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Circulation. 1996;94:983-991

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*Arrhythmia
*Cardiomyopathy

(Circulation. 1996;94:983-991.)
© 1996 American Heart Association, Inc.

Articles

Arrhythmogenic Right Ventricular Cardiomyopathy

Dysplasia, Dystrophy, or Myocarditis?

Cristina Basso, MD; Gaetano Thiene, MD; Domenico Corrado, MD; Annalisa Angelini, MD; Andrea Nava, MD; Marialuisa Valente, MD

the Departments of Pathology and Cardiology, University of Padua Medical School, Padua, Italy.

Correspondence to Gaetano Thiene, MD, Istituto di Anatomia Patologica, Via A. Gabelli, 61, 35121 Padova, Italy.


*    Abstract
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Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a frequent cause of sudden death in young individuals and athletes. Although familial occurrence has been documented and a gene defect was recently localized on chromosome 14q23-q24 the etiopathogenesis of the disease is still obscure.

Methods and Results A pathological study was conducted in 30 hearts with ARVC (age range, 15 to 65 years; mean, 28 years). In the 27 autopsy cases, the mode of death was sudden in 24 and congestive heart failure in 3. ECG, available in 19 cases, showed inverted T waves in the right precordial leads in 15 cases (79%) and ventricular arrhythmias in 15 (79%). Right ventricular aneurysms were present in 15 hearts (50%) and located in the inferior wall in 12. Left ventricle and ventricular septum were involved in 14 (47%) and 6 (20%) cases, respectively. Scattered foci of lymphocytes with myocardial death were observed in 20 cases (67%). Electron microscopy studies, although confirming the myocardial death and lymphocyte infiltrates, did not show any specific ultrastructural substrate. Two pathological patterns, fatty (40%) and fibrofatty (60%), were identified. The fibrofatty pattern was associated with a thinner right ventricular wall (P<.0001) and a higher occurrence of focal myocarditis (P<.001). In sections of right ventricular free wall with maximal fatty infiltration, the mean percentage area of fatty tissue was 35.9±11.1% in control versus 80.4±9.6% in the ARVC, fatty variety (P<.00001). Involvement of the left ventricle and/or ventricular septum, right ventricular aneurysms, and inflammation were found almost exclusively in the fibrofatty variety.

Conclusions In the fibrofatty variety of ARVC, the myocardial atrophy appears to be the consequence of acquired injury (myocyte death) and repair (fibrofatty replacement), mediated by patchy myocarditis. Whether the inflammation is a primary event or a reaction to spontaneous cell death remains unclear.


Key Words: arrhythmia • cardiomyopathy • death, sudden • myocarditis • pathology


*    Introduction
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Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia, is a heart muscle disease of unknown etiology characterized by cardiac electrical instability due to fibrofatty atrophy of the right ventricular myocardium.1 2 3 4 5 6 7 8 9 Originally considered a cause of right ventricular failure,10 ARVC was more recently found to be responsible for severe ventricular arrhythmias in adults11 12 13 14 15 16 17 and sudden death in young persons3 8 18 and athletes.4 19

Clinical findings suggest a familial occurrence with autosomal dominant inheritance, various penetrance, and polymorphic phenotype expression20 21 22 23 24 25 26 27 28 ; a gene defect was recently mapped to chromosome 14q23-q24 in a large family.29 The pathology of this disease is little known, and mostly sporadic reports are available. We studied a large number of heart specimens with ARVC with the aim of characterizing the clinicopathological profile and natural history of this condition and gaining insight into the pathobiological mechanisms underlying the progressive myocardial atrophy.


*    Methods
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Diagnostic Criteria and Definitions
The pathological diagnosis of ARVC was formulated in the presence of gross and/or histological evidence of regional or diffuse transmural fatty or fibrofatty infiltration of the right ventricular free wall reaching the endocardium in the absence of valve, coronary, and pericardial disease or other known cardiac or noncardiac causes of death.

Based on the observation of discrete replacement-type fibrosis interspersed within fatty tissue, we distinguished fibrofatty from isolated fatty infiltration. The fibrofatty variety showed that myocardial loss was replaced by both fibrous and fatty tissue, whereas the fatty variety presented exclusively with fatty replacement, with or without tiny interstitial fibrosis.

Ventricular enlargement was evaluated as mild, moderate, or severe.

Ventricular aneurysms were defined as external bulging or ex vacuum hollow of a thinned ventricular region.

Myocarditis was diagnosed according to the Dallas criteria, ie, only if immunohistochemically proven inflammatory infiltrates were associated with myocyte damage and necrosis.30

Study Population
A search of our cardiac registry disclosed 30 hearts that fulfilled the above criteria for ARVC; 3 were obtained at heart transplantation, and 27 were obtained at autopsy. Among the latter, 22 were cases of juvenile (<=35 years) cardiac sudden death, of which 12 were previously reported.3 Clinical information was available for every case. Because our center collects all explanted hearts and all hearts from cases of juvenile cardiac sudden death3 in the Veneto Region of Italy, we could calculate the prevalence of ARVC in these two specific groups: (1) 1% in explanted hearts (3 of 300 specimens received from 1985 through 1994) and (2) 11.2% in juvenile cardiac sudden death (22 of 195 specimens collected from 1979 through 1994).

Ten hearts from 2 women and 8 men (age range, 20 to 31 years; mean, 23 years) who died from extracardiac causes or drug abuse served as controls.

Protocols of Investigation
Thorough examination of the autopsy cases excluded an extracardiac cause of death.

Formalin-fixed hearts (nine ARVC cases and four controls) were viewed along their long and short axes through spin-echo T1-weighted multislice NMR scanning (Philips Gyroscan T5, 0.5 T). The specimens were placed in a water-filled box during the imaging runs; this technique allows fat (high intensity, bright signal) and fibrous tissue (low intensity, dark signal) to be differentiated from normal myocardium.

At gross examination, the hearts were sectioned along their long or short axis for direct comparison with NMR findings. The thickness of the right ventricular free wall was measured at the mid-third, acute margin, far from aneurysms. Multiple tissue blocks of the ventricular free walls and septum (>=12 from each heart) were fixed in formalin and paraffin embedded, and 6-µm-thick sections were stained according to the hematoxylin and eosin and Azan Mallory techniques. In five cases, a short-axis cut of the whole heart was also embedded in paraffin, cut, and stained as described above.

To compare fatty tissue content in control hearts and hearts with the isolated fatty variety of ARVC, 3-cm-long blocks from the infundibulum, anterior, lateral, and posterior right ventricular free walls were examined. Histological sections stained according to the Azan Mallory technique were assessed quantitatively with a Kontron IBAS 2000 analyzer, as previously described.31 Right ventricular wall thickness and percentage area of fatty tissue (including subepicardial fat) were calculated independently and blindly by two observers. Sections showing maximal fatty infiltration in controls versus the fatty variety of ARVC were compared.

To characterize the cellular infiltrates, paraffin sections were stained with a panel of monoclonal (CD45, CD45RO, CD43, CD20, CD68, MAC387) and polyclonal (factor VIII) antibodies (all from Dako) according to the avidin biotin peroxidase complex method (Vectastain; Sigma).

Ultrastructural studies were conducted in the three explanted hearts. Immediately after surgery, specimens of the right ventricle were taken from both the septum and free wall in the residual myocardium, cut into 1-mm3 blocks, fixed in phosphate-buffered glutaraldehyde (pH 7.2), postfixed in osmium tetroxide, and embedded in Epon. Semithin sections were stained with toluidine blue and observed with a light microscope. Ultrathin sections of selected areas were stained with uranyl acetate and lead citrate and observed with a transmission electron microscope (Hitachi 7000).

Statistical Analysis
The unpaired Student's t test was used to determine significance between continuous variables. The {chi}2 test or Fisher's test was used to assess the significance of differences between subgroups. A value of P=.05 was considered statistically significant.


*    Results
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Clinical Findings
The main clinical data in the 30 ARVC cases are summarized in Table 1Down.


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  		Table 1. Main Clinical Data in 30 Arrhythmogenic Right Ventricular Cardiomyopathy Cases

The series consisted of hearts from 20 men and 10 women (age range, 15 to 65 years; mean age, 28). Familial occurrence of ARVC was established with certainty in 4 cases; 5 other cases had a family history of sudden death. No patient was obese or receiving steroid therapy.

Fourteen patients were athletes: 6 soccer players, 3 dancers, 2 cyclists, 1 runner, 1 swimmer, and 1 skier. Seventeen patients had complained of symptoms: palpitations in 5, syncope in 4, palpitations and syncope in 3, dyspnea and stroke in 2, dyspnea in 2, and palpitations and dyspnea in 1. The remaining 13 patients were fully asymptomatic, and sudden death was the first manifestation of the disease.

A diagnosis of ARVC was accomplished in vivo in only 4 patients.

An ECG was available in 19 cases and showed inverted precordial T waves (at least V1-2) in 15 (79%) (Fig 1aDown), monomorphic or polymorphic ventricular arrhythmias with a left bundle-branch block morphology in 15 (79%) (Fig 1bDown), atrial flutter or fibrillation in 2 (10%), and sinus bradycardia in 1.



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  		Figure 1. An asymptomatic 17-year-old boy died suddenly during a soccer game. Retrospectively, the only signs of the disease were (a) basal ECG showing T-wave inversion in right precordial leads up to V4 and (b) isolated premature ventricular beat of left bundle-branch block morphology during step test.

The mode of death in the autopsy cases was sudden in 24 (13 on effort and 11 at rest) (80%) and congestive heart failure in 3 (with additional cerebral thromboembolism in 1). The 3 patients who underwent cardiac transplantation because of congestive heart failure (NYHA class IV) are alive and doing well.

Pathological Findings
The control hearts had patent coronary arteries, and none showed transmural fatty or fibrofatty replacement in either the right or left ventricle. In particular, fatty tissue in the right ventricle, when observed, was limited to the subepicardium or only infiltrated the outer third of the myocardium. Inflammatory infiltrates were seen occasionally but not in association with myocardial death or damage. In every case, right ventricular free wall thickness was >4 mm.

The main pathological findings in the 30 ARVC cases are summarized in Table 2Down. Heart weights ranged from 270 to 600 g (mean, 400 g), and right ventricular wall thickness ranged from 2 to 7 mm (mean, 3.5 mm). Right ventricular enlargement was mild in 17, moderate in 11, and severe in 2 cases. Right ventricular involvement was diffuse in 25 and regional in 5. Right ventricular aneurysms were present in 15 hearts: inferior in 4; inferior and apical in 3; inferior, apical, and infundibular in 3; infundibular in 3; and inferior and infundibular in 2 (Figs 2 through 5DownDownDownDown). The subendocardial muscular trabeculae appeared to be mostly spared but were occasionally shrunken, and the corresponding intertrabecular spaces were enlarged. At the level of the ventricular aneurysms, the endocardium was thickened, the epicardium was whitish, and the wall was thinner. Gross and histological involvement of the left ventricle was observed in 14 hearts (47%) (Figs 2 and 3Down), and in 6 (20%) it extended to the interventricular septum. Patchy inflammatory infiltrates, consisting of CD45 and CD43 positive lymphocytes, associated with myocardial death, were detected in 20 hearts (67%) (Fig 6Down).


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  		Table 2. Main Pathological Data in 30 Arrhythmogenic Right Ventricular Cardiomyopathy Hearts



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  		Figure 2. Same case as discussed in legend to Fig 1Up. a, In vitro NMR cross-sectional view showing a uniformly whitish right ventricular free wall with anterior and inferior aneurysms; note also a spotty involvement of the posterolateral wall of the left ventricle. b, Corresponding cross section of the heart specimen with infundibular and inferior subtricuspidal aneurysms. c, Panoramic histological view of the inferior aneurysm showing wall thinning with fibrofatty replacement (Azan stain; original magnification, x2.5).



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  		Figure 3. Same case as discussed in legends to Figs 1 and 2UpUp. a, In vitro NMR scan in the long-axis view showing extensive involvement of the anterior free wall of the right ventricle and patchy involvement of the posterior wall of the left ventricle; the interventricular septum is spared. b, Corresponding panoramic histological view of the left ventricle showing a spot of fibrofatty replacement of the myocardium (Azan stain; original magnification, x2.5).



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  		Figure 4. A 26-year-old male cyclist died suddenly at rest. He suffered palpitations and syncope, both on effort and at rest. a, Spontaneous onset of left bundle-branch block ventricular tachycardia (mean rate, 250 bpm). b, Gross view of the heart specimen showing a yellow, dilated pulmonary infundibulum.



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  		Figure 5. Same case as discussed in legend to Fig 4Up. a, In vitro NMR scan in the long-axis view showing bright streaks in the pulmonary infundibulum; left ventricle and interventricular septum are normal. b, The pulmonary infundibulum appears translucent. c, Panoramic histological view of the pulmonary infundibulum showing regional fibrofatty replacement (Azan stain; original magnification, x2.5).



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  		Figure 6. Histology of the fibrofatty variety of ARVC. a, Myocardial atrophy with fibrous and fatty tissue replacement (Azan stain; original magnification, x240). b, Patchy inflammatory infiltrates associated with myocytolysis and scarring (hematoxylin and eosin; original magnification, x240). c, CD45-positive mononuclear infiltrates adjacent to dying and damaged myocytes (avidin biotin peroxidase complex method; original magnification, x240). d, Adipocytes taking the place of myocyte loss (hematoxylin and eosin; original magnification, x240).

According to the histopathological substrate, the specimens could be divided into 2 types: fibrofatty (18 cases) (Figs 2, 3, 5, and 6UpUpUpUp) and fatty (12 cases) (Fig 7Down) myocardial replacement. The dystrophic process was regional in 3 fatty and in 2 fibrofatty cases (Figs 4 and 5UpUp).



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  		Figure 7. A 39-year-old man with a family history of sudden death and left bundle-branch block morphology ventricular arrhythmias died suddenly at rest. a, Gross view of the heart specimen with massive fatty replacement of the right ventricular free wall. b, Histology of the right ventricular myocardium showing almost transmural fatty replacement, frequently reaching the endocardium, in the absence of fibrous tissue (Azan stain; original magnification, x2.5).

Viewed through the light microscope, a transmural myocardial atrophy of the right ventricular free wall was seen in both patterns, with fatty or fibrofatty infiltration much more extensive on the epicardial side. Residual myocytes were scattered within the fibrofatty tissue (Fig 6Up).

Histomorphometrical analysis revealed that at the site of maximal fatty infiltration, the mean wall thickness was 4.2±1.2 mm in control hearts versus 4.3±1.2 mm in hearts with fatty variety of ARVC; the mean percentage area of fatty tissue was 35.9±11.1% in control hearts versus 80.4±9.6% in hearts with the fatty variety of ARVC (P<.00001) (Fig 8Down).



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  		Figure 8. Control heart from a 20-year-old man who died in a motor vehicle accident. Panoramic histological view of the lateral free wall of the right ventricle: the fatty tissue is limited to the subepicardium and only slightly infiltrates the myocardium (Azan stain; original magnification, x2.5).

In reference to NMR investigations, no control heart showed an abnormal bright signal at the level of right ventricular, left ventricular, or septal myocardium; the white signal was limited to the epicardial region, mainly in the atrioventricular groove. Among the nine ARVC cases, NMR was able to detect an abnormal high-intensity bright signal in all, regardless of their histological pattern, and areas of right ventricular wall thinning in six. Two cases showed regional bright streaks at the level of the infundibulum (Fig 5Up), and seven showed a diffuse, uniformly bright signal involving the right ventricular myocardium (Figs 2 and 3UpUp). In addition, a localized spotty involvement of the left ventricle was observed in five cases (Figs 2 and 3UpUp).

Electron microscopy studies in the three explanted hearts disclosed no specific alterations in most of the residual myocytes. Nuclei and myofibrils were normal; mitochondria were regularly packed in the paranuclear zone and underneath the sarcoplasmatic membrane, frequently in association with glycogen granules. No intercalated disc modifications were observed. Lymphocytic infiltrates around capillary vessels, as well as myocyte debris, ascribable to recent cell death, could be observed within the fibrotic areas (Fig 9Down).



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  		Figure 9. Transmission electron microscopic view of the right ventricular myocardium from heart specimens removed at the time of cardiac transplantation, with a histological picture of fibrofatty replacement. a, Cell debris, consisting mainly of swollen mitochondria and lysosomes, are visible adjacent to normal myocytes, suggesting myocyte death (from a 28-year-old woman with biventricular involvement, congestive heart failure, and a history of palpitations and ventricular arrhythmias). b, A lymphocyte is present within fibrotic interstitium, close to a damaged myocyte (from a 41-year-old man with biventricular involvement, congestive heart failure, and a history of palpitations and ventricular arrhythmias).

Correlations of Results
Table 3Down presents a comparison of the clinical and pathological findings in the two histological varieties. The fibrofatty variety showed a significant difference in terms of right ventricular wall thinning (2.9±1.0 versus 4.3±1.2 mm, P<.0001), occurrence of right ventricular aneurysms (78% versus 8%, P<.001), and focal myocarditis (100% versus 17%, P<.001). Involvement of the left ventricle and interventricular septum was exclusive to the fibrofatty variety. No significant difference emerged regarding the occurrence of ventricular arrhythmias and mode of death.


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  		Table 3. Fibrofatty and Fatty Patterns of Arrhythmogenic Right Ventricular Cardiomyopathy: Main Clinicopathological Data

Table 4Down provides a comparison of cases with and without left ventricular involvement. The cases with fibrofatty atrophy affecting the left ventricle were slightly older (mean age, 30±13 versus 25±7 years; P=NS), had slightly heavier hearts (413±77 versus 394±78 g, P=NS), and a higher occurrence of right ventricular aneurysms (86% versus 23%, P<.001); in addition, congestive heart failure was more frequent (36% versus 6%, P=NS), and sudden death was less frequent (64% versus 94%, P=NS). Mural thrombosis and interventricular septum involvement occurred only in cases with biventricular disease, in which the presence of inflammatory infiltrates was a constant finding.


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  		Table 4. Cases With and Without Left Ventricular Involvement: Main Clinicopathological Data

The five cases with severe left ventricular involvement and congestive heart failure presented a mean age of 42±14 years compared with 25±8 years for the other 25 cases without congestive heart failure (P<.02).


*    Discussion
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 *Discussion
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Pathobiology
Although several theories have been advanced,2 5 6 25 32 the etiology and pathogenesis of ARVC are still obscure.

In the disontogenetic theory, the absence of myocardium is considered to be the consequence of a congenital aplasia or hypoplasia of the right ventricular wall, leading to a parchmentlike appearance.1 33 34 35 36 37 38 39 The eponym "Uhl's anomaly" has been commonly used in memory of the 8-month-old infant described by Uhl in 1952 with "almost total absence of the myocardium of the right ventricle."40 Accordingly, the disease should be regarded as a gross cardiac structural defect present at birth and thus listed among the congenital heart diseases.41 The use of the term "dysplasia" (which means "maldevelopment") is in agreement with this view.

In the degenerative theory, the loss of the myocardium is considered to be a consequence of progressive myocyte death due to some metabolic or ultrastructural defect. Familial occurrence suggests a genetic disease with autosomal dominant transmission and variable expression and penetrance.20 21 22 23 24 25 26 27 28 The finding of a gene defect localized on chromosome 14q23-q24 favors a genetically determined atrophy, as observed in the skeletal muscle of patients with Duchenne's and Becker's diseases, and the term "myocardial dystrophy" might appear to be the most appropriate. The 14q23-q24 region includes the genes of ß-spectrin and {alpha}-actinin, the mutation of which might be involved.42 43 However, no abnormality was found in erythrocytes or in skeletal muscle, as would be expected in the case of a defective ß-spectrin gene. The similarity between the myocardial dystrophy observed in ARVC and the skeletal muscular dystrophy observed in Duchenne-Becker diseases and the structural homology between the {alpha}-actinin gene and the amino-terminal domain of dystrophin are highly suggestive of a defective {alpha}-actinin gene.29 Nevertheless, no skeletal muscular involvement was detected in patients affected by ARVC.

In the inflammatory theory, the fibrofatty replacement is viewed as a healing process in the setting of chronic myocarditis.6 8 24 44 The disappearance of the right ventricular myocardium might be the consequence of an inflammatory necrotic injury followed by fibrofatty repair. Thus, an infectious and/or immune myocardial reaction might intervene in the etiology and pathogenesis of the disease.6 This is not in contrast with a familial occurrence because a genetic predisposition to viral infection eliciting immune reactions cannot be excluded. It is noteworthy that some experimental myocarditides are exclusively limited to the right ventricle. Indeed, selective right ventricular perimyocarditis was obtained in BALB/c mice after coxsackievirus infection and in later stages led to the development of ventricular aneurysms.45 Genetic factors may play a role not only in susceptibility to infections but also in the site of cardiac involvement, namely, the myoepicardium of the right ventricle.

Regional sympathetic dysinnervation was recently demonstrated with the use of myocardial scintigraphy.46 Whether this corresponds to an amine depletion or a true nerve disruption remains to be established.

The results of our investigation clearly demonstrate that so-called arrhythmogenic right ventricular dysplasia is a primary heart muscle disorder (cardiomyopathy)47 characterized by a progressive loss of myocardium, with a peculiar fatty or fibrofatty replacement, that accounts for the onset of cardiac electrical instability. Accordingly, Uhl's anomaly, namely, partial or total congenital absence of the right ventricular myocardium, should not be categorized as ARVC. The acquired nature of the disease (possibly postnatal phenotype expression) is corroborated by the age range of the affected patients (15 to 65 years), the nearly preserved distance of the epicardium from the endocardium without apposition of the two layers, and, most important, the observation of patchy myocyte death associated with inflammatory infiltrates and fibrofatty repair in various stages of healing. Whether the inflammation is a primary event or secondary to the spontaneous cell death is an intriguing question. Furthermore, whether the fatty variety of ARVC actually represents a completely different entity remains to be determined.

It was recently advanced that myocardial cell death in ARVC might represent a programmed death ("cell suicide") known as "apoptosis."48 Like involution of the right ventricular myocardium results from a normal postnatal remodeling most probably mediated by apoptosis, in ARVC abnormal bouts of recurring or continued apoptosis could lead to progressive myocardial disappearance followed by fibrofatty replacement. Furthermore, the apoptotic bouts could enhance the electrical vulnerability of the ventricles, thus accounting for the onset of life-threatening arrhythmias. Different viruses may trigger the apoptosis in the absence of an inflammatory response.49 This theory is very attractive because it offers a reasonable explanation for the peculiar right ventricular involvement.

In our experience, intercalated discs did not show morphological alterations. Other researchers have addressed this aspect, but the findings are discordant.8 50

Pathological Substrates Relevant to Clinical Diagnosis
Aneurysms of the right ventricle are a typical deformity of ARVC and are distributed in the "triangle of dysplasia,"2 namely, the right ventricular inflow, apex, and infundibulum. In particular, the inflow aneurysms are located in the inferior, diaphragmatic wall beneath the posterior leaflet of the tricuspid valve. As no other cardiac disease presents such a distinctive topography to our knowledge, ventricular aneurysms at these sites can be considered pathognomonic. This information is relevant to clinical imaging investigations, such as two-dimensional echocardiography and angiography.51 52 53 54 55 56 57 Among the cardiac imaging techniques, new noninvasive radiological methods such as ultrafast CT and NMR allow the clearest visualization of the heart, especially the right ventricle, which is difficult to explore with echocardiography or angiography.57 58 59 60 61 NMR may constitute a useful tool with which to detect myocardial atrophy with fatty infiltration because the fatty tissue gives a bright signal and is readily comparable with the subcutaneous and pericardial fat and because both ARVC histological patterns exhibit myocardial fatty infiltration. Its use in the clinical setting, however, has revealed a higher specificity but a lower sensitivity than other investigative techniques.57 60 61 It is noteworthy that all of our cases, regardless of the histological pattern, gave a regional or diffuse high-intensity bright signal on NMR, thus indicating that even in the fibrofatty variety, the fatty component was sufficient for detection. This finding may have important clinical and diagnostic implications.

An in vivo histological diagnosis through the use of endomyocardial biopsy is feasible in ARVC because the right ventricle is readily accessible by the transvenous approach, the fibrofatty replacement reaches the subendocardium, and it is easily recognizable with a light microscope.31 62 63 64 Myocardial atrophy and fibrofatty tissue replacement have been quantified histomorphometrically on endomyocardial biopsy specimens to establish diagnostic parameters for ARVC.31 Because the interventricular septum is rarely involved (only 20% in the present series), bioptic specimens should be obtained from the free wall of the right ventricle to avoid sampling error. As this implies the risk of ventricular perforation and cardiac tamponade, this diagnostic procedure should be indicated with caution and conducted in cardiac units with surgical standby.

From the original description of ARVC by Frank et al,1 it appears that the dystrophic areas are responsible for depressed conduction in the right ventricle and could provide the substrate for reentrant circuits and the initiation of ventricular arrhythmias. In the clinical setting, late potentials, detected with signal-averaged ECG, are currently considered a noninvasive marker of slow conduction areas in ARVC due to fibrofatty replacement and thus can be used to identify the patients at risk.65 66 67 68 Fibrous more than fatty tissue appears to be responsible for late potentials.69

Natural History and Progression of the Disease
Our clinicopathological data suggest a wide age range, spanning adolescence to adulthood, during which the disease may become symptomatic and fatal.70 Several steps are recognizable, from an early clinically "concealed" phase with or without minor arrhythmias, during which sudden death may be the first manifestation of the disease3 4 5 8 15 18 71 ; to an "overt electrical heart disorder," with severe arrhythmias and impending cardiac arrest2 11 12 13 ; to a final stage of "biventricular pump failure" mimicking dilated cardiomyopathy with cardiomegaly, congestive heart failure requiring transplantation, and the risk of thromboembolic complications.8 10 59 During the concealed phase, affected young persons involved in sports activities are particularly vulnerable to electrical instability at risk of cardiac arrest; early recognition is thus a medical challenge, and restriction from all sports is mandatory.4

The striking pathological feature of ARVC is right ventricular involvement, but the disease migrates to the left ventricle and interventricular septum.28 72 73 74 75 As we observed more severe left ventricular involvement with congestive heart failure only in the fibrofatty variety and in older patients with heavier hearts, we wondered whether fibrous replacement might occur at a later time. Clearly, our study population is unique since it is entirely a pathological series; nevertheless, the observed high prevalence of left ventricular involvement suggests that this disease should no longer be considered as limited to the right ventricle.

Conclusions and Study Perspectives
The pathological substrates of ARVC point to an acquired myocardial atrophy with adipocytes and fibrous tissue replacing the dying myocytes in the setting of a progressive, dynamic injury/repair process.

The frequent finding of lymphocyte infiltrates associated with myocyte death lead to the consideration of the disease as a chronic myocarditis. Although the inflammation may be reactive to spontaneous myocardial death, it is likely that infections and/or immune factors are involved. On the other hand, a genetic predisposition and/or susceptibility to viral infections and immune reactions, as well as a genetically determined spontaneous cell death (apoptosis), cannot be ruled out. Both theories are in keeping with the frequent familial occurrence, which suggests that an underlying genetic factor may favor the onset and progression of the injury-repair phenomenon. The recent mapping of the gene for ARVC to chromosome 14q23-q24 opens new avenues of research for cloning the defective gene and identifying the encoded protein. Future studies should also address the detection of viruses possibly harbored by the damaged myocytes through molecular biology techniques, as well as the assessment of cellular and humoral immune reactions.


*    Acknowledgments
 
This study was supported by National Council for Research, Target Project FAT.MA., Rome; and by Veneto Region, Target Project Juvenile Sudden Death, Venice, Italy.

Received December 19, 1995; revision received February 21, 1996; accepted March 4, 1996.


*    References
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 *References
 

  1. Frank R, Fontaine G, Vedel J, Mialet G, Sol C, Guiraudon G, Grosgogeat Y. Electrocardiologie de quatre cas de dysplasie ventriculaire droite arythmogene. Arch Mal Coeur. 1978;71:963-972.
  2. Marcus FI, Fontaine G, Guiraudon G, Frank R, Laurenceau JL, Malergue S, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384-398.[Abstract/Free Full Text]
  3. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988;318:129-133.[Abstract]
  4. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlation in 22 cases. Am J Med. 1990;89:588-596.[Medline] [Order article via Infotrieve]
  5. Thiene G, Nava A, Angelini A, Daliento L, Scognamiglio R, Corrado D. Anatomoclinical aspects of arrhythmogenic right ventricular cardiomyopathy. In: Baroldi G, Camerini F, Goodwin JF, eds. Advances in Cardiomyopathies. Berlin, Germany: Springer-Verlag; 1990:397-408.
  6. Thiene G, Corrado D, Nava A, Rossi L, Poletti A, Boffa GM, Daliento L, Pennelli N. Right ventricular cardiomyopathy: is there evidence of an inflammatory aetiology? Eur Heart J. 1991;12(suppl D):22-25.
  7. Fontaliran F, Fontaine G, Filette F, Aouate G, Chomette G, Grosgogeat Y. Frontieres nosologiques de la dysplasie arythmogene: variations quantitatives du tissu adipeux ventriculaire droit normal. Arch Mal Coeur. 1991;84:33-38.
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