Julie Rutberg

Misdiagnosis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Introduction: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has major implications for the management of patients and their first‐degree relatives. Diagnosis is based on a set of criteria proposed by the International Task Force for Cardiomyopathies. We report our experience in providing a re‐evaluation for patients who previously have been diagnosed with ARVD/C.

Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis

BACKGROUND Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. METHODS Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. RESULTS Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. CONCLUSIONS The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome.

Magnetic Resonance Imaging Findings in Patients Meeting Task Force Criteria for Arrhythmogenic Right Ventricular Dysplasia

Introduction: Magnet resonance imaging (MRI) findings in patients meeting Task Force criteria for the diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) have not been systematically described. We report qualitative and quantitative MRI findings in ARVD using state‐of‐the‐art MRI.

Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper.

The era of gene discovery and molecular medicine has had a significant impact on clinical practice. Knowledge of specific genetic findings causative for or associated with human disease may enhance diagnostic accuracy and influence treatment decisions. In cardiovascular disease, gene discovery for inherited arrhythmia syndromes has advanced most rapidly. The arrhythmia specialist is often confronted with the challenge of diagnosing and managing genetic arrhythmia syndromes. There is now a clear need for guidelines on the appropriate use of genetic testing for the most common genetic conditions associated with a risk of sudden cardiac death. This document represents the first ever published recommendations outlining the role of genetic testing in various clinical scenarios, the specific genes to be considered for testing, and the utility of test results in the management of patients and their families.

Hyperprolinaemia in patients with deletion (22)(q11.2) syndrome

B. K. Goodman1;5, J. Rutberg2, W. W. Lin6, A. E. Pulver3, G. H. Thomas2;5 and M. T. Geraghty2;4* Departments of 1 Gynecology and Obstetrics, 2 Pediatrics, 3 Psychiatry and 4 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 5 Kennedy Krieger Institute, Baltimore, Maryland, USA; 6 Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan

Inherited duplication Xq27-qter at Xp22.3 in severely affected males: Molecular cytogenetic evaluation and clinical description in three unrelated families

We describe the clinical phenotype in four males from three families with duplication (X)(qter-->q27::p22.3-->qter). This is an unusual duplication of the distal long arm segment, Xq27-qter, onto the distal short arm of the X chromosome at Xp22.3, as shown by fluorescent in situ hybridization analysis with multiple X-specific probes. The patients are young male offspring of three unrelated, phenotypically normal carrier women. The affected males have similar clinical manifestations including severe growth retardation and developmental delay, severe axial hypotonia, and minor anomalies. Such clinical similarity in three unrelated families demonstrates that this chromosome abnormality results in a new and distinct clinical phenotype. Replication studies, performed on two of the mothers, provided evidence that inactivation of the abnormal X chromosome permitted the structural abnormality to persist in these families for a generation or more in females without phenotypic expression.

Utility of SAECG in arrhythmogenic right ventricle dysplasia.

Background: Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by progressive replacement of RV myocardium with fibro‐adipose tissue thought to be responsible for the presence of late potentials (LP) detected by SAECG. The general consensus on the role of SAECG in the diagnosis and prognosis of patients with ARVD is lacking. The purpose of this systematic review was to better define the role of SAECG in ARVD.

Exercise Testing in Asymptomatic Gene Carriers Exposes a Latent Electrical Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy

OBJECTIVES The aim of this study was to determine if exercise testing could expose a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy (ARVC) in asymptomatic gene carriers. BACKGROUND Management of asymptomatic ARVC gene carriers is challenging because of variable penetrance of disease and the recognition that sudden cardiac death may be the first clinical manifestation. METHODS Exercise-induced abnormalities during exercise treadmill testing (ETT) were initially compared in 60 subjects: 30 asymptomatic ARVC gene carriers and 30 healthy controls. In phase 2 of the study, ETT results of 25 patients with ARVC with histories of sustained ventricular arrhythmia or cardiac arrest were evaluated to determine if ETT abnormalities in asymptomatic gene carriers were common to patients with a malignant electrical form of the disease. RESULTS Depolarization abnormalities during ETT were found to develop more frequently in asymptomatic gene carriers compared with healthy controls: epsilon waves appeared in 4 of 28 (14%) compared with 0 of 30 (0%) (p = 0.048), premature ventricular contractions in 17 of 30 (57%) compared with 3 of 30 (10%) (p = 0.0003), and new QRS terminal activation duration ≥ 55 ms in 7 of 22 (32%) compared with 2 of 29 (7%) (p = 0.03). Superior axis premature ventricular contractions occurred only in gene carriers. In the second phase of the study, the frequency of these abnormalities was found to be high in patients with symptomatic ARVC: new epsilon waves appeared in 3 of 18 (17%), superior axis premature ventricular contractions in 21 of 25 (84%), and new terminal activation duration ≥ 55 ms in 8 of 12 (67%). CONCLUSIONS Exercise testing exposes a latent electrical substrate in asymptomatic ARVC gene carriers that is shared by patients with ARVC with histories of ventricular arrhythmia. ETT may be useful in guiding treatment decisions, exercise prescription, and prioritizing medical surveillance in asymptomatic ARVC gene carriers.

Filtered QRS duration on signal-averaged electrocardiography predicts inducibility of ventricular tachycardia in arrhythmogenic right ventricle dysplasia.

Treatment of arrhythmogenic right ventricular dysplasia (ARVD) is mostly based on the prevention of sudden cardiac death that results from arrhythmias. A clinical history suggestive of ARVD requires careful evaluation including electrophysiological study. The potential ability to identify those patients who will have inducible VT with electrophysiological study will enable better risk stratification and selection of vulnerable patients for electrophysiologically guided therapy. The purpose of the study was to evaluate the predictive ability of signal‐averaged electrocardiography (SAECG) to predict inducibility of VT in patients with ARVD. The patient population consisted of 31 ARVD patients diagnosed with McKennas criteria who underwent electrophysiological study. Electrophysiological study was considered positive if sustained monomorphic VT was induced. The sensitivity, specificity, and predictive accuracy of various SAECG criteria for inducibility of sustained monomorphic VT were also calculated. Twenty‐one patients had inducible VT. The filtered QRS duration (fQRS), duration of signal <40 uV (LAS40), and root mean square voltage in the last 40 ms of QRS duration (RMS40) in ARVD patients induced versus noninduced were 122 ± 21 and 103 ± 8 ms (P = 0.007), 45 ± 20 and 28 ± 14 ms (P = 0.02), 19 ± 19 and 32 ± 22 uV (0.03), respectively. The ejection fractions were comparable in both groups. fQRS duration ≥110 ms had sensitivity of 91%, specificity of 90%, and a total predictive accuracy of 90% in predicting inducibility of VT in these patients. Filtered QRS duration on SAECG is predictive of electrophysiological study outcome in ARVD. Further studies will be needed to determine if SAECG results can predict the development of ventricular arrhythmias during follow‐up. (PACE 2003; 26:1955–1960)

Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents an inherited cardiomyopathy that manifests clinically with malignant ventricular arrhythmias, sudden cardiac death, and less commonly heart failure. The condition is characterized by replacement of the myocardium, primarily of the right ventricle, with fibrofatty tissue. Extensive fibrofatty replacement of the myocardium has been previously thought to be pathognomonic of ARVC; however, this report details two other forms of inherited cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and the PRKAG2 cardiac syndrome, that were found to have significant fibrofatty myocardial replacement at pathologic examination. This report represents the first documentation of inherited cardiomyopathies mimicking ARVC and highlights the concept that other cardiac conditions can be associated with fibrofatty replacement of the myocardium.