Arrhythmogenic Cardiomyopathy

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1		Fabrizio Drago	--	1866	2022-05-12 20:47:30	\|
2	Reference format revised.	Lindsay Dong	-5 word(s)	1861	2022-05-13 03:15:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcdd9040098

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy characterized by the occurrence of a high risk of life-threatening ventricular arrhythmias and sudden cardiac death even at presentation.

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1. Definition and Epidemiology

Arrhythmogenic cardiomyopathy (ACM) is a rare cardiac condition characterized by fibrous or fibro-fatty infiltration of the myocardium, leading to arrhythmias and progressive cardiac dysfunction. It is genetically determined and more than 50% of cases harbor variants in desmosomal genes, less commonly non-desmosomal ones.

Despite initially considered a disease exclusively affecting the right ventricle (RV), from the beginning of the 2000s, the concept of an analogous involvement of the left ventricle (LV) became apparent and the original term of arrhythmogenic right ventricular dysplasia (ARVD) was replaced by ACM. In particular Sen-Chowdrry et al. described a “classic” ARVC characterized by RV dominance, a “biventricular” pattern defined by parallel involvement of both ventricles and an LV dominant form with an extensive LV involvement and a “mirror-like” ARVD phenotypic presentation ^[1].

Myocardial loss and fibrous or fibro-fatty substitution with a subepicardialmid-mural distribution or with a transmural involvement in the absence of coronary artery disease has always been the diagnostic element for ACM ^[2].

Electrocardiographic (ECG) abnormalities (T wave inversion in right precordial leads or to the other leads, delayed S-wave upstroke in right precordial leads, right bundle branch block, low voltages in limb leads) and ventricular arrhythmias (isolated premature ventricular contractions, non-sustained or sustained ventricular tachycardias) are the expression of these histologic changes and can precede the structural phenotypic alterations.

ACM usually manifests between the second and fourth decade of life and rarely occurs during adolescence. Early symptoms include palpitations and syncope; sudden cardiac death can sometimes be the first manifestation of the disease, while heart failure is generally a sign of disease progression.

Notably, strenuous exercise can act as a phenotypic modifier and be the trigger for malignant arrhythmias and SCD as well ^[3].

Finally, LV dominant forms should be differentiated by other “phenocopies”, such as neuromuscular diseases with cardiac involvement, myocarditis, sarocoidosis and dilated cardiomyopathies.

2. Diagnostic Criteria

Regarding the diagnosis of this heart disease, initially, the 1994 original Task Force criteria showed limitations concerning the lack of quantitative parameters, especially for grading RV dilatation/dysfunction and the amount of fibrosis at histology. Moreover, the arrhythmic aspects were considered “minor” criteria ^[4].

The 2010 revised International Task Force criteria (2010 ITF), instead, classified the ACM in “definite”, “borderline” and “possible” according to the number of satisfied criteria. Consequentially, these criteria improved the sensitivity of the previous ones giving more quantitative parameters and more consideration of the electrocardiographic and arrhythmic aspects. Notably, the identification of a pathogenic/likely pathogenic genetic variant was listed as a “major” criterion ^[5].

Very recently, the “Padua criteria” have updated the old criteria introducing the concept of the existence of forms limited to LV and the importance of fibrosis detected at cardiac magnetic resonance (CMR) and including three different phenotypic variants: dominant-right variant, dominant-left variant and biventricular variant.

In these innovative criteria, the most important novelties have been: (1) the introduction of late gadolinium enhancement (LGE) at CMR as a major criterion; (2) a more important consideration of right ventricular dilation/dysfunction regardless of severity and of isolated regional abnormalities of left ventricular wall motility (minor criterion) in order to reflect the segmental nature of fibro-adipose substitution; (3) the importance of isolated PVCs not only in terms of absolute number (>500/24 h), but also in terms of morphology. Moreover, fibrous replacement at endomyocardial biopsy is no longer differentiated between major and minor criterion but is a major one, epsilon wave detection at ECG is a minor criterion and late potentials at signal-averaged ECG are no longer considered due to the low diagnostic accuracy.

Notably, the presence of at least one morpho-functional and/or structural major or minor criterion is essential to make diagnosis of ACM and the identification of a pathogenic or likely pathogenic ACM-causing gene mutation is mandatory to reach the diagnosis of “LV dominant” form. These clues give more specificity in the differentiation of ACM from other types of cardiomyopathies (CMPs) or arrhythmias (i.e., idiopathic ventricular tachycardias) ^[6]^[7].

3. Natural History

Sen-Chawdhry et al. reported four different and progressive stages of the disease evolution ^[8].

The early “concealed phase”, also called “hot phase”, is characterized by recurrent myocarditis-like episodes with preserved ventricular morphology and function.

In this phase, the risk of sudden cardiac death (SCD) due to life-threatening arrhythmias exists, potentially being the first manifestation of the disease. These recurrent episodes and the inflammatory process may lead to disease progression. However, it is not well known if the inflammation is the cause of this progression or a reactive phenomenon to myocytes apoptosis in genetically predisposed individuals ^[9].

Subsequent stages are the consequence of fibrous (-fatty) myocytes replacement from the subepicardial to the subendocardial layers. The initial limited extension of the scar is responsible of the “overt phase” manifesting with electrical disorders. Only later, the progression of transmural fibrosis causes myocardial thinning, regional wall motion abnormalities and ventricular dysfunction ^[10].

4. Genetic Background

ACM is genetically determined and transmitted as an autosomal dominant trait, with incomplete penetrance and variable expressivity. Rarely an autosomal recessive transmission is involved in Naxos and Carvajal syndromes presenting with woolly hair palmoplantar keratoderma, nail dystrophy, dental anomalies, pemphigus-like vesicular lesions on palms, soles and knees, erosion and ulcers in perioral and sacral areas or hands and legs dorsal surfaces ^[11].

In at least 50% of patients, pathogenic or likely pathogenic variants (P/LP) (following the American College of Medical Genetics guidelines) of desmosomal genes are detected, even if non-desmosomal ones can also be involved.

Desmosomes are responsible for cell-to-cell adhesion and are part of a structure called intercalated discs (IDs). IDs are composed of adherent junctions, gap junctions and ion channels, which interact together and are responsible of the electrical, matabolic and structural properties of the cardiomyocytes.

On the other hand, desmosomes are linked to the intermediate filaments of the cytoskeleton to guarantee structural stability and integrity against mechanical stress.

Mutation of desmosomal proteins, such as plakoglobin (JUP), plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein (DSG) and desmocollin (DSC2), are historically considered the most involved in ACM pathogenesis.

Mutations in non-desmosomal proteins, such as laminin A/C (LMNA/C), desmin (DES), filamin C (FLNC), transmembrane protein 43 (TMEM43), ryanodine receptor-2 (RyR2), phos-pholamban (PLN) and transforming growth factor-3 (TGFβ), have also been considered as causative of ACM especially in biventricular and left-dominant forms. Genes encoding for adherent junctional proteins such as α-T-catenin (CTNNA3) and N-cadherin (CDH2) are also reported to be relevant for the pathogenesis, as they are essential for the cardiomyocytes interconnections and their alteration result in a common pathway consisting on the one hand of cells death and scarring and on the other hand of electrical disturbances and ions currents alterations.

Despite these considerations and the numerous ACM related genes proposed, a variable and uncertain evidence of association has emerged over time.

Recently, a group of experts reappraised 26 ACM genes reported in the literature and found that only 8 genes have a definite (PKP2, DSP, DSG2, DSC2, JUP, TMEM43) or moderate (PLN, DES) evidence for causing ACM.

RYR2, despite previously reported in association with ACM, was disqualified as an ACM-causative gene due to contradictory evidence and because it proved to be associated to catecholaminergic polymorphic ventricular tachycardia (CPVT) rather than ACM.

Thus, only the previous mentioned variants (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, DES) should be considered as “major criteria” in the diagnosis of ACM.

5. Risk Stratification

Once the diagnosis of ACM is established, the most important issue is the risk stratification for SCD and the decision to implant an ICD.

In 2015, Corrado, considering “major” and “minor” risk factors, proposed an algorithm to classify the patients in three different categories of arrhythmic risk: high, moderate and low. Consequently, ICD implantation can be indicated in class I, IIa, IIb or not indicated. In detail the major risk factors for risk stratification are the experienced cardiac arrest or life-threatening arrhythmias, non-sustained VT (NSVT), the grade of heart dysfunction (RV/LV moderate or severe heart dysfunction) and syncopal events. While the minor risk factors are more heterogeneous and include proband status, male gender, electrical instability (spontaneous VAs or induced at electrophysiological study), younger age, complex genotype and the extent of structural heart disease ^[12]^[13].

Among young patients, the most common presentation of SCD/VF was largely confirmed by Bhonsale et al., along with male sex as a risk factor in terms of SCD, symptoms and life-threatening arrhythmias and otherwise unrelated to the involvement of left ventricle and cardiac arrest ^[14].

More recently, two other algorithms for the prediction of life-threatening VAs have been proposed ^[15]^[16].

Cadrin-Tourigny et al., in 2019, aimed to create a prediction model of VAs and SCD in ACM patients. This necessity emerged from the fact that previous recommendations were based on expert opinions and provided only categorical classes of SCD risk in order to advise ICD implantation. They differently proposed an algorithm seeking to evaluate the SCD risk as a continuum variable using six already known risk predictor variables: sex, age, recent (<6 months) cardiac syncope, NSVT, number of PVCs on 24-h Holter monitoring, extent of T-wave inversion (TWI) on anterior and inferior leads, RV ejection fraction and LV ejection fraction. The primary outcome was the first sustained VA in patients with ACM diagnosis who had never been experienced a similar event before or with an ICD implanted for primary prevention. In this regard, sustained VA was considered as the occurrence of SCD, sustained VT, ventricular fibrillation/flutter and appropriate ICD intervention. This model was proven to accurately distinguish patients who will have VAs for those who will not, allowing an appropriate patient selection and avoiding inappropriate ICD implants and their considerable risk complications especially in young people. In detail this model resulted in a 20.6% reduction of ICD implantations compared to the current algorithm, with a higher net benefit of protection. Of note, this study, even though it was the largest one conducted before 2019 (528 patients), was limited by the higher prevalence of Caucasian patients, the higher prevalence of PKP2 variants identified and the use of ICD shocks as surrogate of SCD, while a great proportion of VTs in ACM patients would have been self-limited in the absence of ICD therapy ^[15].

Subsequently, the same group aimed to specifically predict the risk of life-threatening VAs as a surrogate of SCD, to overcome the risk to overestimate VA cases, considering all the sustained VAs. This was supported by the concept that stable VAs, even if sustained, and the potentially fatal VAs do not underlie the same predictors. They aimed to create a new prediction model for potentially fatal VAs and SCD. In this regard they found that only four of the classically considered risk factors were predictive of life-threatening VAs: male sex, young age at presentation, high PVC burden and number of TWI at ECG.

Interestingly, prior sustained VAs were not predictive of life-threatening arrhythmic events and this could help to not overestimate the SCD risk and the consequent inappropriate ICD implantation, neither the extent of functional impairment (RV and LV dysfunction) nor syncopal event. This apparently weird conclusion may be explained by the concept that an early electrical phase and electrical instability may lead to unstable VAs independently by the structural substrate ^[16].

References

Sen-Chowdhry, S.; Syrris, P.; Prasad, S.K.; Hughes, S.E.; Merrifield, R.; Ward, D.; Pennell, D.; McKenna, W.J. Left-Dominant Arrhythmogenic Cardiomyopathy: An Under-Recognized Clinical Entity. J. Am. Coll. Cardiol. 2008, 52, 2175–2187.
Corrado, D.; Link, M.S.; Calkins, H. Arrhythmogenic Right Ventricular Cardiomyopathy. N. Engl. J. Med. 2017, 376, 61–72.
Corrado, D.; Van Tintelen, P.J.; McKenna, W.J.; Hauer, R.N.W.; Anastastakis, A.; Asimaki, A.; Basso, C.; Bauce, B.; Brunckhorst, C.; Bucciarelli-Ducci, C.; et al. International Experts. Arrhythmogenic right ventricular cardiomyopathy: Evalu-ation of the current diagnostic criteria and differential diagnosis. Eur. Heart J. 2020, 41, 1414–1429.
McKenna, W.J.; Thiene, G.; Nava, A.; Fontaliran, F.; Blomstrom-Lundqvist, C.; Fontaine, G.; Camerini, F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the In-ternational Society and Federation of Cardiology. Br. Heart J. 1994, 71, 215–218.
Marcus, F.I.; McKenna, W.J.; Sherrill, D.; Basso, C.; Bauce, B.; Bluemke, D.A.; Calkins, H.; Corrado, D.; Cox, M.G.; Daubert, J.P.; et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed Modification of the Task Force Criteria. Eur. Heart J. 2010, 121, 1533–1541.
Corrado, D.; Perazzolo Marra, M.; Zorzi, A.; Beffagna, G.; Cipriani, A.; Lazzari, M.; Migliore, F.; Pilichou, K.; Rampazzo, A.; Rigato, I.; et al. Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria. Int. J. Cardiol. 2020, 319, 106–114.
Corrado, D.; Zorzi, A.; Cipriani, A.; Bauce, B.; Bariani, R.; Beffagna, G.; De Lazzari, M.; Migliore, F.; Pilichou, K.; Rampazzo, A.; et al. Evolving Diagnostic Criteria for Arrhythmogenic Cardiomyopathy. J. Am. Hear. Assoc. 2021, 10, e021987.
Sen-Chowdhry, S.; Lowe, M.D.; Sporton, S.C.; McKenna, W.J. Arrhythmogenic right ventricular cardiomyopathy: Clinical presentation, diagnosis, and management. Am. J. Med. 2004, 117, 685–695.
Bariani, R.; Cipriani, A.; Rizzo, S.; Celeghin, R.; Marinas, M.B.; Giorgi, B.; De Gaspari, M.; Rigato, I.; Leoni, L.; Zorzi, A.; et al. ‘Hot phase’ clinical presentation in arrhythmogenic cardiomyopathy. Europace 2021, 23, 907–917.
Mattesi, G.; Cipriani, A.; Bauce, B.; Rigato, I.; Zorzi, A.; Corrado, D. Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria. J. Clin. Med. 2021, 10, 2212.
Riele, A.S.J.M.T.; James, C.A.; Calkins, H.; Tsatsopoulou, A. Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity. Front. Pediatr. 2021, 9, 750916.
Calkins, H.; Corrado, D.; Marcus, F. Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 2017, 136, 2068–2082.
Corrado, D.; Wichter, T.; Link, M.S.; Hauer, R.N.; Marchlinski, F.E.; Anastasakis, A.; Bauce, B.; Basso, C.; Brunckhorst, C.; Tsatsopoulou, A.; et al. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. Circulation 2015, 132, 441–453.
Bhonsale, A.; Groeneweg, J.A.; James, C.A.; Dooijes, D.; Tichnell, C.; Jongbloed, J.D.H.; Murray, B.; Te Riele, A.S.J.M.; Van Den Berg, M.P.; Bikker, H.; et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur. Heart J. 2015, 36, 847–855.
Cadrin-Tourigny, J.; Bosman, L.P.; Nozza, A.; Wang, W.; Tadros, R.; Bhonsale, A.; Bourfiss, M.; Fortier, A.; Lie, Ø.H.; Saguner, A.M.; et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 2019, 40, 1850–1858.
Cadrin-Tourigny, J.; Bosman, L.P.; Wang, W.; Tadros, R.; Bhonsale, A.; Bourfiss, M.; Lie, Ø.H.; Saguner, A.M.; Svensson, A.; Andorin, A.; et al. Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy. Circ. Arrhythmia Electrophysiol. 2021, 14, e008509.

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Fabrizio Drago

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Update Date: 13 May 2022

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