https://orcid.org/0000-0001-6331-649X
A contemporary review of the history of arrhythmogenic cardiomyopathy highlighting the early discoverers and recent genetic work
Introduction
In a recent paper, we discussed the history of arrhythmogenic cardiomyopathy (AC), focusing on the discoveries from the beginning of modern medicine in the XVIII century to the 1970s.1 We move on with a survey of the achievements during the last 40 years, where it took only 20 years to discover the gene defect. Table 1 reports the milestones.
Milestones in the contemporary history of arrhythmogenic cardiomyopathy (AC)
| 1977–78 | Fontaine et al., Electrical instability of the right ventricle8,9 |
| 1982 | Marcus et al., Right ventricular dysplasia and ‘triangle of dysplasia’2 |
| 1986 | Protonotarius and Tsatsopoulou, Naxos disease21 |
| 1988 | Thiene et al., SCD death in the young3 |
| 1988 | Nava et al., Familiarity11 |
| 1994 | McKenna et al., Task force diagnostic criteria37 |
| 1995 | Richardson et al., WHO classification of cardiomyopathies6 |
| 1996 | Basso et al., Myocardial dystrophy4 |
| 1998 | Valente et al., Apoptosis as mode of cell death18 |
| 1999 | Calkins, A national registry in USA |
| 2000 | Nava et al., Genetically determined cardiomyopathy17 |
| 2000 | McKoy et al., JUP recessive mutation in Naxos disease24 |
| 2000 | Norgett et al., DSP recessive mutation in Carvajal syndrome26 |
| 2002 | Rampazzo et al., DSP mutation in dominant form28 |
| 2003 | Corrado et al., ICD for SCD prevention45 |
| 2004 | Marchlinski et al., Electroanatomic mapping10 |
| 2004 | Gerull et al., PKP2 mutations in dominant form30 |
| 2005 | Bauce et al., Genotype–phenotype correlations29 |
| 2005 | Norman et al., Left ventricular variant41 |
| 2006 | Corrado et al., ECG screening programme and prevention of SCD in competitive athletes16 |
| 2006 | Garcia-Gras et al., Loss of Wnt/β-catenin signalling in transgenic mice49 |
| 2006 | Pilichou et al., Mutations in DSG2 in dominant form31 |
| 2006 | Syrris et al., Mutations in DSC2 in dominant form32 |
| 2007 | Asimaki et al., JUP mutations in dominant form34 |
| 2008 | Basso et al., Endomiocardial biopsy40 |
| 2010 | Marcus et al., Update of the Task Force diagnostic criteria38 |
| 2013 | Rigato et al., Compound and digenic heterozygosity35 |
| 2013 | Kim et al., AC with patient-specific iPSCs53 |
| 2014 | Asimaki et al., Zebrafish model in Naxos disease50 |
| 2016 | Sommariva et al., Mesenchymal cells as the source of adipocytes20 |
| 2018 | Giuliodori et al., Loss of Wnt/β-catenin signalling in zebrafish model51 |
| 1977–78 | Fontaine et al., Electrical instability of the right ventricle8,9 |
| 1982 | Marcus et al., Right ventricular dysplasia and ‘triangle of dysplasia’2 |
| 1986 | Protonotarius and Tsatsopoulou, Naxos disease21 |
| 1988 | Thiene et al., SCD death in the young3 |
| 1988 | Nava et al., Familiarity11 |
| 1994 | McKenna et al., Task force diagnostic criteria37 |
| 1995 | Richardson et al., WHO classification of cardiomyopathies6 |
| 1996 | Basso et al., Myocardial dystrophy4 |
| 1998 | Valente et al., Apoptosis as mode of cell death18 |
| 1999 | Calkins, A national registry in USA |
| 2000 | Nava et al., Genetically determined cardiomyopathy17 |
| 2000 | McKoy et al., JUP recessive mutation in Naxos disease24 |
| 2000 | Norgett et al., DSP recessive mutation in Carvajal syndrome26 |
| 2002 | Rampazzo et al., DSP mutation in dominant form28 |
| 2003 | Corrado et al., ICD for SCD prevention45 |
| 2004 | Marchlinski et al., Electroanatomic mapping10 |
| 2004 | Gerull et al., PKP2 mutations in dominant form30 |
| 2005 | Bauce et al., Genotype–phenotype correlations29 |
| 2005 | Norman et al., Left ventricular variant41 |
| 2006 | Corrado et al., ECG screening programme and prevention of SCD in competitive athletes16 |
| 2006 | Garcia-Gras et al., Loss of Wnt/β-catenin signalling in transgenic mice49 |
| 2006 | Pilichou et al., Mutations in DSG2 in dominant form31 |
| 2006 | Syrris et al., Mutations in DSC2 in dominant form32 |
| 2007 | Asimaki et al., JUP mutations in dominant form34 |
| 2008 | Basso et al., Endomiocardial biopsy40 |
| 2010 | Marcus et al., Update of the Task Force diagnostic criteria38 |
| 2013 | Rigato et al., Compound and digenic heterozygosity35 |
| 2013 | Kim et al., AC with patient-specific iPSCs53 |
| 2014 | Asimaki et al., Zebrafish model in Naxos disease50 |
| 2016 | Sommariva et al., Mesenchymal cells as the source of adipocytes20 |
| 2018 | Giuliodori et al., Loss of Wnt/β-catenin signalling in zebrafish model51 |
Milestones in the contemporary history of arrhythmogenic cardiomyopathy (AC)
| 1977–78 | Fontaine et al., Electrical instability of the right ventricle8,9 |
| 1982 | Marcus et al., Right ventricular dysplasia and ‘triangle of dysplasia’2 |
| 1986 | Protonotarius and Tsatsopoulou, Naxos disease21 |
| 1988 | Thiene et al., SCD death in the young3 |
| 1988 | Nava et al., Familiarity11 |
| 1994 | McKenna et al., Task force diagnostic criteria37 |
| 1995 | Richardson et al., WHO classification of cardiomyopathies6 |
| 1996 | Basso et al., Myocardial dystrophy4 |
| 1998 | Valente et al., Apoptosis as mode of cell death18 |
| 1999 | Calkins, A national registry in USA |
| 2000 | Nava et al., Genetically determined cardiomyopathy17 |
| 2000 | McKoy et al., JUP recessive mutation in Naxos disease24 |
| 2000 | Norgett et al., DSP recessive mutation in Carvajal syndrome26 |
| 2002 | Rampazzo et al., DSP mutation in dominant form28 |
| 2003 | Corrado et al., ICD for SCD prevention45 |
| 2004 | Marchlinski et al., Electroanatomic mapping10 |
| 2004 | Gerull et al., PKP2 mutations in dominant form30 |
| 2005 | Bauce et al., Genotype–phenotype correlations29 |
| 2005 | Norman et al., Left ventricular variant41 |
| 2006 | Corrado et al., ECG screening programme and prevention of SCD in competitive athletes16 |
| 2006 | Garcia-Gras et al., Loss of Wnt/β-catenin signalling in transgenic mice49 |
| 2006 | Pilichou et al., Mutations in DSG2 in dominant form31 |
| 2006 | Syrris et al., Mutations in DSC2 in dominant form32 |
| 2007 | Asimaki et al., JUP mutations in dominant form34 |
| 2008 | Basso et al., Endomiocardial biopsy40 |
| 2010 | Marcus et al., Update of the Task Force diagnostic criteria38 |
| 2013 | Rigato et al., Compound and digenic heterozygosity35 |
| 2013 | Kim et al., AC with patient-specific iPSCs53 |
| 2014 | Asimaki et al., Zebrafish model in Naxos disease50 |
| 2016 | Sommariva et al., Mesenchymal cells as the source of adipocytes20 |
| 2018 | Giuliodori et al., Loss of Wnt/β-catenin signalling in zebrafish model51 |
| 1977–78 | Fontaine et al., Electrical instability of the right ventricle8,9 |
| 1982 | Marcus et al., Right ventricular dysplasia and ‘triangle of dysplasia’2 |
| 1986 | Protonotarius and Tsatsopoulou, Naxos disease21 |
| 1988 | Thiene et al., SCD death in the young3 |
| 1988 | Nava et al., Familiarity11 |
| 1994 | McKenna et al., Task force diagnostic criteria37 |
| 1995 | Richardson et al., WHO classification of cardiomyopathies6 |
| 1996 | Basso et al., Myocardial dystrophy4 |
| 1998 | Valente et al., Apoptosis as mode of cell death18 |
| 1999 | Calkins, A national registry in USA |
| 2000 | Nava et al., Genetically determined cardiomyopathy17 |
| 2000 | McKoy et al., JUP recessive mutation in Naxos disease24 |
| 2000 | Norgett et al., DSP recessive mutation in Carvajal syndrome26 |
| 2002 | Rampazzo et al., DSP mutation in dominant form28 |
| 2003 | Corrado et al., ICD for SCD prevention45 |
| 2004 | Marchlinski et al., Electroanatomic mapping10 |
| 2004 | Gerull et al., PKP2 mutations in dominant form30 |
| 2005 | Bauce et al., Genotype–phenotype correlations29 |
| 2005 | Norman et al., Left ventricular variant41 |
| 2006 | Corrado et al., ECG screening programme and prevention of SCD in competitive athletes16 |
| 2006 | Garcia-Gras et al., Loss of Wnt/β-catenin signalling in transgenic mice49 |
| 2006 | Pilichou et al., Mutations in DSG2 in dominant form31 |
| 2006 | Syrris et al., Mutations in DSC2 in dominant form32 |
| 2007 | Asimaki et al., JUP mutations in dominant form34 |
| 2008 | Basso et al., Endomiocardial biopsy40 |
| 2010 | Marcus et al., Update of the Task Force diagnostic criteria38 |
| 2013 | Rigato et al., Compound and digenic heterozygosity35 |
| 2013 | Kim et al., AC with patient-specific iPSCs53 |
| 2014 | Asimaki et al., Zebrafish model in Naxos disease50 |
| 2016 | Sommariva et al., Mesenchymal cells as the source of adipocytes20 |
| 2018 | Giuliodori et al., Loss of Wnt/β-catenin signalling in zebrafish model51 |
Nomenclature
In the past different terminology has been used: right ventricular dysplasia,2 right ventricular cardiomyopathy,3 arrhythmogenic right ventricular cardiomyopathy,4 and arrhythmogenic right ventricular cardiomyopathy/dysplasia.5 This heart muscle disease was definitively introduced into the World Health Organization classification of cardiomyopathy in 1996,6 ruling out the concept of the disease as a congenital malformation. Eventually, with the discovery of the left ventricle (LV) variant, the term AC was coined.7
Heart muscle disease with a peculiar electrical instability
The adjective arrhythmogenic was added to mean the pathognomonic feature of this non-ischaemic heart muscle disease. Guy Fontaine et al., in the late-1970s, realized that the right ventricle (RV) may be a source of arrhythmias with left bundle branch block (LBBB) morphology.8,9 In 1982, Frank Marcus et al. reported a series of patients affected by a new syndrome,2 by establishing the remodelling hallmarks of the RV, with aneurysms located topographically in the inflow, apex, and outflow of the RV (triangle of dysplasia) due to fibro-fatty replacement (Figure 1).
The ECG became fundamental for diagnosis, with inverted T waves in precordial leads, wide QRS, epsilon wave, due to delayed electrical impulse transmission in the RV outflow tract, and premature ventricular beats with LBBB morphology.
Electroanatomic mapping was useful by discovering electrical silence (scars) of the RV (Figure 2).10
(A) Bipolar electroanatomic mapping showing an extensive area (red) of electrical silence of the right ventricle; (B) histology of the anterior wall of the right ventricle of the same case, who died suddenly: note the transmural fibro-fatty replacement (Azan Mallory stain); (C) higher magnification of (B).
Cause of sudden cardiac death in the young and athletes
In May 1979, a young doctor cycling champion (Figure 3) died suddenly whilst playing tennis in Venice. He stopped playing, took his pulse, fainted, and died. Autopsy revealed an extensive fibro-fatty replacement of the RV free wall. A note was found in his diary, dated 4 October 1978: ‘ventricular tachycardia with LBBB’. He was ‘case 0’ of a series of sudden cardiac deaths (SCDs) in young people.3 Nava et al. published the hereditary nature of AC.11 Sports activities increase the risk of SCD five times in AC carriers.12 Prevalence reported in other countries13–15 was much lower, probably due to misdiagnosis in post-mortem investigations. In Italy, the AC rate of SCDs among athletes is 27% and a sharp decline occurred with the use of ECG as a screening tool for sport eligibility.16
‘Case 0’ of sudden cardiac death in the young due to arrhythmogenic cardiomyopathy. A 26-year-old cycling champion physician, on his graduation day. He died suddenly whilst playing tennis in May 1979. Autopsy revealed transmural fibro-fatty replacement of the right ventricle.
AC: hereditary genetic disease of the desmosome
A dominant hereditary form of AC was reported by Nava (Figure 4) et al. in Veneto Region, Italy, and then named ‘Venetian disease’.17 It consisted of a genetically determined cardiomyopathy since the clinical manifestations were absent at birth and became apparent at 10–12 years of age.
Andrea Nava (centre) examines with Frank Marcus (left) and Gaetano Thiene (right) cardiac specimens of sudden death in the young from arrhythmogenic cardiomyopathy at the Institute of Pathological Anatomy, Padua (1994).
Microscopic pathology investigation demonstrated an acquired loss of the myocardium, followed by fibro-fatty replacement as a consequence of ongoing myocardial cell death and repair (Figure 5). The term myocardial dystrophy was considered appropriate.4 Apoptosis was proven to be the mode of cardiomyocyte death.18 Myocardial inflammation is a regular finding: whether a reaction to cell death or a primary immune phenomenon is still controversial.19 The origin of adipocytes was proven to be mesenchymal cells.20
Fibro-fatty replacement under the microscope with high magnification: note the infiltration and proliferation of adipocytes (haematoxylin–eosin stain).
A familiar recessive form of AC, with keratoderma and woolly hairs (cardiocutaneus syndrome), was reported from the island of Naxos in Greece21 (Figure 6).
Naxos disease, a recessive form of arrhythmogenic cardiomyopathy with cardio-cutaneous syndrome. (A) Naxos Island. (B) The recessive hereditary transmission of a patient affected by woolly hair and palmo-plantar keratoderma (courtesy of Adalena Tsatsopoulou).
A race started to discover the genetic basis of AC. In 1996, Ruiz et al., studying the junctional plakoglobin (JUP) in knock-out mice, showed that the absence of JUP affects the formation of desmosome in the heart, with the human gene located in chromosome 17q21.22 In 1998, by linkage analysis, Coonar et al. mapped the locus of the Naxos disease gene on chromosome 17q21.23 In 2000, McKoy et al. identified a deletion of JUP gene in patients with Naxos disease.24
In Ecuador, the dermatologist Carvajal-Huerta detected a recessive mutation of desmoplakin (DSP) in a similar syndrome of a family with dilated cardiomyopathy.25,26 The heart study of a child who died of congestive heart failure revealed a biventricular AC with an RV ‘triangle of dysplasia’.27
DSP also became a candidate gene for the dominant AC form. Molecular genetic investigation in some ‘Venetian’ families revealed mutations of human DSP28 and genotype–phenotype correlations showed biventricular involvement.29
A cascade of gene mutations was then discovered in dominant AC families: plakophilin-2,30 desmoglein-2,31 desmocollin-2,32,33 and plakoglobin,34 confirming that AC is a desmosomal disease. Multiple compound or heterozygous mutations entail a more severe prognosis,35 but the yield of genetic testing in AC remains as low as 50%.
AC was definitively related to the mutation of genes encoding desmosome proteins (Figure 7A). Electron microscopy demonstrated disruption of the intercalated disc36 as the final common pathway of cell death(Figure 7B and C).
(A) Intercalate disc (desmosome) with desmoglein and desmocollin cadherins, plakoglobin and plakophilins armadillo proteins and desmoplakin. (B) Normal and (C) disrupted desmosome on electron microscopy, the latter in arrhythmogenic cardiomyopathy patient.
Advances in clinical diagnosis
Diagnostic criteria for in vivo diagnosis were described in 199437 and updated in 2010.38 Electrocardiogram and echocardiography were crucial. Invasive angiocardiography was employed to detect dyskinesia–akinesia and aneurysms of the RV.39
In vivo endomyocardial biopsy (EMB) was revealed to be the diagnostic gold standard, thanks to the detection of transmural fibro-fatty replacement (Figure 8).40 EMB plays a critical role in differential diagnosis with diseases mimicking AC, such as: myocarditis, sarcoidosis, and idiopathic RV tachycardia.
Endomyocardial biopsy showing (A) fibro-fatty replacement and, at higher magnification (B), proliferating adipocytes (Azan Mallory stain).
The advent of cardiac magnetic resonance (CMR) with late enhancement gadolinium allowed to reveals not only morpho-functional abnormalities but also tissue damage. The use of CMR was crucial to unveil isolated LV involvement, namely LV ‘scars’41,42 (Figure 9).
Cardiac magnetic resonance with late enhanced in short axis (B, D) and four chamber (A, C) views. Note the massive involvement (scars) of the left ventricle (arrows).
Cascade genetic screening is nowadays a routine diagnostic tool in families of AC proband with at least one mutation, in search of genetic carrier kins and results in a prompt translation from bench to bedside.43
Next-generation genetic sequencing made the genetic screening rapid, precise, and produced a large number of indexed cases, clinically affected by AC or identified at post-mortem investigation (molecular autopsy).
Prevention and therapy
The implantable cardioverter defibrillator (ICD)44 proved to be a life-saving device also in subjects with AC.45 Indication for implantation depends upon prognosis: it is mandatory in patients with AC with unexplained syncope, sustained ventricular tachycardia or previous cardiac arrest.46
There are several policies to prevent SCD in AC. Sport disqualification and a lifestyle without exertional activity are simple, effective measures.12
Antiarrhythmic drug therapy is routine, either isolated or in association with ICD.47
Also, ablation of arrhythmogenic foci belongs to the therapeutic armamentarium.48 Unfortunately, it is considered as a palliative procedure because of arrhythmia recurrence.
Automatic external defibrillator should be present in public places, playgrounds and even at the home of affected subjects at the risk of cardiac arrest.
Cardiac transplantation represents the ultimate option in case of terminal congestive heart failure or unbearable electrical storms.
Future research perspectives
We look forward to the time when the treatment of arrhythmias will be no longer the only weapon to manage AC and prevent SCD. Curative therapy has to target the molecular mechanisms involved in the pathogenesis of the disease.
Suppression of Wnt/β catenin signal has been found to recapitulate the AC phenotype, both in transgenic mice49 and zebrafish.50,51
Overexpression of mutated desmoglein-2 resulted in a genetically determined AC in mice, with ‘acquired’ occurrence of cell death, fibrous repair, and aneurysmal biventricular remodelling.52
Human-induced pluripotent stem cells from dermal fibroblasts of AC patients reproduce the disease.53 Precision medicine with personalized patient diagnosis and therapy is on the horizon.
Finally, genetic therapy may be accomplished with transfer of a wild gene by adenovirus vector to replace the pathogenic gene,54 thus giving a 100% chance to produce a healthy child.
Globalization of research
Most of the advances have occurred thanks to international cooperation and competition. In the 1990s, the cardiomyopathy committee of the International Federation of Cardiology, led by Fulvio Camerini, realized that the key to success would be an interdisciplinary approach.
A memorable meeting of experts from both sides of the Atlantic Ocean was organized by Hugh Calkins in Baltimore in June 1999 (Figure 10), who then implemented an AC registry in the USA. A decision was taken to apply for grants to the European Commission and to the National Health Institute, with the aim to discover the AC genes. A meeting of European Partners was held in Naxos on June 2003 (Figure 11). The international collaboration resulted in a final meeting, held in Denver in 2007 and the findings published in international journals and collected in a monograph.55 Meanwhile, many of these giants have died (Camerini, Fontaine, Moss, Nava, Protonotarios, Rossi).
Baltimore meeting June 1999, organized by Hugh Calkins, who then started the arrhythmogenic cardiomyopathy US Registry. European experts (Cristina Basso, Barbara Bauce, Guy H Fontaine, Thomas Wichter, and Gaetano Thiene) and American experts (Frank Marcus, Arthur J Moss, Jeffry A Towbin, Hugh Calkins, Wojciech Zareba, and others) attended the rendezvous.
Meeting in Naxos on June 2003 of European Partners from left to right: Barbara Bauce, Guy Fontaine, Cristina Basso, Nikos Protonotarios, Gaetano Thiene, Katarzyna Wlodarska, Andrea Nava, Elzbieta Czarnowska, Thomas Wichter, Loizos Antoniades, Gian Antonio Danieli, Bill McKenna.
The race was paraphrased by the late Lino Rossi: All of them share the unique merit of a skilful and dedicated engagement in a scientific contest of vital importance which is not comparable to any sports competition; as such, the present overview concludes with the popular saying, ‘who cares who came second?’, here intended in an entirely positive, even laudative sense (personal communication).
Acknowledgements
This investigation was supported by the Registry for Cardio-Cerebro-Vascular Pathology, Veneto Region, Venice, Italy, and by A.R.C.A Foundation, Padua, Italy.
Conflict of interest: none declared.
References
References are available as supplementary material at European Heart Journal online.
