When Rare Illuminates Common: How Cardiocutaneous Syndromes Transformed Our Perspective on Arrhythmogenic Cardiomyopathy

Figures & data

Figure 1. Late gadolinium enhancement of the left ventricular myocardium in left-dominant arrhythmogenic cardiomyopathy.

Cardiovascular magnetic resonance images from a 19-year-old boy with a heterozygous chain termination mutation in desmoplakin. There is late gadolinium enhancement of the septum in a midwall distribution (arrows in left panel; box in right panel), likely representative of fibrous tissue. Ventricular volumes and function were normal and wall motion abnormalities inconspicuous, highlighting the importance of late gadolinium enhancement imaging in establishing the diagnosis. In this family, the majority of affected individuals had left-dominant arrhythmogenic cardiomyopathy, but the biventricular subtype was also present in a few.

Table 1. Clinical Profile of Arrhythmogenic Cardiomyopathy* [After ref (Sen-Chowdhry et al., 2010)].

Subtype	Classic right dominant	Left dominant
12-lead ECG	NormalPoor R-wave progression^†
	Intraventricular conduction delay in V1-3	Leftward QRS axis (−30°< QRS axis < 0) or left axis deviation (QRS axis < 30°)
	Incomplete RBBB	Early transition
	RBBB	LBBB
	Epsilon waves in V1-3	Epsilon waves in inferior (II, III, aVF) and/or lateral leads (V5–V6 ± V4, I, aVL)
	Inverted/flat T-waves in V1-3, extending to V4-6 with LV involvement	Inverted/flat T-waves in (infero)lateral leads, extending to V1-3 with RV involvement
Signal-averaged ECG	Late potentials
Arrhythmia	Both supraventricular tachycardia and atrial fibrillation/flutter are observed in arrhythmogenic cardiomyopathy, but are not contributory to diagnosis
	Frequent PVCs or VT of LBBB morphology (right ventricular origin)	Frequent PVCs or VT of RBBB morphology (left ventricular origin)
Ventricular volumes	Mild, moderate, or severe RV dilation ± dysfunction	Mild, moderate, or severe LV dilation ± dysfunction
RV/LV Volume ratio	≥ 1.2, increases with disease progression	< 1, diminishes with disease progression
Other imaging abnormalities	Localised dilation, WMA, and/or aneurysms in RV, preferentially affecting triangle of dysplasia and mid-free wall	Localised dilation, WMA, and/or aneurysms in LV
	Fat/late enhancement in RV myocardium	Late enhancement in LV myocardium in a subepicardial/midwall distribution
Cardiocutaneous Syndrome Prototype	Naxos syndrome	Carvajal syndrome

ECG, electrocardiogram; RBBB, right bundle branch block; LBBB, left bundle branch block; PVC, premature ventricular complex; VT, ventricular tachycardia; RV, right ventricular; LV, left ventricular; WMA, wall motion abnormality

*The clinical picture in the Biventricular subtype is generally a composite of right-dominant and left-dominant features. Both ventricles are affected to the same extent, with RV/LV volume ratio remaining ≈ 1 throughout the disease course.

^†Poor R-wave progression is the primary ECG abnormality observed in the Newfoundland founder population, in which LV structural abnormalities are prominent (Merner et al., 2008). It has also been reported in ≈ 10% of patients in a cohort including all three subtypes of arrhythmogenic cardiomyopathy.

Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ (2010). Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment. Annu Rev Med. 61: 233–253.

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Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL (2008). Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 82: 809–821.

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