Usefulness of Combined Functional Assessment by Cardiac Magnetic Resonance and Tissue Characterization Versus Task Force Criteria for Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy.

Current task force criteria (TFC) of cardiac magnetic resonance (CMR) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC/D) were generated by comparing probands (mean age of 44 years) to healthy participants of the multi-ethnic study of atherosclerosis (mean age of 60 years). These age differences may be a selection bias because right ventricular end-diastolic volume index decreases 4.6% per decade. Moreover, fat infiltration and late gadolinium enhancement were not included. We evaluated the diagnostic accuracy of TFC using the same methodology used by the task force but comparing probands and age- and gender-matched healthy controls and considering also other morphofunctional and tissue abnormalities detected by CMR. Forty-seven probands with previous diagnosis of ARVC/D (excluding probands if CMR was used for diagnosis) were compared with 216 age- and gender-matched healthy controls. TFC had optimal specificity (100%) but poor sensitivity (20% for major and 13% for minor criteria). The presence of any pre- and post-contrast signal abnormalities had 100% specificity and 81% sensitivity. The best diagnostic accuracy (98%) was achieved by the combined evaluation of any right ventricular wall motion abnormality (excluding hypokinesia) with any signal abnormality (including left ventricular fat infiltration and late gadolinium enhancement) yielding a 100% specificity and 96% sensitivity. Left ventricular was involved in 45% of the probands. Current TFC for CMR presented optimal specificity but poor sensitivity to identify patient with ARVC/D. Signal and wall motion parameters of CMR should be considered together to achieve the best diagnostic accuracy for the diagnosis of ARVC/D.

The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified. METHODS AND RESULTS: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls. CONCLUSION: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.

Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers.

BACKGROUND: The p.Gln554X mutation in desmocollin-2 (DSC2) is prevalent in ≈10% of the Hutterite population. While the homozygous mutation causes severe biventricular arrhythmogenic right ventricular cardiomyopathy, the phenotypic features and prognosis of heterozygotes remain incompletely understood. METHODS AND RESULTS: Eleven homozygotes (mean age 32±8 years, 45% female), 28 heterozygotes (mean age 40±15 years, 50% female), and 22 mutation-negatives (mean age 43±17 years, 41% female) were examined. Diagnostic testing was performed as per the arrhythmogenic right ventricular cardiomyopathy modified Task Force Criteria. Inverted T waves in the right precordial leads on ECG were seen in all homozygotes but not in their counterparts (P<0.001). Homozygotes had higher median daily premature ventricular complex burden than did heterozygotes or mutation-negatives (1407 [IQR 1080 to 2936] versus 2 [IQR 0 to 6] versus 6 [IQR 0 to 214], P=0.0002). Ventricular tachycardia was observed in 60% of homozygotes but in none of the remaining individuals (P<0.001). On cardiac magnetic resonance imaging, homozygotes had significantly larger indexed end-diastolic volumes (right ventricular: 122±24 versus 83±17 versus 83±12 mL/m(2), P<0.0001; left ventricular: 93±18 versus 76±13 versus 80±11 mL/m(2), P=0.0124) and lower ejection fraction values compared with heterozygotes and mutation-negatives (right ventricular ejection fraction: 41±9% versus 59±9% versus 61±6%, P<0.0001; left ventricular ejection fraction: 53±8% versus 65±5% versus 64±5%, P<0.0001). Most affected individuals lacked right ventricular wall motion abnormalities. Thus, few met cardiac magnetic resonance imaging task force criteria. CONCLUSIONS: The ECG reliably identifies homozygous p.Gln554X carriers and may be useful as an initial step in the screening of high-risk Hutterites. The cardiac phenotype of heterozygotes appears benign, but further prospective follow-up of their arrhythmic risk is needed.

Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa.

Little is known about arrhythmogenic right ventricular cardiomyopathy (ARVC) in Africa. The objective of this study was to delineate the clinical characteristics, survival, and genetics of ARVC in South Africa. Information on clinical presentation, electrocardiographic and cardiac imaging findings, histology, and outcome of cases with suspected ARVC was collected using the standardised form of the ARVC Registry of South Africa. Genomic DNA was screened for mutations in plakophylin-2 (PKP2) gene. Survival and its predictors were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods, respectively. Fifty unrelated cases who met the diagnostic criteria for ARVC were enrolled between January 2004 and April 2009. Clinical presentation was similar to that reported in other studies. Annual mortality rate was 2.82%, five-year cumulative mortality rate 10%, and mean age at death 36.9 +/- 14.7 years. Overall survival was similar to the general South African population (P = 0.25). Independent risk factors for death were syncope (Hazard Ratio [HR] 10.73, 95% Confidence Interval [CI] 1.88-61.18, P = 0.008) and sustained ventricular tachycardia (HR = 22.97, 95%CI 2.33-226.18, P = 0.007). Seven PKP2 gene mutations were found in 9/36 (25%) unrelated participants, five being novel. The novel C1162T mutation occurred in four white South Africans sharing a common haplotype, suggesting a founder effect. Compound heterozygotes exhibited a severe phenotype signifying an allele dose effect. ARVC is associated with early mortality that is no different to the general South Africa population whose lifespan is shortened by HIV/AIDS. PKP2 gene mutations are common, have an allele dose effect, and a novel founder effect in white South Africans.