ARVC/D (Desmoplakin Gene Mutation) with Predominant Left Ventricular Involvement, Early Stage Cristina Basso

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Clinical history Asymptomatic athlete, he died suddenly while sleeping. He regularly underwent to annual screening for competitive sport activity. Normal physical examination No symptoms (palpitations, syncope) Normal 12-lead ECG The last 12-lead resting ECG, performed eight months before death for sports eligibility, was available and showed incomplete right bundle branch block, mild ST segment elevation in V1-V2, negative T wave in V1, Q wave in D2, D3 and AVF (Fig.1) Fig.1. 12-lead ECG performed eight months before death shows: incomplete right bundle branch block, mild ST segment elevation in V1-V2, negative T wave in V1, Q wave in D2, D3 and AVF. Autopsy ruled out unnatural (negative toxicologic investigation) and extracardiac causes of death. Gross examination of the heart revealed heart weight of 300 gr, transverse diameter 9,5 cm, longitudinal diameter 9,5 cm. LV wall thickness 13 mm, septal thickness 14 mm, RV free wall 3 mm. Origin and course of coronary arteries were normal, patent. Semilunar and atrioventricular valves were structurally normal. There was no evidence of myocardial hypertrophy, cavity enlargement, fatty infiltration and right and/or left ventricular aneurysm formation. At cross section, an "infarct-like" whitish band was visible in the outer mid subepicardial layer of the postero-septal and postero-lateral walls of the left ventricle (Fig.2). Fig.2. Gross examination of the heart. A) anterior, external view showing a apparently normal heart, in the absence of cardiomegaly, fatty infiltration and right and/or left ventricular aneurysm formation; B) cross sections at mid and apical level showing an "infarct-like" whitish band in the outer mid subepicardial layer of the postero-septal and postero-lateral walls of the left ventricle. Multiple samples of the myocardium were taken for histology as well as for molecular pathology investigation, including spleen and blood (frozen -80°). At histology, acute-subacute myocyte necrosis associated with inflammation was evident in the left ventricular myocardium. The inflammatory infiltrate was polymorphous and was associated with contraction band necrosis, myocytolysis, granulation tissue and loose fibrous and fatty tissue repair. Similar featured were also present focally in the right ventricular myocardium (Fig.3) Fig.3 Histology of the myocardium. A) Panoramic full thickness section of the postero-lateral wall of the left ventricle, confirming the fibrous band in the subepicardial layer; B) Same features in the postero-septal region; C) At higher magnification, acute-subacute myocyte necrosis associated with inflammatory infiltrates is evident. D) The inflammatory infiltrate appears polymorphous and is associated with myocytolysis, granulation tissue and loose fibrous and fatty tissue repair. Few months later, a guy of the same family, who had an aborted sudden death at the age of 18, was found affected by arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) accordingly to the diagnostic criteria score system. He was screened for DSP mutations. Polymerase chain reaction (PCR) primers flanking each exon of the human DSP gene were available. Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing. All amplimers showing abnormal elution profiles were sequenced using the BIG DYE dideoxy-terminator chemistry on an ABI 3730XL DNA sequencer. A single nucleotide substitution (S299R) in exon 7 of desmoplakin (DSP), which modifies a putative phosphorylation site in the N-terminal domain binding plakoglobin, was identified. The same mutation was identified in the blood of the case who died suddenly and in other family members. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 12-lead ECG performed eight months before death shows: incomplete right bundle branch block, mild ST segment elevation in V1-V2, negative T wave in V1, Q wave in D2, D3 and AVF. Figure 2 Gross examination of the heart. A) anterior, external view showing a apparently normal heart, in the absence of cardiomegaly, fatty infiltration and right and/or left ventricular aneurysm formation; B) cross sections at mid and apical level showing an "infarct-like" whitish band in the outer mid subepicardial layer of the postero-septal and postero-lateral walls of the left ventricle. Figure 3A & B Histology of the myocardium. A) Panoramic full thickness section of the postero-lateral wall of the left ventricle, confirming the fibrous band in the subepicardial layer; B) Same features in the postero-septal region. Figure 3C & D Histology of the myocardium. C) At higher magnification, acute-subacute myocyte necrosis associated with inflammatory infiltrates is evident. D) The inflammatory infiltrate appears polymorphous and is associated with myocytolysis, granulation tissue and loose fibrous and fatty tissue repair. Diagnosis ARVC/D (Desmoplakin Gene Mutation) with Predominant Left Ventricular Involvement, Early Stage Discussion According to the 1995 WHO classification, ARVC/D is defined as a heart muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium, initially with typical regional and later global right and some left ventricular involvement, with relative sparing of the septum [1, 2]. The residual myocytes interspersed among adipocytes and fibrous tissue provides the ideal substrate for reentrant life-threatening ventricular arrhythmias. The pathologic diagnosis of ARVC/D in autopsy hearts or those explanted at the time of cardiac transplantation has been traditionally based upon gross and histologic evidence of transmural fatty or fibro-fatty myocardial replacement. [3, 4, 5]. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling [2]. Genotype-phenotype correlations revealed that patients carrying desmoplakin mutations are characterized by a higher occurrence of left ventricular involvement. Ultrastructural investigation in desmosomal gene mutation carriers revealed intercalated disk remodelling with desmosomal abnormalities and intercellular gap widening (38), supporting a cascade of event including myocyte detachment and death, inflammatory response and fibro-fatty healing [6]. However, from the morphologic point of view we must recognize that: 1) the ARVC/D phenotype, although frequently genetically determined, is acquired and progressive. Thus, if sudden death occurs in the early stages, histological abnormalities may consist only of myocyte death and degenerative changes rather than mature fatty and fibrous tissue deposition, and may be confined to the subepicardial regions and not be transmural; 2) the left ventricle is more commonly involved in ARVC/D than initially thought and it should be carefully investigated, particularly in patients dying suddenly and in those who die or are transplanted due to congestive heart failure. Often left ventricular involvement consists of isolated or diffuse fibrous tissue deposition, in the subepicardial or midmural layers as compared to the usual pathology from the right side. Therefore consideration should be given to the terms of arrhythmogenic or desmosomal cardiomyopathy rather than ARVC/D. A representation of the broader real spectrum of ARVC/D has been recently provided by clinico-genetic characterization of families [7], leading to characterize three distinct patterns: 1) the classical RV phenotype, with isolated RV disease or left ventricular involvement in association with significant RV involvement; 2) the left dominant phenotype, with early and prominent left ventricular manifestations and relatively mild RV disease; and 3) the biventricular phenotype, characterized by equal involvement of both ventricles. These findings question the traditional view that left ventricular involvement occurs only at late stages, always preceded by severe RV involvement and support the adoption of the broader term arrhythmogenic cardiomyopathy [8]. Preliminary genotype-phenotype correlation studies show that LV involvement is often remarkable among individuals with chain-termination mutations and/or desmoplakin disease [9, 10]. 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