Even before the publication of the Task Force criteria in 1994, study of relatives of probands diagnosed with ARVC/D identified features of disease which were not as marked as in the proband, suggesting considerable heterogeneity of disease expression, even within relatives carrying the same gene mutation. There was evidence supporting both incomplete and age-related penetrance . From the Veneto region of Italy we have evidence on postmortem of ARVC/D in athletes who did not fulfill the diagnostic criteria antemortem. This so-called concealed phase of ARVC/D is problematic, as fatal arrhythmias can occur in the absence of gross morphological changes [3-5]. Since the publication of the Task Force criteria in 1994, the identification of specific gene mutations responsible for ARVC/D has provided evidence of gene carriers with some features of ARVC/D which are insufficient to fulfill the Task Force criteria. Logic dictates that these subjects have at least a "forme fruste" of ARVC/D and data is still lacking as to whether the natural history for those with incomplete penetrance differs substantially from those who fulfill classical Task Force criteria for ARVC/D.
Previous evaluation of relatives of patients with hypertrophic and dilated cardiomyopathy has shown that some have phenotypic abnormalities which, while non-diagnostic, are indicative of disease expression [54,55]. Hamid et al. evaluated family members of ARVC/D probands to determine if reliance on Task Force criteria to diagnose ARVC/D would result in significant underreporting in the setting of family screening . They evaluated almost 300 relatives of 67 probands (a mean of 4.4 subjects per family). Features of ARVC/D
Table 10.2 • Proposed modification of Task Force criteria f< from  with permission from the BMJ Publishing Group fulfillling diagnostic criteria were identified in 10% of relatives, suggesting familial disease in 28% of probands. This is somewhat less than what reported elsewhere of up to 50% familial disease . However a further 11% of relatives had isolated minor criteria on clinical evaluation. These included T-wave inversion of right precordial leads in 41% and a positive signal-averaged ECG in almost one third. A small proportion had an excess of 200 ventricular ectopics on 24-h Holter monitoring (2%). These "nondiagnostic" cases, if accepted by logic to be affected in the context of a definitely affected relative and 50% gene transmission, would bring the total proportion of familial disease to 50%, which is similar to the findings in dilated car-diomyopathy (when isolated left ventricular enlargement or depressed fractional shortening are included)  and in hypertrophic cardiomyopathy (when isolated ECG abnormalities or mild hypertrophy on echo are included) . The authors therefore propose a modification of the Task Force criteria, which could be used as a diagnostic tool, but only in first degree relatives of a patient with confirmed ARVC/D (Table 10.2). In this context, the presence of any one of right precordial T-wave inversion, late potentials on signal-averaged ECG, ventricular tachycardia with LBBB morphology, or minor functional or morphological changes of the right ventricle on imaging should be considered diagnostic for familial ARVC/D. In addition, they proposed that the arbitrary threshold value of 1,000 ventricular ectopics in a 24-h period be reduced to 200 ventricular ectopics, which would appear to be indicative of familial disease expression (Table 10.2).
As with the Task Force criteria, these proposed modified criteria require validation in prospectively evaluated familial ARVC/D. With the increasing number of disease-causing genes identified, there has been some evidence of improved diagnostic yield incorporating both diagnostic criteria. Bauce et al. described the findings in probands and relatives with four novel desmoplakin mutations . Applying the diagnosis of familial ARVC/D. Adapted and reproduced
Proven ARVC/D in a first-degree relative plus one of the following
T-wave inversion in the right precordial leads (V2 and V3) III. Arrhythmia:
Ventricular tachycardia with left bundle branch block morphology (documented on ECG, Holter monitoring or during exercise testing)
>200 ventricular extrasystoles over 24 hours (Holter monitor)
II. Signal averaged ECG:
Demonstration of late potentials
IV. Structural or functional abnormality of the right ventricle:
Mild global RV dilatation of the RV and/or reduction in ejection fraction with normal LV Mild segmental dilatation of the RV Regional RV hypokinesia
ARVC/D, Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplesia; ECG,electrocardiogram;LV, left ventricle;RV, right ventricle
Task Force criteria, only 54% of gene carriers achieved the threshold for a diagnosis of ARVC/D. However, two thirds of mutation carriers were found to have some abnormality on ECG or echo. One of these with a nonspecific ECG abnormality alone died suddenly shortly after evaluation. Applying the modified criteria of Hamid et al. ,an additional 15% of relatives could be considered affected, bringing gene penetrance for desmoplakin to almost 70%.
Our experience with plakophilin-2 mutations is similar. In eleven probands and their relatives we identified 66% of gene carriers who fulfillled Task Force criteria. Extending the diagnosis to those who fulfill the proposed modified criteria suggests gene penetrance for these families approaches 100% .
While these data support the benefit in modifying diagnostic criteria for familial disease, genotype phe-notype studies have also highlighted limitations of the proposed system. This is perhaps not unexpected, given the nonspecific nature of most of the diagnostic criteria, as previously discussed. In two relatives without plakophilin-2 mutations, clinical evaluation had identified right ventricular enlargement in one, and high volume ventricular ectopy in another, but no other clinical features of ARVC/D in either. This had led to the clinical suspicion of gene carrier status, which was subsequently proved not to be the case . Also, in evaluating families with desmoglein-2 mutations, we identified a mother and daughter whose only abnormal finding was late potentials on signal-averaged ECG. As their father/grandfather had died suddenly at the age of 54, it was assumed that this was likely related to ARVC/D (as his nephew had died with postmortem pathological confirmation of ARVC/D). It was subsequently confirmed that the 54-year-old man died as a result of myocardial infarction, with fresh coronary thrombosis identified at postmortem, and the disease both clinically and genetically segregated with the other side of the proband's family. Therefore exclusive use of Task Force criteria has been shown to result in false negative diagnoses, and exclusive application of the proposed modified criteria within the context of familial ARVC/D will result in false positive diagnoses.
A further limitation of both criteria is the exclusion of left ventricular disease as an indicator of disease expression. Indeed, the Task Force criteria by definition exclude those with more than mild reduction in left ventricular systolic function. Many case series over the last 20 years have described varying proportions of patients exhibiting signs of left ventricular involvement. These range from 16%  to 27% , and if only those with Task Force criteria disease expression are considered, for desmoplakin the prevalence is over 40%. A review of pathological findings of 47 patients whose hearts were examined at autopsy or cardiac transplantation found that 76% had evidence of left ventricular involvement, either microscopically or macro- and microscopically, and these patients had a higher incidence of clinical complications (arrhythmias and heart failure)  (Fig. 10.3).
We have recently published our findings related to a large family with a novel desmoplakin mutation . On evaluating nine living relatives of a proband with isolated left ventricular fibrofatty change on postmortem, only four of these mutation carriers ful-fillled Task Force criteria for a diagnosis of ARVC/D. Left ventricular disease was noted to be a prominent feature, both on imaging and in evidence of left precordial variants of the ECG patterns associated with ARVC/D. By modifying the Task Force criteria to include left ventricular rather than right ventricular abnormalities, the penetrance of this mutation was 93%, and the one patient who did not fulfill left ventricular Task Force criteria actually fulfillled right ventricular traditional criteria.
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