C a r d i o p u l m o n a r y I m a g i n g • P i c t o r i a l E s s ay Murphy et al. Cardiac MRI in Cardiomyopathy

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Cardiopulmonary Imaging Pictorial Essay

Cardiac MRI in Arrhythmogenic Right Ventricular Cardiomyopathy Darra T. Murphy 1 Suzanne C. Shine1 Andrea Cradock1 Joseph M. Galvin2 Edward T. Keelan2 John G. Murray 1 Murphy DT, Shine SC, Cradock A, Galvin JM, Keelan ET, Murray JG

Keywords: arrhythmogenic right ventricular cardiomyopathy and dysplasia, ARVC, ARVD, cardiac MRI, sudden cardiac death DOI:10.2214/AJR.09.3450 Received August 9, 2009; accepted after revision October 12, 2009. 1 Department of Radiology, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland. Address correspondence to D. T. Murphy ([email protected]).  2 Department of Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland.

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OBJECTIVE. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cause of sudden cardiac death in otherwise healthy young adults. This article outlines the spectrum of MRI findings in ARVC using a combination of static and cine images. CONCLUSION. The detection of right ventricular enlargement, fatty infiltration, fibrosis, and wall motion abnormalities at MRI is useful in the diagnosis of ARVC.

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rrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia (ARVD), is characterized by progressive fibrofatty replacement of the right ventricular myocardium. It represents an underdiagnosed cardiac entity leading to syncope, recurrent ventricular tachycardia, heart failure, and occasionally sudden cardiac death in a younger population [1]. The pathogenesis of ARVC is not fully established, but there appears to be a genetic basis in many patients. The prevalence in the population is estimated at 1 per 1,000– 5,000. Familial occurrence can approach 50%. ARVC accounts for 3–4% of deaths in sports and 5% of sudden cardiac deaths in people younger than 65 years [2, 3]. Patients may present at any age but are usually young or middle-aged. There is a 3:1 maleto-female ratio. A broad range of symptoms may occur, including palpitations, fatigue, syncope, and chest pain. In some cases, cardiac arrest after physical exertion, such as participation in sports, may be the initial presenting complaint [4]. Many patients are asymptomatic and are diagnosed by familial screening. The diagnosis of ARVC is based on established criteria determined by a task force comprising the European Society of Cardiology and the International Society and Federation of Cardiology [5]. Pathophysiology ARVC is characterized by progressive replacement of normal myocardium in the right ventricle by fibrofatty tissue. The most common location for this tissue transforma-

tion is between the anterior infundibulum, the right ventricular apex, and the inferior or diaphragmatic aspect of the right ventricle, the so-called “triangle of dysplasia.” Dysplasia in this region may lead to dilatation or aneurysm formation with associated paradoxical motion. The left ventricle and septum are usually spared from the fibrofatty transformation, although they may be involved in more extensive cases. In addition, the conduction system of the heart is usually spared. The presence of arrhythmias and the characteristic ECG findings are caused by the dispersion of myocytes that can incite tachycardic events as the dysplasia progresses. Two forms of fibrofatty replacement have been described. In fibrolipomatosis type I, there is predominantly fatty replacement with a small amount of fibrosis surrounding surviving myocardial cells. In fibrolipomatosis type II, there is a much greater amount of fibrosis [2]. Previous authors have attempted to distinguish between these two histologic forms of ARVC. The predominantly fatty replacement type is described as typical ARVD, and the mixed fibrofatty type is described as a more cardiomyopathic form of the disease [6]. Further attempts have been made to investigate morphologic variants of ARVC on the basis of morphologic and MRI findings [7]. The mode of inheritance of ARVC in most patients is autosomal dominant with incomplete penetrance. There is also an autosomal recessive form called “Naxos disease,” in which there are skin (palmoplantar keratoses) and hair (woolly hair) manifestations, in addition to ARVC. Genetic testing has identified genetic and chromosomal muta-

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Murphy et al. tions in certain subgroups, and, more recently, ARVC has been increasingly attributed to a desmosomal protein disorder. This was initially described in the autosomal recessive form in 2000 [8] and subsequently in the autosomal-dominant form in 2002 [9]. At least 10 further gene mutations have since been described in the autosomal dominant form. Diagnosis Physical Examination and ECG Physical examination is normal in at least 50% of patients with ARVC. Diagnosis is often made following a workup for tachycardia in an otherwise healthy adult; 50–90% of people with ARVC will have characteristic findings on a resting ECG. These findings include T-wave inversion in the anterior precordial leads (V1–V6), premature ventricular beats > 200 over 24 hours, epsilon waves, and ventricular tachycardia with a left bundle branch block pattern. Epsilon waves are small deflections just beyond the QRS complex that are best seen on a signal-averaged ECG in leads V1–V3. Diagnostic Criteria The diagnosis of ARVC is based on the presence of major and minor criteria (Appendix 1). These criteria encompass structural, histologic, ECG, arrhythmic, and genetic factors, as described elsewhere [5]. Although these criteria are specific, they lack sensitivity and have never been validated, in part because there is no single definitive means of making the diagnosis. A revision of these diagnostic guidelines has been proposed, aiming to improve diagnostic sensitivity, particularly in first-degree relatives of patients, for whom there may be incomplete phenotypic expression [10]. The preferred method for making the diagnosis is based on histologic evidence of fibrofatty myocardium. Unfortunately, however, biopsy lacks sufficient sensitivity because of the segmental nature of the disease process, resulting in sampling error, and because many clinicians biopsy the septum rather than the free wall of the right ventricle to avoid the risk of ventricular perforation. A patient is considered to have ARVC if two major criteria, or one major and two minor criteria, or four minor criteria are satisfied. Imaging Techniques and Findings Imaging techniques for detection of the morphologic and functional abnormalities of ARVC include conventional angiography, echocardiography, MDCT, and, most impor-

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tantly, MRI. Angiography is invasive, does not detect fatty infiltration, and relies on wall motion abnormalities that are often missed unless multiple projections are obtained. Echocardiography, although excellent in the assessment of the left ventricle, is limited in the evaluation of the right ventricle. This is because much of the free wall lies directly behind the sternum and ribs and is not seen. Experience with CT in the diagnosis of ARVC is limited, but it has been used in the detection of morphologic abnormalities and wall motion abnormalities, particularly in patients with implantable defibrillators [11]. MRI is established as the imaging technique of choice in the assessment of ARVC. Standard protocol in our institution consists of axial breath-hold double inversion recovery turbo spin-echo sequences (“black blood”) with and without fat saturation from the base of the heart to the bifurcation of the pulmonary artery; true fast imaging with steadystate precession (TrueFISP (“bright blood”) cine sequences of the right ventricular outflow tract, vertical long axis, horizontal long access, and short axis of the heart from the mitral valve to the cardiac apex; short axis breath-hold double inversion-recovery turbo spin-echo; and delayed contrast-enhanced MRI sequences using segmented recovery turbo FLASH in both the axial plane (eight axial images through the heart) and short axis images from the mitral valve the cardiac apex. Gadolinium dose is 0.2 mmol/kg. MRI can detect fatty infiltration in the right ventricle (Figs. 1–6) and occasionally in the left ventricle (Fig. 3); however, fat infiltration of the ventricles is currently only a major criterion for diagnosis of ARVC on cardiac biopsy. MRI can detect right ventricular dilatation and aneurysm formation (Figs. 7–9), as well as wall-motion abnormalities including right ventricular dyskinesia, a corrugated pattern to the right ventricular wall known as the “accordion sign” (Figs. 10–14). Focal left ventricular dyskinesia can also be present in the setting of fatty infiltration within the left ventricle. MRI is also very useful in the evaluation of myocardial fibrosis and scarring (Fig. 14). The black blood spin-echo sequences provide excellent anatomic detail and are the most important for the detection of fat in the right ventricular myocardium. The bright blood TrueFISP cine is useful for evaluation of wall motion abnormalities and ventricular size, and STIR sequences null the fat. More recently, delayed right ventricular myocardi-

al enhancement on gadolinium-enhanced inversion recovery sequences has been used to confirm the presence of myocardial fibrosis [12]. Late left ventricular enhancement has also been described in patients with ARVC [13]. Suppression of arrhythmias plays a role in adequate ECG triggering and optimization of image acquisition. Treatment Treatment of ARVC aims to prevent sudden cardiac death. Treatment options include avoidance of strenuous exercise and competitive sports or training, β blockade, antiarrhythmic medications, catheter ablation [14], implantable cardioverter defibrillator therapy [15], and cardiac transplant. The optimal treatment technique depends on the individual patient, and no one therapy is correct for every patient [16]. Further research in treatment options, as well as maintenance of international patient registries, is vital for future risk stratification and optimization of treatment of patients with ARVC. Acknowledgments We thank Niall Mulligan for the pathological image and description included in this article and John O’Dea for his assistance with obtaining the electroanatomic voltage map. References 1. Corrado D, Basso C, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: an update. Heart 2009; 95:766–773 2. 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 3. Peters S, Peters H, Thierfelder L. Risk stratification of sudden cardiac death and malignant ventricular arrhythmias in right ventricular dysplasia-cardiomyopathy. Int J Cardiol 1999; 71: 243–250 4. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation 2005; 112:3823–3832 5. McKenna WJ, Thiene G, Nava A, 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; 71:215–218 6. d’Amati G, Leone O, di Gioia CR, et al. Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition

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Cardiac MRI in Cardiomyopathy of pathologic patterns. Hum Pathol 2001; 32:1078– 1086 7. Dalal D, Tandri H, Judge DP, et al. Morphologic variants of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy a geneticsmagnetic resonance imaging correlation study. J Am Coll Cardiol 2009; 53:1289–1299 8. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000; 355:2119–2124 9. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002; 71:1200–1206

10. Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/ dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol 2002; 40:1445–1450 11. Bomma C, Dalal D, Tandri H, et al. Evolving role of multidetector computed tomography in evaluation of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Cardiol 2007; 100:99– 105 12. Tandri H, Saranathan M, Rodriguez ER, et al. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol 2005; 45:98–103 13. Sen-Chowdhry S, Prasad SK, Syrris P, et al. Cardiovascular magnetic resonance in arrhythmogen-

ic right ventricular cardiomyopathy revisited: comparison with task force criteria and genotype. J Am Coll Cardiol 2006; 48:2132–2140 14. Dalal D, Jain R, Tandri H, et al. Long-term efficacy of catheter ablation of ventricular tachycardia in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007; 50:432–440 15. Corrado D, Leoni L, Link MS, et al. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003; 108:3084–3091 16. Wichter T, Paul TM, Eckardt L, et al. Arrhythmogenic right ventricular cardiomyopathy. Antiarrhythmic drugs, catheter ablation, or ICD? Herz 2005; 30:91–101

APPENDIX 1:  Criteria for Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy I. Global and/or regional dysfunction and structural alterations • Major – Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) left ventricular impairment – Localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulging) – Severe segmental dilatation of the right ventricle • Minor – Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle – Mild segmental dilatation of the right ventricle – Regional right ventricular hypokinesia II. Tissue characterization of walls • Major – Fibrofatty replacement of myocardium at endomyocardial biopsy III. Repolarization abnormalities • Minor – Inverted T waves in right precordial leads (V2 and V3) (people > 12 years old; in absence of right bundle branch block) IV. Depolarization of conduction abnormalities • Major – Epsilon waves or localized prolongation (> 110 milliseconds) of the QRS complex in right precordial leads (V1–V3) • Minor – Late potentials (signal-averaged ECG) V. Arrhythmias • Minor – Left bundle branch block type ventricular tachycardia (sustained and nonsustained (ECG, Holter, exercise testing) – Frequent ventricular extrasystoles on Holter (1,000 > 24 hours) VI. Family history • Major – Familial disease confirmed at necropsy or surgery • Minor – Familial history of premature sudden death (35 years) due to suspected right ventricular cardiomyopathy – Familial history (clinical diagnosis based on present criteria) Note—Diagnosis is made if two major, or one major and two minor, or four minor criteria are satisfied. List is adapted from [5].

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Fig. 1—53-year-old man who presented after episode of collapse. T1-weighted MR image shows diffuse fatty infiltration of free wall of right ventricle. Note linear high signal corresponding to fat within myocardium (arrows) in contrast to epicardial fat (arrowhead).

Fig. 2—14-year-old girl with palpitations. Black blood breath-hold T1-weighted MR image shows diffuse fatty infiltration of right ventricle. Note increased signal intensity from fat in free wall of right ventricle (arrows), compared with intermediate signal intensity from septum and left ventricular wall (arrowheads).

Fig. 3—25-year-old woman undergoing family screening. T1-weighted MR image shows fat infiltration of both ventricles. There is diffuse fat within right ventricular free wall (arrowhead) in addition to focal fat in left ventricular wall (arrow). Fatty infiltration of both ventricles is rare in arrhythmogenic right ventricular cardiomyopathy.

Fig. 4—23-year-old man under investigation for tachycardia and abnormal ECG. A, T1-weighted MR image shows fat in right ventricular outflow tract (arrows). B, True fast imaging with steady-state precession image from cardiac cine shows aneurysm formation of right ventricular wall (arrow). (See also Fig. S4, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Fig. 5—46-year-old man with history of palpitations and abnormal ECG. A, T1-weighted MR image shows extensive areas of fatty infiltration in right ventricular free wall (arrows). B, True fast imaging with steady-state precession image in systole shows marked dilatation of right ventricle. These findings satisfy two major diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. (See also Fig. S5, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Cardiac MRI in Cardiomyopathy

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Fig. 6—64-year-old asymptomatic man with first-degree relative diagnosed with arrhythmogenic right ventricular cardiomyopathy. A, True fast imaging with steady-state precession sequence shows focal dyskinesia with aneurysm of free wall of right ventricle (arrow). B and C, T1-weighted MR images in diastole (B) and systole (C) show fatty infiltration of right ventricular free wall. Note also dilatation of right ventricle in systole. In all, two major criteria and one minor criterion are satisfied.

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Fig. 7—16-year-old boy who sustained out-of-hospital cardiac arrest (ventricular fibrillation) that was successfully treated. He subsequently had implantable cardioverter defibrillator implanted. Four first-degree relatives were screened and were negative. A, Axial spin-echo (black-blood) T2-weighted image obtained during breath-hold. Note lack of contraction and wall thinning at distal right ventricular free wall close to apex (arrow), where there is systolic bulging and aneurysm formation. This is example of major dyskinesia (major criterion). Mild anterior systolic out pouching is not specific for arrhythmogenic right ventricular cardiomyopathy and can be seen in healthy subjects. It should not be confused with aneurysm formation. B and C, Still images from true fast imaging with steady-state precession (bright blood) cardiac cine loop in both diastole (B) and systole (C) show aneurysm formation. (See also Fig. S7, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Fig. 8—18-year-old man with palpitations. A, True fast imaging with steady-state precession MR image shows aneurysmal bulging of right ventricular free wall. B, Bulging becomes more prominent during systole (arrow).

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Fig. 9—32-year-old man under investigation of tachycardia and abnormal ECG. A–C, True fast imaging with steady-state precession MR images at various stages of cardiac cycle from diastole through systole show focal dyskinesia with aneurysm formation at anterior aspect of right ventricular outflow tract (arrow, C).

Fig. 10—37-year-old woman under investigation of palpitations and abnormal ECG. True fast imaging with steady-state precession images were taken at level of right ventricular outflow tract. A, At rest, appearances are normal. B, During systole, there is dyskinesia of anterior wall of right ventricular outflow tract that gives corrugated appearance, so-called “accordion sign” (arrows). (See also Fig. S10, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Cardiac MRI in Cardiomyopathy Fig. 11—39-year-old man who presented with atypical chest pain. He had normal coronary angiogram. A–D, True fast imaging with steady-state precession MR images in short axis (A and B) and long axis (C and D) show right ventricular aneurysm, corrugated right ventricular wall (accordion sign), and dyskinesia. E, T1-weighted image confirms presence of fat in right ventricular wall (arrow). (See also Fig. S11, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Fig. 12—38-year-old woman under investigation of palpitations. ECG was normal. T1-weighted MRI shows abnormal wall motion with corrugation and aneurysm formation at apex. Note that no fat in seen in right ventricle in this case. (See also Fig. S12, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Fig. 13—20-year-old woman with history of ventricular tachycardia. A and B, True fast imaging with steady-state precession images in horizontal long axis (A) and short axis (B) during systole show right ventricular dilatation with secondary dilatation of right atrium from tricuspid valve incompetence. There is marked hypokinesia of right ventricle myocardium with focal areas of dyskinesia best appreciated on cine loop. Note lack of right ventricular muscle thickening and contraction in systole on shortaxis views in comparison with normal left ventricle. No fatty infiltration was identified on black blood images. Therefore, two major criteria are satisfied. (See also Fig. S13, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.)

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Fig. 14—21-year-old woman with syncope and family history of sudden cardiac death. A, Delayed contrast-enhanced MR images show delayed enhancement (arrows) confirming presence of fibrosis. Note right ventricular enlargement. True fast imaging with steady-state precession cine reveals localized dyskinesia of anterior free wall with markedly diminished ejection fraction. (See also Fig. S14, cine images, which is in the AJR electronic supplement to this article, available at www.ajronline.org.) B, Three-dimensional electroanatomic voltage map of heart in right anterior oblique projection viewed inferiorly. This shows abnormal areas of low voltage (orange) in inferior and free walls of right ventricle, representing electroanatomic scar tissue. Normal voltage (purple) is seen in surrounding myocardium. C and D, Endomyocardial biopsy shows myocardium with fatty infiltration (arrows, C) and patchy fibrosis (arrow, D). (H and E; original magnifications, ×100 [C] and ×200 [D])

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