Arrhythmogenic Cardiomyopathy


This work has been supported by TRANSAC, University of Padua Strategic Project CPDA133979/13, Padua, Italy; Registry for Cardio-cerebro-vascular Pathology, Veneto Region, Venice, Italy; Target Project, Regional Health System, Venice, Italy; PRIN Ministry of Education, University and Research 2010BWY8E9_004, Rome, Italy; University Research Grant CPDA144300, Padua, Italy.

Arrhythmogenic cardiomyopathy (AC) is a rare, genetically determined cardiomyopathy featured by progressive myocardial dystrophy with fibrofatty replacement afflicting the right ventricle (RV), left ventricle (LV), or both. AC shows an age-related penetrance, manifesting with palpitations, syncope, or cardiac arrest usually in adolescence or young adulthood, and represents one of the major causes of sudden death in the young and athletes. It is caused mostly by heterozygous or compound heterozygous mutations in genes encoding proteins of the desmosomal complex (approximately 50% of probands). Cases with a recessive trait of inheritance have been reported, either associated or not with skin/hair abnormalities. The estimated prevalence of AC in the general population ranges from 1:2000 to 1:5000. AC affects more frequently males than females (up to 3:1), despite a similar prevalence of carrier status, and becomes clinically overt most often in the second to fourth decade of life.

Pathologic Findings

AC is a “structural” cardiomyopathy characterized by the replacement of the ventricular myocardium by fibrofatty tissue. Myocardial atrophy occurs progressively with time, starts from the epicardium, and eventually extends down to reach the endocardium as to become transmural. This entity should not be confused with Uhl disease, a congenital heart defect in which the RV myocardium fails to develop during embryonic life. The gross pathognomonic features of AC consist of RV aneurysms, whether single or multiple, located in the so-called triangle of dysplasia (ie, inflow, apex, and outflow tract). Cases with isolated or predominant LV involvement are not so rare. Indeed, up to 76% of the AC hearts studied at post mortem revealed an LV involvement, usually limited to the subepicardium or midmural layers of the posterolateral free wall. Hearts with end-stage disease and congestive heart failure show usually multiple RV aneurysms, thinning of the RV free wall, and huge chamber dilatation, with a high prevalence of biventricular involvement, whereas the ventricular septum is mostly spared.

Histologic examination reveals islands of surviving myocytes, interspersed with fibrous and fatty tissue. Fatty infiltration of the RV is not a sufficient morphologic hallmark of AC 12 and replacement-type fibrosis and myocyte degenerative changes should be always searched for. Myocyte necrosis is seldom evident and may be associated with inflammatory infiltrates. Myocardial inflammation has been reported in up to 75% of hearts at autopsy. An apoptotic mechanism of myocyte death has been also demonstrated in humans. Rather than being a continuous ongoing process, disease progression may occur through periodic “acute bursts” of an otherwise stable disease, as to mimic “infarct-like” myocarditis or simulate myocardial infarction. In a desmoglein-2 transgenic animal model, spontaneous myocyte necrosis was demonstrated to be the key initiator of myocardial injury, triggering progressive myocardial damage, followed by an inflammatory response. The detection of viral genomes in humans led to the possibility of an infective viral etiology, but it is most likely that either viruses are innocent bystanders or that myocardial cell degeneration may serve as a milieu favoring viral settlement.

Pathogenesis of Arrhythmogenic Cardiomyopathy

Transgenic animal models that mimic the human AC phenotype (mice and zebrafish) and induced pluripotent stem cells (iPSCs) from affected patients are useful tools to explore how the mechanical and/or functional disruption of cell junctions by mutant desmosomal proteins leads to cardiomyocyte death and subsequent repair with fibrous and adipose tissue.

Abnormal Cell-Cell Adhesion

Even before the discovery of desmosomal genes in AC, electron microscopy studies, demonstrating intercalated disc disruption, first raised the hypothesis of an abnormal cell-cell adhesion in disease pathogenesis. However, more recent studies point to the possible role of mutant desmosomal proteins in intracellular signaling rather than adhesion remodeling, as initially assumed.

Abnormal Intercellular Junction Proteins and Intracellular Signaling

The role of mutant desmosomal proteins in the intracellular signaling was first demonstrated in a Desmoplakin (DSP)-deficient mouse model, with the Wnt signaling pathway suppression leading to adipogenesis as a consequence of the abnormal distribution of intercalated disc proteins. More recent studies in different experimental models further support this hypothesis, showing an additional suppression of the canonical Wnt signaling leading due to aberrant activation of the Hippo kinase cascade pathway, which resulted into phosphorylation and cytoplasmic retention of yes associated protein (YAP) leading to enhanced myocyte death and fibroadipogenesis as a consequence of β-catenin and junctional plakoglobin (JUP) cytoplasmic sequestration.

However, cellular reprogramming of patient-derived somatic cells (ie, dermal fibroblasts) into iPSCs from AC patients with plakophilin-2 (PKP2) mutations, demonstrated that the abnormal JUP nuclear translocation and decreased β-catenin activity is insufficient to reproduce the pathologic phenotype in standard conditions and only the induction of an adult-like metabolism in a lipogenic milieu coactivated peroxisome proliferator-activated receptor (PPAR)-γ pathway with lipogenesis, apoptosis, and calcium-handling deficit.

It is noteworthy that transgenic experimental animal models and iPSC-derived cardiomyocytes demonstrated only abnormal “lipogenesis,” but not adipocyte formation or sudden death. Thus cells other than cardiomyocytes must be involved in the abnormal adipogenesis and fibrosis, which is also an essential feature of AC phenotype. A role of cardiac mesenchymal stromal cells as a source of adipocytes in AC has been recently advanced.

Gap Junction and Ion Channel Remodeling

Desmosomes, gap junctions, and sodium channels act as a functional triad in which changes in the composition of one constituent can affect the function and integrity of the others. Recent studies demonstrated diminished connexin-43 expression at intercellular junctions of most AC human myocardial specimens and reduced cardiac sodium current in experimental models of AC. These findings led to the hypothesis that life-threatening ventricular arrhythmias could occur in AC patients, even preceding the structural abnormalities (prephenotypic stage) due to electrical uncoupling and reduced sodium current prevention. However, it remains to be proven in humans.

From Experimental Models to Target Therapy

Finally, in a transgenic AC zebrafish model with cardiac specific expression of the human JUP deletion, high-throughput drug screening identified SB216763, an activator of the canonical Wnt signaling pathway, as able to prevent heart failure and normalize survival. Treatment with the SB216763 compound restores the subcellular distribution of JUP, connexin 43, Nav1.5, and SAP97, a protein known to mediate the forward trafficking of Nav1.5 and Kir2.1, opening the door to the identification of a curative therapy in AC by targeting a final common pathway of disease pathogenesis.

Clinical Findings and Natural History

In adolescents or young adults, AC usually presents with heart palpitations, syncope, or cardiac arrest. Premature ventricular complexes (PVC) or ventricular tachycardia (VT) with left bundle branch block (LBBB) morphology and T wave inversion in V 1 to V 3 on the electrocardiogram (ECG) are the most common signs suggesting the presence of AC. Less common presentations are RV or biventricular dilatation, with or without heart failure symptoms, mimicking dilated cardiomyopathy and requiring heart transplantation at the end stage. Clinical manifestations vary with age and stage of disease.

Syncope, palpitations, and ventricular arrhythmias are also common in the pediatric age. Frequent nonspecific clinical features comprise myocarditis or a myocardial infarction-like picture with chest pain, dynamic ST-T wave changes on the 12-lead ECG, or myocardial enzyme release in the setting of normal coronary arteries.

Four phases are recognizable in the natural history of the classic AC variant :

  • 1.

    Concealed—with subtle RV structural changes, with or without ventricular arrhythmias, during which sudden death may even be the first disease presentation.

  • 2.

    Overt electrical disorder—with symptomatic life-threatening ventricular arrhythmias associated with clear-cut RV morphofunctional abnormalities.

  • 3.

    RV failure—due to progression and extension of the RV disease.

  • 4.

    Biventricular failure—caused also by pronounced LV disease.

Electrical instability that may lead to arrhythmic sudden death can occur at any time during the course of the disease. AC has been reported as the second leading cause of sudden death in the young and the first cause in competitive athletes in the Veneto region in Italy. The incidence of sudden death ranges from 0.08% to 3.6 % per year in adults with AC. Although patients with an overt disease phenotype more often experience scar-related reentrant VT, those with an early stage or “hot phase” of the disease may manifest with ventricular fibrillation (VF) due to acute myocyte death and reactive inflammation. More recently, gap junction remodeling and sodium channel interference have been advanced in experimental models as an alternative explanation for life-threatening arrhythmias even in the prephenotypic disease stage.

Arrhythmogenic Cardiomyopathy Diagnosis

There is no single gold-standard feature in the diagnosis of AC. Multiple criteria are needed, combining different sources of diagnostic information, such as morphofunctional (by echocardiography and/or angiography and/or cardiac magnetic resonance [CMR]), histopathologic on endomyocardial biopsy, ECG, arrhythmias, and familial history, including genetics ( Fig. 63.1 ). The diagnostic criteria, originally put forward in 1994, were revised in 2010 to improve diagnostic sensitivity, but with the important prerequisite of maintaining diagnostic specificity ( Table 63.1 ). To this aim, quantitative parameters have been included and abnormalities are defined, based on the comparison with normal subject data. Moreover, T wave inversion in V1 to V3 and VT with a LBBB morphology with superior or indeterminate QRS axis (either sustained or no sustained) have become major diagnostic criteria ; and T wave inversion in V 1 to V 2 in the absence of right bundle branch block (RBBB) and in V 1 to V 4 , in the presence of complete RBBB have been included among the minor criteria. Finally, in the family history category, the confirmation of AC in a first-degree relative, by either meeting current criteria or pathologically (at autopsy or transplantation), and the identification of a pathogenic mutation, categorized as associated or probably associated with AC, are considered major criteria. However, because of the diagnostic implications, caution is highly recommended, since the pathogenic significance of a single mutation is increasingly questioned (see Genetics section).

Figure 63.1

Diagnostic tools to achieve a clinical diagnosis of classic right ventricle (RV) arrhythmogenic cardiomyopathy.

A–C, echocardiographic, Cardiac magnetic resonance and angiography showing RV dilatation and aneurysms; D, tissue characterization through endomyocardial biopsy; E, 12-lead electrocardiogram with inverted T waves V 1 to V 3 , left bundle branch block morphology premature ventricular complexes and ventricular tachycardia; F, post-excitation epsilon wave in precordial leads V 1 to V 3 (arrows) ; G, Signal-averaged electrocardiogram with late potentials (40-Hz high-pass filtering); H, Family pedigree with autosomal dominant inheritance of the disease. AoV, Aortic valve; RVOT, right ventricular outflow tract.

TABLE 63.1

2010 Revised Task Force Criteria for Arrhythmogenic Cardiomyopathy

I. Global or Regional Dysfunction and Structural Alterations
By 2D echo
Regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (end-diastole):

  • PLAX RVOT ≥32 mm (corrected for body size [PLAX/BSA] ≥19 mm/m 2 )

  • PSAX RVOT ≥36 mm (corrected for body size [PSAX/BSA] ≥21 mm/m 2 )

  • or fractional area change ≤33%

Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following:

  • Ratio of RV end-diastolic volume to BSA ≥110 mL/m 2 (male) or ≥100 mL/m 2 (female)

  • or RV ejection fraction ≤40%

By RV angiography
Regional RV akinesia, dyskinesia, or aneurysm
By 2D echo
Regional RV akinesia or dyskinesia and 1 of the following (end diastole):

  • PLAX RVOT ≥29-<32 mm (corrected for body size [PLAX/BSA] ≥16-<19 m/m 2 )

  • PSAX RVOT ≥32-<36 mm (corrected for body size [PSAX/BSA] ≥18-<21 mm/m 2 )

  • or fractional area change >33%–≤40%

Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following:

  • Ratio of RV end-diastolic volume to BSA ≥100-<110 mL/m 2 (male) or ≥90-<100 mL/m 2 (female)

  • or RV ejection fraction >40%–≤45%

II. Tissue Characterization of Wall
Fibrofatty replacement of myocardium on endomyocardial biopsy
Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on EMB
Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on EMB
III. Repolarization Abnormalities

  • Inverted T waves in right precordial leads (V 1 , V 2 , and V 3 ) or beyond in individuals >14 years of age (in the absence of complete RBBB QRS ≥120 ms)


  • Inverted T waves in leads V 1 and V 2 in individuals >14 years of age (in the absence of complete RBBB) or in V 4 , V 5 , or V 6

  • Inverted T waves in leads V 1 , V 2 , V 3 , and V 4 in individuals >14 years of age in the presence of complete RBBB

IV. Depolarization/Conduction Abnormalities

  • Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads (V 1 -V 3 )


  • Late potentials by SAEKG in ≥1 of 3 parameters in the absence of a QRS duration of ≥110 ms on the standard ECG

  • fQRS duration ≥114 ms

  • Duration of terminal QRS <40 μV (low-amplitude signal duration) ≥38 ms

  • Root mean square voltage of terminal 40 ms ≤20 μV

  • Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R′, in V 1 , V 2 , or V 3 , in the absence of complete RBBB

V. Arrhythmias

  • Nonsustained or sustained VT of LBBB morphology with superior axis (negative or indeterminate QRS in leads II, III, and aVF and positive in lead aVL)


  • Nonsustained or sustained VT of RVOT, LBBB morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis

  • >500 PVCs per 24 hours (Holter)

VI. Family History

  • AC confirmed in a first-degree relative who meets current Task Force criteria

  • AC confirmed pathologically at autopsy or surgery in a first-degree relative

  • Identification of a pathogenic mutation categorized as associated or probably associated with AC in the patient under evaluation


  • History of AC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria

  • Premature sudden death (35 years of age) due to suspected AC in a first-degree relative

  • AC confirmed pathologically or by current Task Force Criteria in second-degree relative

Two major, or one major and two minor, or four minor criteria from different categories: definite AC diagnosis. One major and one minor, or three minor criteria: borderline AC diagnosis. One major of two minor criteria: possible AC diagnosis.

AC, Arrhythmogenic cardiomyopathy; BSA, body surface area; CMR, cardiac magnetic resonance; ECG, electrocardiogram; EMB, endomyocardial biopsy; fQRS, filtered QRS; LBBB, left bundle branch block; PLAX, parasternal long-axis view; PSAX, parasternal short-axis view; PVC, premature ventricular complex; RBBB, right bundle branch block; RV, right ventricle; RVOT, RV outflow tract; SAEKG , signal average electrocardiogram; VT, ventricular tachycardia.

Hypokinesis is not included in the definition of RV regional wall motion abnormalities in the proposed modified criteria.

A pathogenic mutation is a DNA alteration associated with AC that alters or is expected to alter the encoded protein, is unobserved or rare in a large non-AC control population, and either alters or is predicted to alter the structure or function of the protein or has demonstrated linkage to the disease phenotype in a conclusive pedigree.

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Feb 26, 2019 | Posted by in CARDIOLOGY | Comments Off on Arrhythmogenic Cardiomyopathy
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