483

Arrhythmogenic Right Ventricular Cardiomyopathy:Time for a New Look

VICTOR A. FERRARI, M.D., and CRAIG H. SCOTT, M.D.

From the Division of Cardiovascular Medicine, Department of Medicine, Hospital of the University of Pennsylvania,Philadelphia, Pennsylvania, USA

Editorial Comment

Arrhythmogenic right ventricular dysplasia/cardiomyo-pathy (ARVC), first described in 1977, remains an enigmaticdisease.1 ARVC is a rare disorder, but it is the most commoncause of sudden cardiac death (SCD) in younger populations.ARVC is a progressive disease2,3 characterized by structuraland functional abnormalities of the heart, initially presentingin the right ventricle (RV) but eventually resulting in a biven-tricular cardiomyopathy in its late stages. The disorder oftenis familial in origin (30%–50% of cases), with both auto-somal dominant and autosomal recessive (“Naxos disease”)inheritance patterns. The genetic defect appears to map tochromosomes 1, 2, 3, and 14 for the dominant pattern andto chromosome 17 in the recessive form of the disease.4 Themajor pathologic finding is replacement of the myocardiumby fatty and fibrous tissue, and numerous structural abnor-malities of the RV, including areas of thinning with singleor multiple aneurysms, or formation of diverticula. Currentopinion indicates that this replacement process is due to 1 of 3processes: apoptosis, inflammatory heart disease, or a genet-ically determined myocardial dystrophy.1 These structuralabnormalities predispose patients to a number of arrhyth-mias of RV origin, ranging from single premature ventricularcontractions to sustained ventricular tachycardia (VT). Notuncommonly, the initial presentation may be ventricular fib-rillation and SCD. An imbalance of adrenergic innervationhas been detected in ARVC patients,5,6 resulting in disper-sion of refractoriness and development of delayed afterdepo-larizations, which promote an arrhythmic substrate. In a re-cent study of SCD victims who had autopsy-proven ARVC,a premortem QRS dispersion of ≥40 msec was the strongestpredictor of sudden death.7

Four stages of the disease have been proposed: (1) a “con-cealed” phase, in which anatomic changes are subtle andarrhythmias may be minor, but where SCD may be the firstindication of the disease; (2) an overt electrical disorder pre-senting with VT or SCD, in which RV structural and func-tional abnormalities are more apparent; (3) progressive RVfailure with preserved left ventricular function; and (4) biven-tricular dysfunction.8 Despite advances in diagnostic tech-niques and the availability of formalized diagnostic criteria,identification of ARVC remains problematic, particularly inindividuals with the concealed form of the disease.

Endomyocardial biopsy has been used to confirm the pres-ence of the characteristic fibrofatty infiltration in vivo.9 How-

J Cardiovasc Electrophysiol, Vol. 14, pp. 483-484, May 2003.

Address for correspondence: Victor A. Ferrari, M.D., Division of Cardiovas-cular Medicine, Department of Medicine, 9014 E. Gates Pavilion, Hospitalof the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA19104. Fax: 215-349-8190; E-mail: ferrariv@mail.med.upenn.edu

ever, to minimize perforation risk, biopsies usually are takenfrom the interventricular septum, which is not frequently in-volved in the disease and limits the sensitivity of this test.Magnetic resonance imaging (MRI) has been reported to bea more sensitive method for identifying the pathologic ab-normalities in ARVC and other RV arrhythmias.10 Focal ordiffuse fatty infiltrates and abnormal thickening of regionsof focal dyskinesia have been proposed as criteria for thediagnosis of RV dysplasia by MRI. However, the diagnos-tic sensitivity and specificity of MRI still need to be definedin larger series. At present, the interpretation of images mayvary with operator experience. In particular, quantitative dataon intraobserver and interobserver variability are lacking, andstudies are needed to provide this important data to clinicians.

Limitations of the published MRI series for ARVC in-clude a nonuniform patient selection process, the use of olderimaging methods, and the lack of quantitative analyses. Inthis issue of the Journal, Tandri et al.11 present importantMRI data in the ongoing effort to better define this diseaseprocess. They selected a group of patients using diagnosticcriteria proposed by the Task Force of the Working Group onCardiomyopathies,12 the first of the more recent MRI studiesto identify patients in this prospective manner. In addition,they used an improved MRI technique, known as a doubleinversion recovery (or “black blood”) sequence, which nullsthe blood signal and provides improved contrast between theblood and endocardial surface, thereby minimizing artifactsrelated to static or moving blood. This is the first report ofthis technique applied to ARVC patients. It also is the first re-ported use of a newer rapid cine MRI (or “movie”) sequencein ARVC patients. This technique, known as “steady-statefree procession,” provides the highest quality data for as-sessing cardiac function and improves quantitative analysisof chamber volumes and ejection fraction. Using these im-proved methods, the authors found that intramyocardial hy-perintense signals consistent with fat were seen in 75% ofthe patients they studied, which makes this the second high-est report of intramyocardial fat signals in the modern era ofMRI. Quantitative analysis confirmed that the RV sizes werelarger and the RV ejection fractions were lower in ARVCthan in control patients, which supports a common theme inprevious studies of ARVC.

However, patients with ARVC may present at a timewhen arrhythmic symptoms precede detectable anatomicchanges. In such patients, minor structural abnormalities maybe missed by echocardiography, ventriculography, and evenMRI. Recent data support the addition of electroanatomicmapping to current diagnostic modalities in patients withARVC.13 Detection of the dysplastic process by the pres-ence of low-amplitude electrograms may be used as a newcriterion in the diagnostic evaluation. In addition, this tech-nique may be useful in differentiating ARVC from RV

484 Journal of Cardiovascular Electrophysiology Vol. 14, No. 5, May 2003

outflow tract (RVOT) tachycardia, which usually is a be-nign condition with a different pathologic mechanism andtreatment. Further studies need to be performed using bothelectroanatomic mapping and MRI to determine whether RVabnormalities are present in patients with RVOT tachycardia.MRI abnormalities have been reported in RVOT tachycar-dia14; however, these patients were not rigorously screenedusing the Task Force criteria, and controversy remains as towhether the patients with abnormal MRI scans actually hada form of ARVC.

The optimal therapy for patients with ARVC remains un-known. The lack of clinical outcome predictors make rationalchoices among antiarrhythmic therapy, radiofrequency abla-tion, and implantable cardioverter defibrillators challenging.Therapeutic strategies often are based on regional preferencesand experience rather than data on efficacy. The roles of ra-diofrequency ablation and implantable cardioverter defibril-lator therapy for ARVC, particularly in light of the progres-sive nature of the disease, need to be defined by studies inlarger groups of patients.15,16

Many questions remain regarding ARVC, including thetrue incidence of the disorder, the likely age at onset, and therate of progression of the disease. In addition, the clinicaldiagnostic criteria, natural history, and risk stratification allneed greater definition. Based on the incomplete data avail-able in this rare but important disease, the need for an inter-national registry to pool information and experience is com-pelling. Fortunately, such a database has been organized bya collaborative effort by the European Society of Cardiologyand the World Heart Federation.17 A wealth of knowledgeshould become available as data collection and analysis pro-ceed. Given that ARVC is a progressive disease, we must becognizant of the fact that a single negative MRI scan does notexclude the diagnosis and that ARVC remains very much aclinical diagnosis. The optimal interval for follow-up testingin patients with an initial negative study is uncertain. There-fore, in patients who have a high suspicion for ARVC but donot exhibit objective manifestations of the disease, repeat-ing the scan in 1 year, or if new symptoms or signs appear,may be a reasonable approach. Siblings and close relativesshould be screened at least once; however, annual screeningis not supported by current data. With additional data fromthe registry, particularly from information derived from ge-netic testing, we may make more rational testing decisionsand provide additional prognostic data to family members.18

An important milestone will be whether advances in electro-cardiographic, electrophysiologic, or MRI techniques such asthose described by Tandri et al. will improve our diagnosticcapabilities and permit enhanced detection of ARVC in theconcealed phase of the disease, both in patients and in theirimmediate families.

References

1. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M: Ar-rhythmogenic right ventricular cardiomyopathy: Dysplasia, dystrophy,or myocarditis? Circulation 1996;94:983-991.

2. Obata H, Mitsuoka T, Kikuchi Y, Sakurada T, Kusajima K, KawamuraY, Kikuchi K: Twenty-seven-year follow-up of arrhythmogenic rightventricular dysplasia. Pacing Clin Electrophysiol 2001;24(Pt I):510-511.

3. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, VillanovaC, Daliento L, Buja G, Corrado D, Danieli GA, Thiene G: Clinicalprofile and long-term follow-up of 37 families with arrhythmogenicright ventricular cardiomyopathy. J Am Coll Cardiol 2000;36:2226-2233.

4. Danielli GA, Rampazzo A: Genetics of arrhythmogenic right ventricularcardiomyopathy. Curr Opin Cardiol 2002;17:218-221.

5. Wichter T, Hindricks G, Lerch H, Bartenstein P, Borggrefe M, SchoberO, Breithardt G: Regional myocardial sympathetic dysinnervation inarrhythmogenic right ventricular cardiomyopathy: An analysis using123I-meta-iodobenzylguanidine scintigraphy. Circulation 1994;89:667-683.

6. Wichter T, Schafers M, Rhodes CG, Borggrefe M, Lerch H,Lammertsma AA, Hermansen F, Schober O, Breithardt G, Camici PG:Abnormalities of cardiac sympathetic innervation in arrhythmogenicright ventricular cardiomyopathy: Quantitative assessment of presynap-tic norepinephrine reuptake and postsynaptic beta-adrenergic receptordensity with positron emission tomography. Circulation 2000;101:1552-1558.

7. Turrini P, Corrado D, Basso C, Nava A, Bauce B, Thiene G: Dispersionof ventricular depolarization-repolarization: A noninvasive marker forrisk stratification in arrhythmogenic right ventricular cardiomyopathy.Circulation 2001;103:3075-3080.

8. Thiene G, Nava A, Angelini A, et al: Anatomoclinical aspects of arrhyth-mogenic right ventricular cardiomyopathy. In Baroldi G, Camerini F,Goodwin JF, eds: Advances in Cardiomyopathy. Berlin: Springer Ver-lag, 1990, pp. 397-408.

9. Angelini A, Basso C, Nava A, Thiene G: Endomyocardial biopsyin arrhythmogenic right ventricular cardiomyopathy. Am Heart J1996;132:203-206.

10. Pennell D, Casolo G: Right ventricular arrhythmia: Emergence ofmagnetic resonance imaging as an investigative tool. Eur Heart J1997;18:1843-1845.

11. Tandri H, Calkins H, Nasir K, Bomma C, Castillo E, Rutberg J, TichnellC, Lima JAC, Bluemke DA: Magnetic resonance imaging findings inpatients meeting task force criteria for arrhythmogenic right ventriculardysplasia. J Cardiovasc Electrophysiol 2003;14:476-482.

12. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C,Fontaine G, Camerini F: Diagnosis of arrhythmogenic right ventriculardysplasia/cardiomyopathy. Br Heart J 1994;71:215-218.

13. Boulos M, Lashevsky I, Reisner S, Gepstein L: Electroanatomic map-ping of arrhythmogenic right ventricular dysplasia. J Am Coll Cardiol2001;38:2020-2027.

14. Carlson MD, White RD, Trohman RG, Adler LP, Biblio LA, MerkatzKA, Waldo AL: Right ventricular outflow tract tachycardia: Detectionof previously unrecognized anatomic abnormalities using cine magneticresonance imaging. J Am Coll Cardiol 1994;24:720-727.

15. Ellison KE, Friedman PL, Ganz LI, Stevenson WG: Entrainment map-ping and radiofrequency catheter ablation of ventricular tachycar-dia in right ventricular dysplasia. J Am Coll Cardiol 1998;32:724-728.

16. Link MS, Wang PJ, Haugh CJ, Homoud MK, Foote CB, Costeas XB,Estes NAM III: Arrhythmogenic right ventricular dysplasia: Clinicalresults with implantable cardioverter defibrillators. J Interv Card Elec-trophysiol 1997;1:41-48.

17. Corrado D, Fontaine G, Marcus FI, McKenna WJ, Nava A, ThieneG, Wichter T, et al: Arrhythmogenic right ventricular dyspla-sia/cardiomyopathy: Need for an international registry. Circulation2000;101:e101-e106.

18. Hamid MS, Norman M, Quraishi A, Firoozi S, Thaman R,Gimeno JR, Sachdev B, Rowland E, Elliott PM, McKennaWJ: Prospective evaluation of relatives for familial arrhythmo-genic right ventricular cardiomyopathy/dysplasia reveals a needto broaden diagnostic criteria. J Am Coll Cardiol 2002;40:1445-1450.