediatric heart transplant patients are very limited. This study tested the hypothesis that CICFA is a clinically useful test in this transplant population. METHODS: All children undergoing heart transplantation at the study center (1989-2006) for whom CICFA levels were obtained were reviewed. The association of CICFA levels with episodes of AR and significant infections was determined. RESULTS: Among 83 patients (34 girls, 41%), 367 CICFA levels were obtained (median, 4.0; interquartile range [IQR], 2.0-6.0 per patient). There were 26 episodes of AR in 17 patients (20%) and 38 infections in 34 patients (41%). CICFA levels were similar among patients with AR at the time of the CICFA measurement (median, 325 [IQR, 163-480] adenosine triphosphate [ATP] ng/ml) vs patients without AR (median, 330 [IQR, 227-441] ATP ng/ml; p = 0.36). CICFA levels were similar among patients with infections within 1 month of CICFA measurement (median, 295 [IQR, 216-366] ATP ng/ml) and those without infections (median, 330 [IQR, 226-453] ATP ng/ml; p = 0.24). CONCLUSIONS: The CICFA is not predictive of AR or significant infections in pediatric heart transplant patients. On the basis of the available evidence, this assay cannot be recommended as part of the routine management of pediatric heart transplant patients.

Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy.

Alpha T-catenin is a novel member of the alpha-catenin family, which shows most abundant expression in cardiomyocytes and in peritubular myoid cells of the testis, pointing to a specific function for alpha T-catenin in particular muscle tissues. Like other alpha-catenins, alpha T-catenin provides an indispensable link between the cadherin-based cell-cell adhesion complex and the cytoskeleton, to mediate cell-cell adhesion. By isolating genomic clones, combined with database sequence analysis, we have been able to determine the structure of the CTNNA3 and Ctnna3 genes, encoding human and mouse alpha T-catenin, respectively. The positions of the exon-exon boundaries are completely conserved in CTNNA3, Ctnna3, and the alpha N-catenin encoding CTNNA2 gene. They overlap largely with the boundaries of the CTNNA1 and CTNNAL1 genes encoding alpha E-catenin and alpha-catulin, respectively. This emphasizes that these alpha-catenin genes evolved from the same ancestor gene. Nevertheless, the introns of CTNNA3 and Ctnna3 are remarkably large (often more than 100 kb) compared with introns of other CTNNA genes. The CTNNA3 gene was mapped to chromosome band 10q21 by both fluorescence in situ hybridization and polymerase-chain-reaction-based hybrid mapping. This region encodes a gene for autosomal dominant familial dilated cardiomyopathy (DCM), a common cause of morbidity and mortality. As alpha T-catenin is highly expressed in healthy heart tissue, we have considered CTNNA3 as a candidate disease gene in a family showing DCM linkage to the 10q21-q23 locus. Mutation screening of all 18 exons of the CTNNA3 gene in this family has, however, not detected any DCM-linked CTNNA3 mutations.