Lower spatial QRS-T angle rules out sustained ventricular arrhythmias in children with hypertrophic cardiomyopathy.

Introduction The spatial peaks QRS-T angle accurately distinguishes children with hypertrophic cardiomyopathy from their healthy counterparts. The spatial peaks QRS-T angle is also useful in risk stratification for ventricular arrhythmias. We hypothesised that the spatial peaks QRS-T angle would be useful for the prediction of ventricular arrhythmias in hypertrophic cardiomyopathy patients under 23 years of age. METHODS: Corrected QT interval and spatial peaks QRS-T angles were retrospectively assessed in 133 paediatric hypertrophic cardiomyopathy patients (12.4±6.6 years) with versus without ventricular arrhythmias of 30 seconds or longer. Significance, positive/negative predictive values, and odds ratios were calculated based on receiver operating characteristic curve cut-off values. RESULTS: In total, 10 patients with ventricular arrhythmias were identified. Although the corrected QT interval did not differentiate those with versus without ventricular arrhythmias, the spatial peaks QRS-T angle did (151.4±19.0 versus 116.8±42.6 degrees, respectively, p<0.001). At an optimal cut-off value (124.1 degrees), the positive and negative predictive values of the spatial peaks QRS-T angle were 15.4 and 100.0%, respectively, with an odds ratio of 25.9 (95% CI 1.5-452.2). CONCLUSION: In children with hypertrophic cardiomyopathy, the spatial peaks QRS-T angle is associated with ventricular arrhythmia burden with high negative predictive value and odds ratio.

The spatial QRS-T angle outperforms the Italian and Seattle ECG-based criteria for detection of hypertrophic cardiomyopathy in pediatric patients.

INTRODUCTION: The spatial peaks QRS-T angle has been shown to differentiate adult patients with hypertrophic cardiomyopathy (HCM) from controls. We hypothesized that the spatial peaks QRS-T angle would, in isolation, be more accurate than the Italian 12-lead ECG Pre-participation Screening criteria or the Seattle criteria for detecting hypertrophic cardiomyopathy (HCM) in pediatric patients. METHODS: A retrospective study of pediatric patients with HCM compared to age and gender-matched control patients was undertaken. Significance, odds ratios, sensitivity and specificity of HCM detection of the visually derived spatial peaks QRS-T angle were compared to those of traditional 12-lead ECG criteria using: 1) Italy's National Pre-participation Screening Programme criteria; and 2) described criteria from Seattle. RESULTS: ECG results from 130 pediatric HCM patients (14.2±4.4years) were compared to 470 control patients (normal echocardiograms, mean age 13.4±4.6years). Mean±standard deviation (SD) values for spatial peaks QRS-T angles were 120.4±40.7 and 21.3±13.7 degrees for HCM and controls, respectively (P<0.001). A spatial peaks QRS-T angle cutoff value of >54.9 degrees yielded greater sensitivity and specificity (93.1% and 98.7%, respectively) for detecting HCM over ECG criteria from Italy (68.5% and 48.1%, respectively) or Seattle (64.6% and 78.9%, respectively) with odds ratios at 1039.70 (95% CI 363.03 to 2977.67), 2.01 (95% CI 1.33 to 3.04) and 6.84 (4.49-10.44), respectively. CONCLUSION: In our cohort, a visually derived spatial peaks QRS-T angle has increased sensitivity and specificity for detection of HCM in pediatric patients compared to currently utilized Italian or Seattle ECG criteria.

Prevalence of desmin mutations in dilated cardiomyopathy.

BACKGROUND: Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known. METHODS AND RESULTS: Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects. CONCLUSIONS: The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy.

BACKGROUND: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM. METHODS AND RESULTS: A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for alphaMyHC gene (MYH6) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure. CONCLUSIONS: This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.

Discovery of a potentially deleterious variant in TMEM87B in a patient with a hemizygous 2q13 microdeletion suggests a recessive condition characterized by congenital heart disease and restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare cause of heart muscle disease with the highest mortality rate among cardiomyopathy types. The etiology of RCM is poorly understood, although genetic causes have been implicated, and syndromic associations have been described. Here, we describe a patient with an atrial septal defect and restrictive cardiomyopathy along with craniofacial anomalies and intellectual disabilities. Initial screening using chromosomal microarray analysis (CMA) identified a maternally inherited 2q13 microdeletion. The patient had many of the features reported in previous cases with the recurrent 2q13 microdeletion syndrome. However, the inheritance of the microdeletion from an unaffected mother combined with the low incidence (10%) and milder forms of cardiac defects in previously reported cases made the clinical significance of the CMA results unclear. Whole-exome sequencing (WES) with trio-based analysis was performed and identified a paternally inherited TMEM87B mutation (c.1366A>G, p.Asn456Asp) in the patient. TMEM87B, a highly conserved, transmembrane protein of currently unknown function, lies within the critical region of the recurrent 2q13 microdeletion syndrome. Furthermore, a recent study had demonstrated that depletion of TMEM87B in zebrafish embryos affected cardiac development and led to cardiac hypoplasia. Thus, by combining CMA and WES, we potentially uncover an autosomal-recessive disorder characterized by a severe cardiac phenotype caused by mutations in TMEM87B. This study expands the spectrum of phenotypes associated with the recurrent 2q13 microdeletion syndrome and also further suggests the role of TMEM87B in its etiology, especially the cardiac pathology.

Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy.

Thymopoietin or TMPO (indicated by its alternative gene symbol, LAP2, in this work) has been proposed as a candidate disease gene for dilated cardiomyopathy (DCM), since a LAP2 product associates with nucleoplasmic lamins A/C, which are encoded by the DCM gene LMNA. We developed a study to screen for genetic mutations in LAP2 in a large collection of DCM patients and families. A total of 113 subjects from 88 families (56 with familial DCM (FDC) and 32 with sporadic DCM) were screened for LAP2 mutations using denaturing high-performance liquid chromatography and sequence analysis. We found a single putative mutation affecting the LAP2alpha isoform in one FDC pedigree. The mutation predicts an Arg690Cys substitution (c.2068C>T; p.R690C) located in the C-terminal domain of the LAP2alpha protein, a region that is known to interact with lamin A/C. RT-PCR, Western blot analyses, and immunolocalization revealed low-level LAP2alpha expression in adult cardiac muscle, and localization to a subset of nuclei. Mutated Arg690Cys LAP2alpha expressed in HeLa cells localized to the nucleoplasm like wild-type LAP2alpha, with no effect on peripheral and nucleoplasmic lamin A distribution. However, the in vitro interaction of mutated LAP2alpha with the pre-lamin A C-terminus was significantly compromised compared to the wild-type protein. LAP2 mutations may represent a rare cause of DCM. The Arg690Cys mutation altered the observed LAP2alpha interaction with A-type lamins. Our finding implicates a novel nuclear lamina-associated protein in the pathogenesis of genetic forms of dilated cardiomyopathy.

Predicting recovery: successful explant of a ventricular assist device in a child with dilated cardiomyopathy.

A previously healthy, 13-year-old girl presented with new-onset dilated cardiomyopathy, and is placed on a left ventricular assist device (VAD). Herein we describe a unique VAD weaning protocol used to determine the timing and feasibility of a VAD explant.

Danon disease presenting with dilated cardiomyopathy and a complex phenotype.

X-linked dilated cardiomyopathy (XLCM) was first described in 1987 and associated with dystrophin gene (DMD) mutations a decade later in one of the original two families. Here we report long-term follow-up of the second family (XLCM-2), for which a DMD mutation was never found. Analysis of the lysosome-associated membrane protein-2 (LAMP-2) gene detected a novel mutation, confirming a diagnosis of Danon disease. The broad phenotype in this family included dilated and hypertrophic cardiomyopathy, cardiac pre-excitation, skeletal myopathy with high serum creatinine kinase, cognitive impairement (in males), and and a pigmentary retinopathy in affected females. Cardiac biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. We conclude that XLCM may be the presenting sign of Danon disease and, in the presence of familial history of HCM, pre-excitation, skeletal muscle involvement and retinal pigmentary dystrophy should prompt LAMP-2 clinical testing. Furthermore, the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.