Case 1 -
ARVC/D (Desmoplakin Gene Mutation) with Predominant Left Ventricular Involvement, Early Stage
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Asymptomatic athlete, he died suddenly while sleeping.
He regularly underwent to annual screening for competitive sport activity.
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)
- Normal physical examination
- No symptoms (palpitations, syncope)
- Normal 12-lead ECG
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.
Case 1 - Slide 1
Case 1 - 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.
Case 1 - 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.
Case 1 - 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.
Case 1 - 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.
ARVC/D (Desmoplakin Gene Mutation) with Predominant Left Ventricular Involvement, Early Stage
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
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.
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 .
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 .
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 , 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 .
Preliminary genotype-phenotype correlation studies show that LV involvement is often remarkable among
individuals with chain-termination mutations and/or desmoplakin disease
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