Arrhythmogenic ventricular cardiomyopathy: A paradigm shift from right to biventricular disease

Table 1 Characteristics of arrhythmogenic ventricular cardiomyopathy

	Classic right dominant form (ARVC/D)	Left dominant form
12-lead surface ECG	Intraventricular conduction delay in V1-V3	Leftward QRS axis (< 0°)
	QRS complex prolongation V1-V3	ε like waves in inferior or lateral leads
	ε wave in V1-V3	LBBB
	(Incomplete) RBBB	Inverted T-waves in infero-lateral leads
	Inverted T-waves in V1-V3	Inverted T-waves V1-6 with biventricular involvement
	Inverted T-waves in V1-V6 with biventricular involvement	-
	ST elevation in V1-V3	-
	Poor R wave progression
Signal-averaged ECG	Late potentials	-
Arrhythmia	PVC/VT of LBBB configuration	PVC/VT of RBBB configuration
Ventricular volumes	Mild to severe RV-dilation ± dysfunction	Mild to severe LV-dilation ± dysfunction
RV/LV volume ratio	≥ 1.2, increases with disease expression	< 1.0
Other imaging abnormalities	Regional wall motion abnormalities in RV	Regional wall motion abnormalities in LV
	RV aneurysms	Non-compacted appearance
	Fat/LGE in RV myocardium	LGE in the subepicardial and midwall LV myocardium
Genetics	Affected genes currently known to be associated with AVC	Association with TMEM43 and phospholamban mutations[1]

Adapted from Jacoby et al[84]. ARVC/D: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; ECG: Electrocardiogram; ε: Epsilon; LBBB: Left bundle branch block; LGE: Late gadolinium enhancement; LV: Left ventricle; PVC: Premature ventricular contraction; RBBB: Right bundle branch block; RV: Right ventricle; VT: Ventricular tachycardia; AVC: Arrhythmogenic ventricular cardiomyopathy; TMEM43: Transmembrane protein 43.

Table 2 Arrhythmogenic ventricular cardiomyopathy classification, from OMIMTM Online Mendelian inheritance in Man

AVC subtype	Chromosome/locus	Mode of transmission	Encoded protein
ARVC/D 1	14q23-q24	Autosomal-dominant	TGFβ3
ARVC/D 2	1q42-q43	Autosomal-dominant	RyR2
ARVC/D 3	14q12-q22	Autosomal-dominant	-
ARVC/D 4	2q32	Autosomal-dominant	TTN
ARVC/D 5	3p23	Autosomal-dominant	TMEM43
ARVC/D 6	10p12-p14	Autosomal-dominant	-
ARVC/D 7	10q22	Autosomal-dominant	-
ARVC/D 8	6p24	Autosomal-dominant	DSP
ARVC/D 9	12p11	Autosomal-dominant	PKP2
ARVC/D 10	18q12	Autosomal-dominant	DSG2
ARVC/D 11	18q12.1	Autosomal-dominant	DSC2
ARVC/D 12	17q21	Autosomal-dominant	JUP
Naxos disease	17q21	Autosomal-recessive	JUP

AVC: Arrhythmogenic ventricular cardiomyopathy; ARVC/D: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; TGF: Transforming growth factor; RyR2: Ryanodine receptor 2; TTN: Titin; TMEM43: Transmembrane protein 43; DSP: Desmoplakin; PKP2: Plakophilin-2; DSG2: Desmoglein-2; DSC2: Desmocollin-2; JUP: Junction plakoglobin.

Table 3 Future candidate proteins for arrhythmogenic ventricular cardiomyopathy

Encoded protein

Components of the desmosome

Plectin

Emerin

Components of the adherens junction

β-catenin

α-catenin

N-cadherin

Components of the gap junction

Connexin 43

Myotonic dystrophy protein kinase-1

Laminin receptor-1

Components of dystrophin-glycoprotein complex

Table 4 Revised (2010) task force criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia, adapted from Marcus et al[92]

	Structural alterations
Major	TTE regional RV akinesia, dyskinesia, or aneurysm and 1 of the following criteria (end diastole)
	PLAX RVOT ≥ 32 mm [(PLAX/BSA) ≥ 19 mm/m2]
	PSAX RVOT ≥ 36 mm [(PSAX/BSA) ≥ 21 mm/m2]
	Or RV fractional area change ≤ 33%
	CMR regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and 1 of the following criteria (end diastole)
	RV end-diastolic volume/BSA ≥ 110 mL/m2 (♂) or ≥ 100 mL/m2 (♀)
	Or RV ejection fraction ≤ 40%
	RV angiography regional RV akinesia, dyskinesia, or aneurysm
Minor	TTE regional RV akinesia, or dyskinesia and 1 of the following criteria (end diastole)
	PLAX RVOT ≥ 29-31mm [(PLAX/BSA) ≥ 16-18 mm/m2]
	PSAX RVOT ≥ 32-35 mm [(PSAX/BSA) ≥ 18-20 mm/m2]
	RV fractional area change > 33%-39%
	CMR regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and 1 of the following criteria (end diastolic)
	RV end-diastolic volume/BSA ≥ 100-109 mL/m2 (♂) or ≥ 90-99 mL/m2 (♀)
	Or RV ejection fraction > 40%-44%
	Histopathology (endomyocardial biopsy)
Major	Residual myocytes < 60% by morphometric analysis with fibrous replacement of the RV free wall myocardium ≥ 1 sample, with or without fatty replacement
Minor	Residual myocytes 60%-75% by morphometric analysis with fibrous
	Replacement of the RV free wall ≥ 1 sample
	Repolarization abnormalities (> 14 years of age)
Major	T-wave inversions V1-V3 or beyond (in absence of complete RBBB)
Minor	T-wave inversions V1-V2 or V4-V6 (in absence of complete RBBB)
	T-wave inversions V1-V4, if complete RBBB present
	Depolarization abnormalities
Major	Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T-wave) in V1 to V3
Minor	SAECG with late potentials (if QRS complex on standard surface ECG < 110 ms) or terminal activation duration of QRS ≥ 55 ms in V1, V2 or V3
	Arrhythmias
Major	VT of LBBB morphology with superior axis
Minor	VT of RVOT configuration, LBBB morphology with inferior axis or of unknown axis
	> 500 PVC per 24 h (holter)
	Family history
Major	ARVC/D in a first-degree relative who meets current TFC
	ARVC/D confirmed pathologically at autopsy or surgery in a first-degree relative
	Identification of a pathogenic mutation categorized associated with ARVC/D in an index patient
Minor	Suspected ARVC/D in a first-degree relative-premature SCD (< 35 years of age) due to suspected ARVC/D in a first-degree relative
	ARVC/D confirmed pathologically or by current TFC in second-degree relatives

Definite diagnosis: two major or one major and two minor criteria or four minor from different categories; Borderline diagnosis: one major and one minor or three minor criteria from different categories; Possible diagnosis: one major or two minor criteria from different categories. BSA: Body surface area; CMR: Cardiac magnetic resonance tomography; LV: Left ventricle; PLAX: Parasternal long-axis view; PSAX: Parasternal short-axis view; RBBB: Right bundle branch block; RVOT: Right ventricular outflow tract; RV: Right ventricle, TTE: Transthoracic echocardiogram, PVC: Premature ventricular contraction VT: Ventricular tachycardia; SAECG: Signal-averaged electrocardiographic; LBBB: Left bundle branch block; ARVC/D: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; TFC: Task force criteria; SCD: Sudden cardiac death.