Increasing Role of Magnetic Resonance in Diagnosis and Prognosis of Arrhythmogenic Right Ventricle Dysplasia/Cardiomyopathy

A 33-year-old woman with previous diagnosis of asymptomatic frequent premature ventricular complexes (PVC), without documented structural disease in echocardiography. She presented recently with palpitations and dizziness. Another echocardiogram was performed suggesting for the first time right ventricle (RV) dilation and possible hypokinesia of RV apex. Electrocardiogram showed T-wave inversion in V1-V2 and Epsilon wave in V1. Holter documented 2869 polymorphic isolated PVC. Cardiovascular magnetic resonance (CMR) showed moderate RV dilation (end-diastolic volume of 125 ml/m 2 ), RV systolic dysfunction (RV ejection fraction 33%) with RV free wall hypokinesia, a focal area of dyskinesia (“buldging”) in RV outflow tract and trabecular disarray. Case Study There was no evidence of intra-myocardial fat. Positive Late gadolinium enhancement was evident in RV free wall and RV outflow tract. Genetic test showed heterozygous desmoglein-2 (DSG2) mutation. The patient fulfilled criteria for Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy (ARVD/C).Diagnosis of ARVD/C can be challenging, requiring closer follow up and evaluation of multiple parameters. CMR is the imaging method of choice for diagnostic, structural evaluation and risk stratification.

There was no evidence of intra-myocardial fat. Positive Late gadolinium enhancement was evident in RV free wall and RV outflow tract. Genetic test showed heterozygous desmoglein-2 (DSG2) mutation. The patient fulfilled criteria for Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy (ARVD/C). Diagnosis of ARVD/C can be challenging, requiring closer follow up and evaluation of multiple parameters. CMR is the imaging method of choice for diagnostic, structural evaluation and risk stratification.

INTRODUCTION
Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement primarily of right ventricular myocardium. The clinical presentation is characterized by arrhythmia, heart failure and sudden death.
Diagnosis criteria include several parameters such as right ventricular (RV) dysfunction, structural alterations, tissue characterisation, electrical abnormalities, family history and genetic mutations. Cardiovascular magnetic resonance (CMR) has emerged as the imaging modality of choice for diagnostic.
The present paper reported a well documented case of ARVD/C, emphasising the role CMR in diagnosis and risk stratification.

CASE REPORT
33-year-old woman with frequent premature ventricular complexes (PVC) for 15 years, asymptomatic, without regular medication. During this period echocardiograms were persistently unremarkable. Patient had no relevant family medical history. Since the beginning of pregnancy, the patient presented palpitations and dizziness, including at rest. Another echocardiogram was performed, suggesting for the first time RV dilation, with hypokinesia of RV apex. Electrocardiogram (ECG) showed sinus rhythm, T-wave inversion in V1 and V2 with distinct small waves after the QRS complex in V1 -Epsilon wave (Fig. 1). Twenty four hours Holter recording documented 2869 polymorphic isolated PVC and one triplet (2.6% of registry). After childbirth a CMR, with gadolinium administration, was performed in a 3 Tesla scanner. Quantitative analysis of right and left ventricle volumes was performed over short axis images, with 10 slices (8 mm thickness, 2mm gap) encompassing the entire ventricular cavities, using a breath-hold steady state free precession (SSFP) sequence, gated to the electrocardiogram. SSFP images were also obtained in two, four chamber and long axis views and axial and oblique right-sided planes. Dark blood T1 weighted (fat-suppressed and non-fat-suppressed) images in short axis were acquired with double inversion recovery blood suppression and short TI inversion recovery (STIR) sequence. Delayed gadolinium enhancement images were obtained in short and long axis, 10 minutes after intravenous administration of 0.2 mmol/Kg of gadolinium, using phase sensitive inversion recovery (PSIR) reconstruction.
CMR documented RV dilation (end-diastolic volume of 125 ml/m 2 ), RV systolic dysfunction (RV ejection fraction 33%), hypokinesia of RV free wall and RV outflow tract, with focal area of dyskinesia ("bulging") and trabecular disarray in RV free wall (Fig. 2). There was no evidence of intra-myocardial fat in dark blood images. No changes were documented in left ventricle. Late gadolinium enhancement (LGE) was present in RV free wall and RV outflow tract (Fig. 3).
The patient fulfilled criteria for ARVD/C, since she presented three major criteria (Epsilon wave in ECG, major criteria in CMR and genetic mutation) and two minor criteria (> 1000 PVC/24 hours and inverted T waves in V1 and V2) ( Table 1).
The most common feature is only segmental right ventricular disease, but evolution to more diffuse right and left ventricular involvement may occur [6].
This progressive replacement is responsible for the clinical presentation and patients may present themselves with arrhythmia, heart failure and sudden death. ARVD/C is an important cause of sudden death among young people, particularly during strenuous activity [7].
The gold standard for diagnosis is the histopathologic evidence of transmural fibrofatty replacement of right ventricular myocardium, but diagnosis based on biopsy is difficult due to the patchy distribution [6]. In this context diagnosis should be based on multiple criteria including clinical demonstration of structural, functional, and electrophysiological abnormalities [6,8].
McKenna and co-workers presented diagnostic criteria in 1994, revised and updated in 2010, and proposed that the diagnosis of ARVD/C is fulfilled by the presence of two major criteria or one major plus two minor criteria or four minor criteria (Table 1) [6,2].  As shown in our case report, the cardiac investigation may be unremarkable in the concealed phase of ARVD/C, and electrical abnormalities precede structural changes [9]. Therefore a continuous follow up is needed to diagnose the development of new clinical features in order to reach the correct diagnosis.

Fig. 2. Cardiovascular Magnetic Resonance -Steady state free precession imaging documented right ventricular (RV) dilation, dyskinesia and trabecular disarray of RV free wall and outflow tract in short axis view (A and B) and four chamber views (D and E). Oblique RV outflow tract view (C and F) shows focal area of dyskinesia -"bulging" (arrow) in RV free wall
Our patient presented Epsilon wave in ECG, which is the result of modification in electrical activation, as well as a T-wave inversion in V1 and V2 which is the result of modification in repolarization secondary to anatomic damage present in ARVD/C. Nasir et al.
[10] showed an Epsilon wave prevalence of 53% in diffuse ARVD/C and 15% in localized ARVD/C. T-wave inversion in V1 through V3 was observed in 85% of ARVD/C patients and, as In this particular study, T-wave inversion only in V1 and V2 was observed in 10% of patients.
Echocardiography and CMR are the Imaging modalities commonly used to diagnose and evaluate ARVD/C. However, echocardiography has significant limitations in ARVD/C assessment due to RV complex geometry and CMR has emerged as the imaging modality of choice. CMR allows more detailed morphological and functional evaluation and also tissue characterization. Using the diagnostic criteria showed in Table 1, major CMR criteria have a specificity of 95% and a sensitivity of 68 to 76% and minor criteria have a sensitivity of 79 to 89% and a specificity of 85 to 97% [11].
Common findings in CMR include RV dilation, RV diastolic/systolic dysfunction and focal wall motion abnormalities such as localized area of akinesia (lack of motion), dyskinesia (the segment of myocardium bulges outward in systole) and regional dysynchronous movement (peak contraction occurring at different times). These abnormalities are more commonly seen in RV inflow / outflow tract and apico-lateral region, but can also be noticed in subtricuspid region and basal RV free wall [11,12,13]. Regional dysfunction is observed in most of the patients, even in the presence of normal global function [13]. Trabecular disarray and wall thinning are common [11].
The identification of myocardial fat by CMR is challenging and has lower sensitivity, since areas of adipose infiltration are small and focal. Furthermore, Tandri et al. [14] showed that this finding may not be specific and it is the least reproducible CMR parameter. Even double inversion-recovery fast spin-echo sequences alone and combined with fat suppression are limited in spatial resolution for detecting intramyocardial fat [15]. Therefore, as LGE is a well validated technique for assessment of myocardial fibrosis, this is the preferred approach for RV tissue characterization and identification of fibro-adipose replacement [11,12]. In addition there is a high degree of correlation between LGE and RV biopsy, RV function and inducible ventricular arrhythmias on electrophysiologic study, making LGE an important tool in the management of these patients, including risk stratification [16]. In a previous study with ARVD/C associated mutation carriers without prior sustained ventricular arrhythmias, te Riele et al. [17] demonstrated that a combined strategy using electrocardiography, Holter and CMR identified patients at high risk for arrhythmias. Patients with both electrical and CMR abnormalities had a higher incidence of arrhythmic events, suggesting that patients with this clinical profile might eventually benefit from prophylactic implantable cardioverterdefibrillator.

CONCLUSION
In conclusion, diagnosis and follow up of ARVD/C require a rigorous evaluation of multiple parameters, particularly electrical and structural assessment, being CMR the imaging modality of choice for diagnostic and risk stratification.
LGE is emerging as a very relevant data for diagnosis and prognosis, substituting the search for intramyocardial fat. In this context, we can postulate that maybe LGE could be included in diagnostic criteria for ARVD/C.

CONSENT
All authors declare that written informed consent was obtained from the patient for publication of this paper and accompanying images.

ETHICAL APPROVAL
It is not applicable.