Arrhythmogenic cardiomyopathy (ACM)
(1 ml)
Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease that is usually inherited in an autosomal dominant pattern. It causes heart muscle tissue to be progressively replaced by fat and connective tissue, primarily affecting the right ventricle and leading to ventricular arrhythmias. These arrhythmias can be triggered by physical exertion and lead to sudden cardiac death, especially in adolescents aged 14–20 years. Approximately 50–60% of ACM cases have pathogenic variants in genes for desmosomes.
The heart muscle in the myocardium is progressively replaced by fatty and connective tissue. The connective tissue remodelling, which primarily affects the right ventricle, initially leads to conduction disturbances with ventricular arrhythmias, palpitations, or syncope. The arrhythmias that can lead to sudden cardiac death are usually triggered by physical exertion. Approximately one-third of index patients die suddenly between the ages of 14 and 20. This age appears to be a vulnerable period for fatal arrhythmias. However, half of those who carry a pathogenic ACM-related variant don’t show any clinical symptoms until they’re over 50, and about 1/3 remain asymptomatic into old age.
ACM is a rare inherited cardiomyopathy, but reported prevalence estimates vary considerably, ranging from approximately 1:1,000–1:1,250 to 1:5,000–1:10,000 depending on disease definition, diagnostic criteria, ascertainment, and study population. Higher local frequencies have been reported in founder populations, such as parts of Italy and Naxos. Overall, ACM prevalence remains difficult to determine precisely, particularly because mild, age-dependent, or subclinical forms may be underdiagnosed.
The most common forms are caused by variants in genes that code for components of the desmosomes (cell–cell connections). Molecular genetic analysis of the genes that encode desmoplakin (DSP), plakophilin-2 (PKP2), and desmoglein-2 (DSG2) reveals variants in about 50–60% of patients. In about 5% of cases, the hereditary form of ACM is caused by variants of other desmosomal protein genes such as plakoglobin (JUP) and desmocollin-2 (DSC2), as well as other genes such as transmembrane protein 43 (TMEM43) and transforming growth factor beta-3 (TGFB3). To date, no genetic cause can be proven in about 40% of ACM cases.
ACM is most commonly inherited in an autosomal dominant manner with variable penetrance; rare autosomal recessive forms are usually syndromic and may present with characteristic extracardiac features, particularly woolly hair and palmoplantar keratoderma, as seen in Naxos disease or Carvajal syndrome.
The diagnosis of arrhythmogenic cardiomyopathy (ACM) relies on a multiparametric approach, as no single test is sufficient to establish the diagnosis. According to contemporary reviews and the updated International Task Force / Padua criteria, ACM is identified through a combination of clinical assessment, ECG features, cardiac imaging, arrhythmic burden, family history, and genetic testing. Electrocardiography may demonstrate repolarisation and depolarisation abnormalities, such as T‑wave inversion in right precordial leads, prolonged terminal activation, or epsilon‑like potentials, but these findings alone have limited sensitivity and are not diagnostic by themselves. Cardiac MRI is now central to the diagnostic process and allows assessment of ventricular morphology, wall motion abnormalities, and tissue characterisation, including detection of late gadolinium enhancement (LGE) and myocardial fibrosis. LGE patterns in ACM typically reflect non‑ischemic myocardial scarring, often involving the subepicardium or mid‑wall, and can be present in the left or right ventricle. Such findings significantly improve recognition of left‑dominant or biventricular ACM phenotypes. Importantly, recurrent myocarditis‑like presentations (“hot phases”) with LGE patterns consistent with fibro‑fatty scar formation have become recognized as part of the ACM spectrum, and their presence should raise suspicion for ACM in the appropriate clinical and familial context. Diagnosis is further supported by ventricular arrhythmias, family history of ACM or sudden cardiac death, and identification of a pathogenic variant associated with the disease. Because of the heterogeneity of ACM and its phenocopies, a structured combination of these parameters—as outlined in the and —is necessary for establishing a definite, borderline, or possible diagnosis.
Main differential diagnoses include:
- : left ventricular dilation and systolic dysfunction without right-ventricular fibrofatty replacement; LMNA, MYBPC3, MYH7, TTN
- Catecholaminergic polymorphic ventricular tachycardia: exercise- or emotion-triggered polymorphic VT in a structurally normal heart; RYR2
- Cardiac sarcoidosis / myocarditis: inflammatory myocardial infiltrates causing ventricular arrhythmias and wall-motion abnormalities; non-genetic (acquired) in classical cases
- In arrhythmogenic cardiomyopathy genetic testing is central because the disease is commonly inherited and may present with incomplete, age-dependent, or variable clinical expression. Identification of a pathogenic germline variant — most often in desmosomal genes such as PKP2, DSP, DSG2, DSC2, or JUP — can confirm the molecular diagnosis, support differentiation from phenocopies such as myocarditis or dilated cardiomyopathy, and help define genotype-specific disease patterns and arrhythmic risk.
- The result may guide individualised clinical management, including surveillance intensity, exercise recommendations, family counselling, and risk assessment for ventricular arrhythmias and sudden cardiac death. Once the causative variant has been identified in the index patient, targeted cascade testing enables early identification of at-risk relatives who require cardiological follow-up, while non-carriers can often be spared unnecessary surveillance. In minors, predictive testing should be considered within genetic counselling, taking into account age-dependent penetrance, preventive options, and psychosocial implications.
- McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic right ventricular cardiomyopathy overview. 2005 Apr 18 [Updated 2023 May 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301310.
- Groeneweg JA, Bhonsale A, James CA, te Riele AS, Dooijes D, Tichnell C, et al. Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc Genet. 2015;8(3):437-46. doi:10.1161/CIRCGENETICS.114.001003. PMID:.
- Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A, et al. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J. 2020;41(14):1414-29. doi:10.1093/eurheartj/ehz669. PMID:; PMCID: PMC7138528.
- Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24(8):1307-67. doi:10.1093/europace/euac030. PMID:; PMCID: .
- Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997-4126. doi:10.1093/eurheartj/ehac262. PMID:.
- Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194. PMID:.
- Muller SA, Bertoli G, Wang J, Gasperetti A, Cox MGPJ, Calkins H, et al. Arrhythmogenic cardiomyopathy: towards genotype based diagnoses and management. J Cardiovasc Electrophysiol. 2025;36(9):2662-70. doi:10.1111/jce.16519. PMID:; PMCID: PMC12530674.
- Iezzi L, Sorella A, Galanti K, Gallina S, Chahal AA, Bauce B, et al. Arrhythmogenic cardiomyopathy diagnosis and management: a systematic review of clinical practice guidelines and recommendations with insights for future research. Eur Heart J Qual Care Clin Outcomes. 2025;11(7):1033-69. doi:10.1093/ehjqcco/qcaf029. PMID:; PMCID: PMC12587283.
Created by
Our editorial team consists of medical specialists and scientists in the field of human genetics. All content is created and reviewed in accordance with current scientific standards.
Get in touch with us
Our team of experts is here to support you at every stage.
Are you a patient?
Why Medicover Genetics
Leader in genetic testing with >25 years of experience in counselling and diagnostics
Comprehensive CE-IVD kit portfolio and seamless Technology Transfer solution for laboratories of any size
End-to-end clinical workflow from sample processing to sequencing analysis and reporting
CAP- accredited, GMP- and ISO9001, 15189 and 13485 certified
Certified laboratories
