History of the discovery of Arrhythmogenic Cardiomyopathy

Giovanni Maria Lancisi (1654–1720), anatomist in Rome and Pope archiater, famous for his investigations on Sudden Death, is known for his posthumous book of 1728 entitled De motu cordis et aneurysmatibus (On the movement of the heart and aneurysms),1 divided in two parts (Figure 1). In the second book on aneurysms, he dealt with hereditary cardiac aneurysms. In Chapter VI, he started quoting the Father of Medicine: ‘In Hippocrates it is distinctly taught that diseases may be handed down from parents to children2 […]. Therefore no one will deny that disorders of the heart can be handed down […] from the very moment of conception’. The discovery of arrhythmogenic cardiomyopathy (AC), nowadays a well-known genetically determined heart muscle disease, dates back to the XVIII century when in 1728, Lancisi reported a four-generation family affected by palpitations, heart failure, and sudden death, in which autopsy revealed dilatation and aneurysms of the right ventricle (RV). The parchment heart, mentioned by Osler in his ‘The principles and practice of Medicine’ in 1905, belonged to a man who died while climbing a steep hill. Uhl in 1952 described the absence of the right ventricular myocardium in an infant who died of congestive heart failure, most probably a congenital malformation. In the 1960's Dalla Volta in Padua first described the haemodynamic features of AC with the name ‘auricularization of the right ventricle pressure’. (Left) Giovanni Maria Lancisi portrait (Bo Palace, Medicine Hall, Padua). (Right) Title page of his book De motu cordis et aneurysmatibus. Roma, G.M. Salvioni, 1728. Referring to cardiac aneurysms, Lancisi wrote that ‘An important sign of that hereditary trouble is a certain pulsation of the right side of the heart. Those who suffer from it, though in other respects in good health, assert that they can distinctly feel this after violent physical exertion […]’. Lancisi reported a family with recurrent disease in four generations and palpitations, heart failure, aneurysm of the RV, and sudden death. The great-grandfather (1st generation) died suddenly and was found affected by an aneurysm of the RV at autopsy. The grandfather (2nd generation) complained ‘frequent palpitations of the heart, difficult respiration, oedematous swellings of the feet, […] wavelike motion of the jugular veins […]. The patient’s cadaver was opened, and the right cavity of the heart was found to be larger than a clenched fist would fill’. An uncle, brother of the father (3rd generation) ‘a still living youngish man over forty […] feels an annoying pulsation in the right side of the chest […]. I can only hope that he may not going to end in the same way’. The index child (4th generation), ‘[…] little son of the brother of the youngish man past described, died of children’s epilepsy. I laid open the cadaver […] and found in it this same hereditary weakness of the precordium’. Figure 2 represents the genealogical tree in keeping with hereditary dominant disease. The genealogical tree reconstruction of the family reported by Lancisi in 1728, in keeping with a dominant Mendelian hereditary disease. No doubt we are facing a clinico-pathologic description of AC, since we are aware that hereditary aneurysms of the RV are pathognomonic of the disease. Interestingly, there is a visionary statement by Lancisi at the end of the report: ‘It may well be that what I had so far observed only in the right cavities of the heart can also occur in other channels of the blood as well’ (left ventricular AC?). Almost a century later, in 1819, René Laennec (1781–1826) published in Paris the book De l’auscultation mediate (Figure 3),3 a treatise on the diseases of the chest and on mediated auscultation by the stethoscope. In Book II, Chapter XV on the accumulation of fat around the heart, he noted: ‘In medical writing we find many examples of the heart being overloaded with fat […] and even the sudden death […]. The fatter the heart is, the thinner […] are its walls. Sometimes these are extremely thin, being reduced almost to nothing, especially at the apex of the heart and the posterior side of the right ventricle. […] On examining ventricles […] the scalpel seems to reach the cavity without encountering almost any muscular substance […]’.3 The description by Laennec is unequivocal: the lesions are located in topographic sites, known nowadays clinically as ‘triangle of dysplasia’4 and supported by pathology studies.5 (Left) René Laennec portrait. (Right) Title page of the book De l'auscultation médiate ou traité du diagnostic des maladies des poumons et du coeur, fondé principalment sur ce nouveau moyen d'exploration. Paris, Brosson & Chaudé, 1819. In Middlemarch, published by George Eliot (1819–1880) in 1871,6 the protagonist Dr Lydgate, talking with one of his patients, says: ‘I believe that you are suffering from what is called fatty degeneration of the heart, a disease which was first divined and explored by Laennec, the man who gave us the stethoscope, not so many years ago. […] it is my duty to tell you that death from this disease is often sudden. At the same time, no such result can be predicted […]’. The concept of fatty heart (adipositas cordis) was also known by other writers. Charles Dickens (1812–1870) described an obese, dyspnoeic, and sleepy boy (‘the fatty Joe’) in his book Pickwick Circle, 1836–1837.7 In the classic textbooks of pathology, e.g. Eduard Kauffman (1860–1931) Lehrbuch der speziellen pathologischen Anatomie (Treatise of special pathological anatomy), 1896, lipomatosis, adipositas or obesitas cordis (‘Fettherz’) of the RV received peculiar attention, being observed in subjects dying suddenly.8 Nowadays adipositas cordis is distinguished from AC.9 In 1905, William Osler (1849–1919) (Figure 4A) in the VI edition of his famous treatise The principles and practice of Medicine10 stated: ‘Dilatation may be an acute process and quite transitory as after severe muscular effort, or it may be chronic, in which case it is associated with hypertrophy. Not always, however; there is an extraordinary heart in the McGill College Museum showing a parchment-like thinning of the walls with uniform dilatation of all the chambers; in places in the right auricle and ventricle only the epicardium remains’. The pathologist Maude Abbott (1869–1940), curator of the McGill College Museum, found the aforementioned specimen among those donated by Osler during his professorship in Montreal between 1874 and 1884. Unfortunately, the specimen was not accompanied by clinical and autopsy records, but Madame Abbott remembered vaguely that it belonged to a man who had died suddenly in Montreal while climbing a steep hill. (A) William Osler. (B) Drawing of Osler’s ‘Parchment heart’ with paper-thin walls of both ventricles, reported by Segall in 1950.12 The same Abbott, in a book of memoirs published by MacDermot,11 recounted that Osler, back in Montreal and visiting the McGill College Museum, might have again seen the specimen, then mentioned it in the new edition of his treatise.10 Harold Segall (1897–1990) had the opportunity to examine the original specimen, preserved in a formalin-filled jar, which appeared as a large cyst (Figure 4B).12 It could only be identified as a heart thanks to the presence of cardiac valves. Since the coronary arteries were patent, an ischaemic cause could be ruled out. Both ventricular walls appeared paper-thin, thus he coined the term ‘Osler parchment heart’.12 Oddly enough, the ventricular septum appeared almost spared. It was amazing to realize a chronic dilatation without hypertrophy and cardiomegaly: the heart weight was only 168 g! The presence of a few atherosclerotic plaques in the aortic root suggested that the heart might have belonged to a 40- to 50-year-old person. Histology disclosed very rare cardiomyocytes in the paper-thin ventricular walls. As far as aetio-pathogenesis, Segall advanced the following hypothesis: ‘Among the various mechanisms that merit consideration, dystrophy of myocardium in a person with generalized muscular dystrophy offers the possibility of an explanation. That the right auricle and ventricle are larger than the left suggests an element of cor pulmonale which may have been due to impairment in function of respiratory muscles’.12 For the first time this morbid cardiac entity was interpreted as a myocardial dystrophy, like that occurring in the skeletal muscle of Duchenne and Becker diseases. However, it is difficult to believe that the patient could have been affected by a generalized skeletal muscle dystrophy, since he was able to climb a hill. A controversial case, which has been the source of subsequent misconceptions, was the one observed by Henry Uhl (1921–2009) in 1952 at the Johns Hopkins Hospital in Baltimore in an 8-month-old female infant who died of congestive heart failure in the absence of arrhythmias and was published with the title A previously undescribed congenital malformation of the heart: almost total absence of the myocardium of the right ventricle.13 The description by Uhl is eloquent: ‘Externally the heart appears greatly enlarged […] almost the entire dilated chamber (RV) was occupied by a large laminated mural thrombosis which adhered firmly to the endocardium along the anterior wall of the ventricle. Examination of the cut edge of the ventricle wall revealed it to be paper-thin with no myocardium visible […]. In the RV wall, epicardium and endocardium lie adjacent to each other with no intervening cardiac muscle […] no fibro-fatty tissue in the RV free wall was observed’13 (Figure 5). The early age and the peculiar pathological description point to a structural heart disease present at birth (congenital malformation), as emphasized in the title itself. Clinical presentation was characterized neither by cardiac arrhythmias nor by a family history of heart disease. Thereafter, adult cases with paper-thin ventricular walls, recently reviewed by Basso et al.,9 have been published with the eponym of Uhl’s anomaly, clearly a misnomer because the parchment heart in adults is the end stage of a late progressive loss of the myocardium followed by fibro-fatty replacement. The parchment heart cases reported in the adults (including the Osler heart) varied from 17 to 81 years and died either of congestive heart failure or electrical cardiac arrest. In contrast, the cases reported in the literature of infants under the age of 15 months with the eponym of Uhl’s anomaly all featured heart failure and isolated RV involvement (whether segmental or diffuse) without arrhythmias, in keeping with the original description by Uhl. Uhl’s anomaly original drawings. (Left) Opened right ventricle with huge dilatation. (Right) The right ventricular free wall is extremely thin with endocardium and epicardium lying adjacent to each other.13 Since the early 1960s, the University of Padua has laid milestones in the history of the disease. Sergio Dalla Volta et al. in 1961 and 1965, by right cardiac catheterization, described similar cases under the name of ‘auricularization of the right ventricular pressure’, to emphasize the behaviour of the RV without an effective contraction, blood being pushed to the pulmonary artery by right atrial systole.14,15 In two cases, final clinical and autopsy diagnosis was ‘sclerosis of the right ventricle after a myocardial infarct without coronary obstruction’, clearly a misdiagnosis. The concept of non-ischaemic cardiomyopathy was still difficult to conceive. Interesting, out of the six documented cases, ranging from 21 to 40 years, two had ventricular arrhythmias, five inverted T waves in right precordial leads, and four congestive heart failure. One of these, a 21-year-old lady, thereafter in 1996 developed ventricular tachycardia of left bundle branch morphology, right ventricular failure, and died following cardiac transplantation. The recipient heart showed an extremely dilated RV with parchment-like wall (Figure 6). (Top) Cross-section of the heart from a lady who underwent to cardiac transplantation in 1996 (formerly reported by Dalla Volta in 1961): note the huge dilatation of the RV. (Bottom) In vitro cardiac magnetic resonance. The right ventricular free wall appears paper-thin. Whereas the left ventricle is almost intact.14 In 1965, Paolo Rizzon from the University of Bari reported a similar case but with the misnomer of Uhl’s syndrome.16 In 1968 the French investigators Robert Froment and Robert Loire, cardiologist and pathologist respectively, published five cases of ‘ventricule droit papyracé’, two of which with an autopsy report. They first demonstrated that fibro-fatty infiltration of the RV free wall was associated with inverted T waves in right precordial leads of the electrocardiogram.17 In 1970 Vito Terribile Wiel Marin (1939–2015), pathologist at the University of Padua, performed a post-mortem of a 43-year-old woman with a history of palpitations and congestive heart failure, who died of pulmonary embolism. In the autopsy report, he described the heart having extreme dilatation, mural thrombosis, and adipositas cordis of the RV, as well as left ventricular ‘myocardial sclerosis’, all features in keeping with what we today call biventricular AC (Figure 7). Autopsy report and drawings of a case of arrhythmogenic cardiomyopathy in a patient who died in 1970 of pulmonary embolism, with adipositas cordis in the RV and foci of myocardial sclerosis in the left ventricle. We thank Dr Maria Bueno Marinas for her support in producing the genealogy tree. Conflict of interest: none declared. References are available as supplementary material at European Heart Journal online.