Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease.

ACM is caused by genetic defects of parts of the cardiac muscle known as desmosomes, areas on the surface of muscle cells which link them together. The desmosomes are composed of several proteins, and many of those proteins can have harmful mutations.

ARVC can also develop in intense endurance athletes in the absence of desmosomal abnormalities. Exercise-induced ARVC is possibly a result of excessive right ventricular wall stress during high intensity exercise.

The disease is a type of non-ischemic cardiomyopathy that primarily involves the right ventricle, though cases of exclusive left ventricular disease have been reported. It is characterized by hypokinetic areas involving the free wall of the ventricle, with fibrofatty replacement of the myocardium, with associated arrhythmias often originating in the right ventricle. The nomenclature ARVD is currently thought to be inappropriate and misleading as ACM does not involve dysplasia of the ventricular wall. Cases of ACM originating from the left ventricle led to the abandonment of the name ARVC.

ACM can be found in association with diffuse palmoplantar keratoderma, and woolly hair, in an autosomal recessive condition called Naxos disease, because this genetic abnormality can also affect the integrity of the superficial layers of the skin most exposed to pressure stress.

ACM is an important cause of ventricular arrhythmias in children and young adults. It is seen predominantly in males, and 30–50% of cases have a familial distribution.

Signs and symptoms Those affected by arrhythmogenic cardiomyopathy may not have any symptoms at all despite having significant abnormalities in the structure of their hearts. If symptoms do occur, the initial presentation is often due to abnormal heart rhythms (arrhythmias) which in arrhythmogenic cardiomyopathy may take the form of palpitations, or blackouts. Sudden death may be the first presentation of ACM without any preceding symptoms. These symptoms often occur during adolescence and early adulthood, but signs of ACM may rarely be seen in infants.

As ACM progresses, the muscle tissue within the ventricles may dilate and weaken. The right ventricle typically weakens first, leading to fatigue and ankle swelling. In the later stages of the disease in which both ventricles are involved shortness of breath may develop, especially when lying flat.

Causes

Genetics ACM is usually inherited in an autosomal dominant pattern, with variable expression. Only 30% to 50% of individuals affected by ACM will test positive to one of the known genetic mutations in chromosomal loci associated with the disease. Novel studies showed that mutations (point mutations) in genes encoding for desmosomal proteins (see intercalated disc) are the main causatives for the development of this disease. Recently it has been shown, that mutations in the desmin DES gene could cause ACM. Desmin is an intermediate filament protein, which is linked to the desmosomes. Different DES mutations cause an abnormal aggregation of desmin and associated proteins. The penetrance is 20–35% in general, but significantly higher in Italy. Seven gene loci have been implicated in ACM. It is unclear whether the pathogenesis varies with the different loci involved. Standard genetic screening test are currently tested and evaluated in different state of the art cardiovascular research centres and hospitals. Types include:

Type OMIM Gene LocusReference ARVD1lpl TGFB3 14q23-q24 ARVD2 RYR2 1q42-q43 ARVD3 ? 14q12-q22 ARVD4 ? 2q32.1-q32.3 ARVD5 TMEM43 3p23 ARVD6 ? 10p14-p12 ARVD7 DES 10q22.3 ARVD8 DSP 6p24 ARVD9 PKP2 12p11 ARVD10 DSG2 18q12.1-q12 ARVD11 DSC2 18q12.1 ARVD12 JUP 17q21ILK11p15.4LMNA

Exercise-induced ARVC In recent years, several studies have found that excessive long-term sports activity can cause exercise-induced arrhythmogenic right ventricular cardiomyopathy (EIARVC). For some athletes ARVC might develop due to high-endurance exercise and it most often develops without an underlying desmosomal abnormalities. This could possibly be a result of excessive right ventricular (RV) wall stress during very high volumes of training, which is known to be causing a disproportionate remodeling of RV.

In a 2003 study, 46 endurance athletes, mostly cyclists, presented with various symptoms suggestive of arrhythmia of RV origin. 59% of participants tested met the criteria for ARVC, and another 30% for possible ARVC. Only 1 athlete of the group had a family history of hereditary ARVC.

Exercise-induced ARVC and athlete's heart have overlapping features.

Pathogenesis The pathogenesis of ACM is largely unknown. Apoptosis (programmed cell death) appears to play a large role. It was previously thought that only the right ventricle is involved, but recent cohorts have shown many cases of left ventricular disease and biventricular disease. The disease process starts in the subepicardial region and works its way towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the ventricles). Residual myocardium is confined to the subendocardial region and the trabeculae of the ventricles. These trabeculae may become hypertrophied.

Aneurysmal dilatation is seen in 50% of cases at autopsy. It usually occurs in the diaphragmatic, apical, and infundibular regions (known as the triangle of dysplasia). The left ventricle is involved in 50–67% of individuals. If the left ventricle is involved, it is usually late in the course of disease, and confers a poor prognosis.

There are two pathological patterns seen in ACM, Fatty infiltration and fibro-fatty infiltration.

Fatty infiltration At first, fatty infiltration, is confined to the right ventricle. This involves a partial or near-complete substitution of myocardium with fatty tissue without wall thinning. It involves predominantly the apical and infundibular regions of the RV. The left ventricle and ventricular septum are usually spared. No inflammatory infiltrates are seen in fatty infiltration. There is evidence of myocyte (myocardial cell) degeneration and death seen in 50% of cases of fatty infiltration.

Fibro-fatty infiltration The second, fibro-fatty infiltration, involves replacement of myocytes with fibrofatty tissue. A patchy myocarditis is involved in up to 2/3 of cases, with inflammatory infiltrates (mostly T cells) seen on microscopy. Myocardial atrophy is due to injury and apoptosis. This leads to thinning of the RV free wall (to < 3 mm thickness) Myocytes are replaced with fibrofatty tissue. The regions preferentially involved include the RV inflow tract, the RV outflow tract, and the RV apex. However, the LV free wall may be involved in some cases. Involvement of the ventricular septum is rare. The areas involved are prone to aneurysm formation.

The Role of Exercise Recently, some studies have identified strenuous exercise as a novel risk for accelerated progression of the disease. One retrospective study on 301 patients conclusively demonstrated that the subpopulations participating in strenuous physical activity (professional athletes for example) had an earlier onset of symptoms and earlier mortality compared to other populations.

Ventricular arrhythmias

Ventricular arrhythmias due to ACM typically arise from the diseased right ventricle. The type of arrhythmia ranges from frequent premature ventricular complexes (PVCs) to ventricular tachycardia (VT) to ventricular fibrillation (VF).

While the initiating factor of the ventricular arrhythmias is unclear, it may be due to triggered activity or reentry.

Ventricular arrhythmias are usually exercise-related, suggesting that they are sensitive to catecholamines. The ventricular beats typically have a right axis deviation. Multiple morphologies of ventricular tachycardia may be present in the same individual, suggesting multiple arrhythmogenic foci or pathways.

Right ventricular outflow tract (RVOT) tachycardia is the most common VT seen in individuals with ACM. In this case, the EKG shows a left bundle branch block (LBBB) morphology with an inferior axis.

Diagnosis The differential diagnosis for the ventricular tachycardia due to ACM include: Congenital heart disease Repaired tetralogy of Fallot Ebstein's anomaly Uhl's anomaly Atrial septal defect Partial anomalous venous return Acquired heart disease Tricuspid valve disease Pulmonary hypertension Right ventricular infarction Bundle-branch re-entrant tachycardia Miscellaneous Pre-excited AV re-entry tachycardia Idiopathic RVOT tachycardia Sarcoidosis

In order to make the diagnosis of ACM, a number of clinical tests are employed, including the electrocardiogram (EKG), echocardiography, right ventricular angiography, cardiac MRI, and genetic testing.

Electrocardiogram 90% of individuals with ARVD have some EKG abnormality. The most common EKG abnormality seen in ACM is T wave inversion in leads V1 to V3. However, this is a non-specific finding, and may be considered a normal variant in right bundle branch block (RBBB), women, and children under 12 years old.

RBBB itself is seen frequently in individuals with ACM. This may be due to delayed activation of the right ventricle, rather than any intrinsic abnormality in the right bundle branch.

The epsilon wave is found in about 50% of those with ACM. This is described as a terminal notch in the QRS complex. It is due to slowed intraventricular conduction. The epsilon wave may be seen on a surface EKG; however, it is more commonly seen on signal averaged EKGs.

Ventricular ectopy seen on a surface EKG in the setting of ACM is typically of left bundle branch block (LBBB) morphology, with a QRS axis of −90 to +110 degrees. The origin of the ectopic beats is usually from one of the three regions of fatty degeneration (the "triangle of dysplasia"): the RV outflow tract, the RV inflow tract, and the RV apex.

Signal-averaged ECG (SAECG) is used to detect late potentials and epsilon waves in individuals with ACM.

Echocardiography Echocardiography may reveal an enlarged, hypokinetic right ventricle with a paper-thin RV free wall. The dilatation of the RV will cause dilatation of the tricuspid valve annulus, with subsequent tricuspid regurgitation. Paradoxical septal motion may also be present.

Magnetic resonance imaging

Fatty infiltration of the RV free wall can be visible on cardiac MRI. Fat has increased intensity in T1-weighted images. However, it may be difficult to differentiate intramyocardial fat and the epicardial fat that is commonly seen adjacent to the normal heart. Also, the sub-tricuspid region may be difficult to distinguish from the atrioventricular sulcus, which is rich in fat.

Cardiac MRI can visualize the extreme thinning and akinesis of the RV free wall. However, the normal RV free wall may be about 3 mm thick, making the test less sensitive.

Angiography Right ventricular angiography is considered the gold standard for the diagnosis of ACM. Findings consistent with ACM are an akinetic or dyskinetic bulging localized to the infundibular, apical, and subtricuspid regions of the RV. The specificity is 90%; however, the test is observer dependent.

Biopsy Transvenous biopsy of the right ventricle can be highly specific for ACM, but it has low sensitivity. False positives include other conditions with fatty infiltration of the ventricle, such as long-term excessive alcohol use and Duchenne or Becker muscular dystrophy.

False negatives are common, however, because the disease progresses typically from the epicardium to the endocardium (with the biopsy sample coming from the endocardium), and the segmental nature of the disease. Also, due to the paper-thin right ventricular free wall that is common in this disease process, most biopsy samples are taken from the ventricular septum, which is commonly not involved in the disease process.