Elsevier

Heart Failure Clinics

Volume 14, Issue 2, April 2018, Pages 201-213
Heart Failure Clinics

Diagnostic Criteria, Genetics, and Molecular Basis of Arrhythmogenic Cardiomyopathy

https://doi.org/10.1016/j.hfc.2018.01.002Get rights and content

Section snippets

Key points

  • Clinical presentation is characterized by ventricular arrhythmias at risk of sudden death. More rarely, right ventricular or biventricular dysfunction leading to heart failure is reported

  • Generally referred as right ventricular disease, recognition of left-dominant and biventricular subtypes prompted the use of the broader term AC.

  • Effort is a trigger of disease onset and progression as well as ventricular arrhythmias.

  • Disease causing genes mostly encode for desmosomal proteins, although

Clinical features

Clinical manifestations vary with age and disease stage. Despite the similar prevalence of mutation carriers in both genders, the clinical expression of the disease is usually more severe in men, with a higher prevalence of male than female patients who fulfill the diagnostic criteria (up to 3:1).3, 5 Palpitations, syncope, and cardiac arrest are common symptoms in young adults or adolescents, and the most typical signs of AC are ventricular arrhythmias with left bundle branch block (LBBB)

Diagnostic criteria

Because there is no single gold standard, AC diagnosis requires multiple criteria, combining different sources of diagnostic information, such as morphofunctional (by echocardiography and/or angiography and/or cardiac magnetic resonance [CMR]), histopathological on endomyocardial biopsy, ECG, arrhythmias, and familial history, including genetics (Fig. 1).

The original diagnostic criteria15 were revised in 201016 to improve diagnostic sensitivity, by maintaining diagnostic specificity (Box 1).

Genetics

Although AC has been recognized as an inherited disease since the 1980s,29 the first disease-causing gene was identified in 2000, when the investigations carried out on a similar disorder in the Naxos Island marked the turning point in the understanding of the genetic background. In a cohort of people with palmoplantar keratoderma, wooly hair, and AC cosegregating in a recessive pattern, a haplotype on chromosome 17q21 was first identified, and further analysis led to the discovery of a

Pathogenesis

Experimental animal and cellular models are useful tools to explore how mutant desmosomal proteins lead to cardiomyocyte death and subsequent repair with fibrous and fatty tissue.4, 7, 60, 61

Future perspectives

The most important goals of clinical management of AC patients are sudden cardiac death prevention and improvement quality of life by decreasing or suppressing palpitations, VT recurrences, or ICD discharges.12 Current therapeutic approaches, which are discussed in detail elsewhere and out of the scope of this review, regard lifestyle modifications, pharmacologic treatment, catheter ablation, ICD implantation, and exceptionally, heart transplantation. However, they are all palliative tools of

Acknowledgments

This work has been supported by TRANSAC, University of Padua Strategic Grant CPDA133979/13, Padua, Italy; Registry for Cardio-Cerebro-Vascular Pathology, Veneto Region, Venice, Italy; Target Project, Regional Health System (RF-2014-00000394), Venice, Italy; PRIN Ministry of Education (2015ZLNETW), University and Research, Rome, Italy.

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References (73)

  • A. Asimaki et al.

    A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy

    Am J Hum Genet

    (2007)
  • N.D. Merner et al.

    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

    (2008)
  • J.P. van Tintelen et al.

    Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene

    Heart Rhythm

    (2009)
  • M.F. Ortiz-Genga et al.

    Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies

    J Am Coll Cardiol

    (2016)
  • W.W. Franke et al.

    The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins

    Eur J Cell Biol

    (2006)
  • B. Bauce et al.

    Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia

    Heart Rhythm

    (2010)
  • T. Xu et al.

    Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy

    J Am Coll Cardiol

    (2010)
  • D. Dalal et al.

    Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy

    J Am Coll Cardiol

    (2006)
  • C.A. James et al.

    Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers

    J Am Coll Cardiol

    (2013)
  • M. Noorman et al.

    Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy

    Heart Rhythm

    (2013)
  • G. Thiene et al.

    Right ventricular cardiomyopathy and sudden death in young people

    N Engl J Med

    (1988)
  • C. Basso et al.

    Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis?

    Circulation

    (1996)
  • C. Basso et al.

    Pathophysiology of arrhythmogenic cardiomyopathy

    Nat Rev Cardiol

    (2011)
  • D. Corrado et al.

    Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program

    JAMA

    (2006)
  • K. Pilichou et al.

    Arrhythmogenic cardiomyopathy

    Orphanet J Rare Dis

    (2016)
  • S. Sen-Chowdhry et al.

    Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression

    Circulation

    (2007)
  • G. Thiene et al.

    Anatomoclinical aspects of arrhythmogenic right ventricular cardiomyopathy

  • C. Basso et al.

    Arrhythmogenic right ventricular cardiomyopathy

    Circ Arrhythm Electrophysiol

    (2012)
  • D. Corrado et al.

    Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an International Task Force Consensus statement

    Circulation

    (2015)
  • S. Rizzo et al.

    Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes

    Cardiovasc Res

    (2012)
  • M. Cerrone et al.

    Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency

    Cardiovasc Res

    (2012)
  • W.J. McKenna et al.

    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 International Society and Federation of Cardiology

    Br Heart J

    (1994)
  • F.I. Marcus et al.

    Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria

    Circulation

    (2010)
  • F. Migliore et al.

    Prevalence of cardiomyopathy in Italian asymptomatic children with electrocardiographic T-wave inversion at preparticipation screening

    Circulation

    (2012)
  • B. Bauce et al.

    Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations

    Eur Heart J

    (2005)
  • M. Perazzolo Marra et al.

    Imaging study of ventricular scar in arrhythmogenic right ventricular cardiomyopathy: comparison of 3D standard electroanatomical voltage mapping and contrast-enhanced cardiac magnetic resonance

    Circ Arrhythm Electrophysiol

    (2012)
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      Arrhythmogenic Cardiomyopathy (AC) is a familial heart disease at risk of stress-related arrhythmic sudden cardiac death (SCD) in the young and athletes [1,2]. In about 50% of genetically diagnosed cases, AC is caused by mutations in desmosomal genes, while the remainder patients either carry pathogenic variants in genes with various functions (i.e. ion channels, sarcomeric and signaling proteins) or are mutation-negative in standard test panels [3–5]. AC diagnosis is based on clinical/pathologic criteria, including morpho-functional cardiac abnormalities, tissue characterization on endomyocardial biopsy, electrocardiographic changes, ventricular arrhythmias and family history [6].

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