Incremental Value of Cardiac Magnetic Resonance Imaging in Arrhythmic Risk Stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated Desmosomal Mutation Carriers

Abstract

Objectives

To identify the incremental value and optimal role of Cardiac Magnetic Resonance (CMR) imaging in arrhythmic risk stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) associated desmosomal mutation carriers without a prior history of sustained ventricular arrhythmia.

Background

Risk stratification of ARVD/C mutation carriers is challenging.

Methods

We included 69 patients (age 27.0 ± 15.3 years, 42% male) harboring ARVD/C associated pathogenic mutations (83% PKP-2) without prior sustained ventricular arrhythmias. Electrocardiography (ECG) and 24-hours Holter monitoring closest to presentation were analyzed for electrical abnormalities as per revised Task Force Criteria. CMR studies were done to identify abnormal cardiac structure and function according to the revised Task Force Criteria.

Results

Overall, 42 (61%) patients presented with electrical abnormalities based on their ECG and Holter monitor, of whom 20 (48%) had an abnormal CMR. Only 1 (4%) of 27 patients without electrical abnormalities at initial evaluation had an abnormal CMR. Over a mean follow-up of 5.8 ± 4.4 years, 11 (16%) patients experienced a sustained ventricular arrhythmia, exclusively in patients with both electrical abnormalities (ECG and/or Holter) and abnormal CMR.

Conclusion

Our results suggest that electrical abnormalities on ECG and Holter monitoring precede detectable structural abnormalities in ARVD/C mutation carriers. Therefore, evaluation of cardiac structure and function using CMR is probably not necessary in the absence of baseline electrical abnormalities. Among ARVD/C mutation carriers, the presence of both electrical and CMR abnormalities identifies patients at high risk of events and thus patients who might benefit from prophylactic implantable cardioverter-defibrillator implantation.

Introduction

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by a high incidence of ventricular arrhythmias and an increased risk of sudden cardiac death (SCD)(1,2). Over the last decade, pathogenic ARVD/C associated mutations have been identified in five desmosomal genes (3-7), and clinical genetic testing is now routinely performed (8). Consequently, the cardiologist will be more often confronted with the question of how to manage asymptomatic mutation carriers. Because familial ARVD/C is a clinically heterogeneous disorder with incomplete penetrance and variable expressivity (9-11), management of mutation carriers remains challenging and the optimal approach to risk stratification is yet to be elucidated.

Current guidelines recommend serial screening of genetically predisposed individuals using a combination of electrocardiography (ECG), Holter monitoring and imaging modalities (12). Many studies have shown that ECG (13-15) and Holter monitors (16) are useful tools in the risk stratification of ARVD/C patients. Because of the anatomical, functional and tissue-specific characteristics of ARVD/C, cardiac magnetic resonance (CMR) imaging is an ideal technique for the diagnostic work-up (17). The incremental value and optimal timing of CMR in the prognostic work-up of mutation carriers, however, is not well defined.

In ARVD/C patients, both electrical uncoupling (18-20) and altered tissue architecture (3,6,20) are thought to contribute to arrhythmic propensity. We hypothesized that mutation carriers with both electrical and structural abnormalities on clinical evaluation are at particularly high risk of developing a life threatening arrhythmia, and that CMR is a valuable tool to risk stratify patients with abnormal electrical baseline testing.

Through prospective follow-up of ARVD/C mutation carriers with no prior history of sustained ventricular arrhythmia, we sought to identify the optimal role of CMR within a risk stratification paradigm in these patients. As a secondary objective, we aimed to characterize the association between abnormal electrical testing (based on ECG and Holter monitor) and CMR abnormalities in ARVD/C mutation carriers.

Methods

Study population

The study population was identified from the Johns Hopkins ARVD/C Registry (www.ARVD.com). The Johns Hopkins ARVD/C registry, established in 1999, prospectively enrolls patients and their family members referred to the Johns Hopkins ARVD/C Center with a possible history of this disease. Participants are contacted and updated medical records are collected annually. For the present study, 69 registry enrollees were included who 1) harbored a pathogenic ARVD/C associated desmosomal mutation; 2) had no history of sustained ventricular tachycardia (VT) or fibrillation (VF) at time of enrollment; and 3) underwent CMR available for analysis. The majority (n=54, 78%) of study subjects were first-degree relatives of ARVD/C probands who were identified through family screening. The remainder (n=15, 22%) presented with syncope (n=6), palpitations (n=3) or chest pain (n=1) that was not associated with a documented arrhythmia; 5 were incidentally discovered during routine medical examination. All registry participants provided written informed consent and the study protocol was approved by the Johns Hopkins School of Medicine Institutional Review Board.

Clinical electrical baseline testing

Participants were evaluated as described previously (16,21). Medical records for each patient were obtained at enrollment. For the purpose of this study, 12-lead ECGs and Holter monitoring closest to presentation were obtained and carefully reviewed for the presence of electrical abnormalities as per revised Task Force Criteria (TFC)(22) (Supplementary Table 1).

All 69 patients underwent routine 12-lead ECG (recorded at rest, 10 mm/mV at paper speed 25 mm/s). ECG was classified as abnormal when repolarization (precordial T-wave inversion in V1-2 or beyond) and/or depolarization (epsilon waves or terminal activation duration ≥ 55 ms) criteria for ARVD/C were present. No individual was taking antiarrhythmic or other medications known to affect the QRS complex at time of ECG acquisition.

Overall, 54 (78%) patients underwent 24-hour Holter monitoring. The Holter monitor was analyzed for ventricular ectopy, defined as isolated premature ventricular complexes (PVC) count exceeding 500/24 hours and/or recorded runs of non-sustained VT (≥3 consecutive premature beats at >100 bpm).

ECG and Holter monitoring were combined to obtain a composite measure of electrical abnormalities at presentation. Any participant meeting at least one minor ECG or Holter TFC (22) was considered to have evidence of electrical abnormality.

Cardiac Magnetic Resonance Imaging

All 69 study participants underwent CMR. CMRs were performed according to standard protocols for ARVD/C, which have previously been described in detail (23,24). All images were acquired on a 1.5-T scanner with a phased array cardiac coil during breath-holds gated to the ECG. Cine images were acquired in axial and short-axis planes covering the entire right (RV) and left ventricle (LV) with a steady state free precession technique. Fast spin-echo (both fat-suppressed and non-fat suppressed) images were acquired in both axial and short-axis planes with double-inversion recovery blood suppression pulses. A gadolinium-based contrast agent was administered intravenously, and contrast-enhanced images were acquired on average 10 minutes after contrast administration with a phase-sensitive inversion recovery sequence in both axial and short-axis planes.

CMR studies were analyzed for fulfillment of modified TFC (22), defined as presence of a RV regional wall motion abnormality (akinesia, dyskinesia, or dyssynchronous contraction) combined with enlarged RV end-diastolic volume (≥100 mL/m² (male) or ≥90 mL/m² (female)) and/or reduced RV ejection fraction (≤45%) (Supplementary Table 1).

CMR analysis was based on consensus agreement of radiologists with special interest in ARVD/C, who were blinded to all clinical data of included patients. CMR was classified as abnormal if at least a minor TFC for ARVD/C was present. Additionally, the CMR analysts ascertained presence of qualitative findings that were previously associated with ARVD/C (fatty infiltration and delayed gadolinium enhancement, as well as LV involvement).

Follow-up and outcome measure

Patient management was performed at the discretion of the treating physician. According to ARVD/C Registry protocol, patients were prospectively followed at yearly intervals. Primary outcome measure was the occurrence of a sustained ventricular arrhythmia (a composite measure of the occurrence of spontaneous sustained VT, aborted SCD, SCD, or appropriate implantable cardioverter-defibrillator (ICD) intervention for a ventricular arrhythmia; definitions provided in Supplementary Table 2). In patients without an ICD, the primary outcome was adjudicated based on reviewing ECGs and medical records; in patients with an ICD, the device stored ECGs were reviewed for appropriateness of ICD therapy. In patients with multiple endpoints, the first event was considered the censoring event.

Statistical analysis

All continuous data were presented as mean ± standard deviation and categorical variables as numbers (percentages). Continuous variables were compared using the independent Student t-test or Mann-Whitney U test and categorical data using Chi-square or Fisher's exact tests. The cumulative freedom from the composite arrhythmic outcome since presentation was determined by Kaplan Meier method. Differences in survival among groups were evaluated with a log-rank test. A p-value of <0.05 was considered significant. Statistical calculations were performed using SPSS version 19.0 (IBM, Chicago, Illinois).

Results

Clinical characterization

The study population comprised 69 individuals from 40 families who were identified as harboring a pathogenic ARVD/C-associated desmosomal mutation (83% Plakophilin-2 (PKP-2), Supplementary Table 3).

Characteristics of study participants are shown in Table 1. Mean age at presentation was 27.0 ± 15.3 years and 42% were men. Of 69 subjects, 47 (68%) participants were asymptomatic at presentation; the remainder (n=22, 32%) had a history of syncope, presyncope, palpitations, or chest pain.

Table 1.

Patient Characteristics

	Overall (n=69)	Normal electrical baseline testing (n=27)	Abnormal electrical baseline testing (n=42)	p-value
Male	29 (42)	12 (44)	17 (40)	NS
Follow-up (yrs)	5.8 ± 4.4	7.0 ± 4.2	5.1 ± 4.5	NS
Age at presentation (yrs)	27.0 ± 15.3	24.2 ± 16.7	28.8 ± 14.2	NS
Symptomatic at presentation	22 (32)	3 (11)	19 (45)	0.003
Syncope	9 (13)	0 (0)	9 (21)	0.010
Presyncope	6 (9)	0 (0)	6 (14)	0.040
Palpitations	16 (23)	3 (11)	13 (31)	NS
Chest pain	3 (4)	0 (0)	3 (7)	NS
ICD implantation during FU	26 (38)	2 (7)	24 (57)	<0.001
Age at implantation (yrs)	29.7 ± 12.6	47.1 ± 10.5	28.1 ± 11.8	NS

Abbreviations: ICD: implantable cardioverter-defibrillator, NS: non significant.

Overall, 42 (61%) patients had abnormal baseline electrical testing defined as at least a minor criteria for ARVD/C based on evaluation of ECG and Holter monitor (Table 2). In the total cohort, an abnormal ECG was observed in 39 (57%) patients and an abnormal Holter was observed in 14/54 (26%) patients. Overall, 35 (51%) patients fulfilled repolarization criteria for ARVD/C (28 major and 7 minor), 13 (19%) patients fulfilled depolarization criteria for ARVD/C (1 major and 12 minor) and 14 (26%) patients fulfilled arrhythmia criteria for ARVD/C (all minor criteria). ICDs were implanted in 26 (38%) patients, of whom the majority (n=24, 92%) had abnormal ECG and/or Holter at baseline (Table 1). Prognostic work-up for the study population is shown in Figure 1.

Table 2.

Electrical Baseline Tests in ARVD/C Mutation Carriers Without Prior Ventricular Arrhythmia

ECG abnormal	39 (57)
Negative T waves V1-2	7 (10)
Negative T waves V1-3 or beyond	28 (41)
Negative T waves V4-6 in presence of RBBB	0 (0)
Epsilon waves	1 (1)
Terminal activation duration ≥ 55ms	13 (19)
Holter abnormal*	14 (26)
> 500 PVC / 24 hours	13 (24)
Non-sustained VT recorded	9 (17)
Electrical abnormalities †	42 (61)

Reported percentages are valid percentages.

^*54 patients underwent Holter monitoring.

^†Defined as presence of ≥1 abnormal ECG and/or Holter monitoring parameter.

Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, ECG: electrocardiography, PVC: premature ventricular complex, RBBB: right bundle branch block, VT: ventricular tachycardia.

Figure 1. Patient Flowchart.

Patient flowchart showing prognostic work-up and arrhythmic events in the study population. Abbreviations: CMR: cardiac magnetic resonance, ECG: electrocardiogram.

Cardiac Magnetic Resonance findings

Structural and functional CMR abnormalities in the entire cohort are summarized in Table 3. Overall, 21 (30%) patients had an abnormal CMR fulfilling TFC for ARVD/C. The majority of patients with an abnormal CMR fulfilled major TFC (17/21 patients, 81%). Symptomatic patients were significantly more likely to fulfill TFC for CMR than asymptomatic patients (14 (64%) versus 7 (15%) individuals, p<0.001). Mean time between presentation and CMR was 3.4 ± 3.9 years. There was no statistically significant difference in age at CMR for patients with a normal versus abnormal CMR (31.5 ± 16.6 versus 28.0 ± 11.7 years, p=NS).

Table 3.

Quantitative and Qualitative Cardiac Magnetic Resonance Findings in the Study Population.

	Overall (n=69)	Normal electrical baseline testing (n=27)	Abnormal electrical baseline testing (n=42)	p-value
Fulfilment of TFC for CMR	21 (30)	1 (4)	20 (48)	<0.001
Major criterion	17 (25)	0 (0)	17 (41)	<0.001
Minor criterion	4 (6)	1 (4)	3 (7)	NS
Quantitative parameters
RV EDV/BSA (ml/m2)	84.5 ± 21.2	77.6 ± 16.1	90.6 ± 24.0	0.012
RV ESV/BSA (ml/m2)	46.0 ± 18.7	37.3 ± 8.7	52.6 ± 22.5	0.006
RV EF (%)	47.2 ± 10.1	52.0 ± 5.2	43.2 ± 11.9	0.002
LV EDV/BSA (ml/m2)	80.2 ± 14.9	76.2 ± 14.5	82.3 ± 14.7	NS
LV ESV/BSA (ml/m2)	37.4 ± 10.2	32.7 ± 8.1	40.2 ± 10.5	0.004
LV EF (%)	53.8 ± 6.8	57.7 ± 4.6	51.4 ± 6.7	<0.001
LVEDV/RVEDV	0.97 ± 0.17	0.99 ± 0.07	0.95 ± 0.20	NS
Qualitative parameters
Global RV dilatation	16 (23)	0 (0)	16 (38)	<0.001
Global RV hypokinesia	12 (17)	0 (0)	12 (29)	0.002
Global LV dilatation	2 (3)	0 (0)	2 (5)	NS
Global LV hypokinesia	4 (6)	0 (0)	4 (10)	NS
RV regional wall motion abnormalities	24 (35)	3 (11)	21 (50)	0.001
RV regional aneurysm	6 (9)	1 (4)	5 (12)	NS
RV regional fatty infiltration	9/68 (13)	1/27 (4)	8/41 (20)	NS
RV regional delayed enhancement	2/61 (3)	0/24 (0)	2/37 (5)	NS
LV regional wall motion abnormalities	6 (9)	0 (0)	6 (14)	0.040
LV regional aneurysm	0 (0)	0 (0)	0 (0)	-
LV regional fatty infiltration	13 (19)	1 (4)	12 (29)	0.010
LV regional delayed enhancement	7/61 (11)	1/24 (4)	6/37 (16)	NS
Involvement
RV involvement only	12 (17)	2 (7)	10 (24)	NS
LV involvement only	3 (4)	1 (4)	2 (5)	NS
Biventricular involvement	15 (22)	1 (4)	14 (33)	0.004

Abbreviations: BSA: body surface area, CMR: magnetic resonance imaging, EDV: end-diastolic volume, EF: ejection fraction, ESV: end-systolic volume, LV: left ventricular, NS: non significant, RV: right ventricular, TFC: Task Force Criteria.

Compared to patients with normal electrical baseline testing, patients with electrical abnormalities based on ECG and Holter evaluation were significantly more likely to have an abnormal CMR (20 (48%) versus 1 (4%) patients, p<0.001) with higher RV volumes and lower biventricular ejection fractions (Table 3). The only patient with normal electrical tests and an abnormal CMR had dyskinesia of the RV free wall and mildly diminished RV ejection fraction (45%), fulfilling a minor TFC on CMR. This patient had isolated T-wave inversions in V1 and V3 on the ECG (Supplementary Figure 1) and 20 PVCs on 24-hours Holter monitor, thus not fulfilling TFC for ECG or Holter monitoring.

Arrhythmic outcome

Over a mean follow-up of 5.8 ± 4.4 years, 11 (16%) patients experienced a sustained ventricular arrhythmia. Characteristics of patients experiencing an arrhythmic event are shown in Table 4. Of 11 patients experiencing an event, the majority were men and probands (both n=8, 73%). Mean age at first arrhythmic event was 25.2 ± 5.0 years (range 17-32 yrs), and mean cycle length of the event was 258 ± 42 ms (range 188 - 323 ms). For 7 (64%) patients, the first arrhythmic event was an appropriate ICD intervention; 4 patients had a spontaneous VT/VF. The cycle length of the tachyarrhythmia was similar for patients who experienced an ICD intervention as compared to those with a spontaneous episode of sustained VT/VF (260 ± 37 versus 255 ± 57 ms, respectively, p=NS). ICD details are provided in Supplementary Table 4. ICD programming was not significantly different between ICD carriers with and without appropriate intervention (rate cut-off 189 ± 12 and 191 ± 15 bpm, respectively, p=NS). None of the study population required cardiac transplantation or died during follow-up.

Table 4.

Characteristics of Patients According to Arrhythmic Outcome.

	No arrhythmic event (n=58)	Arrhythmic event (n=11)	p-value
Male	21 (36)	8 (73)	0.024
Proband	7 (12)	8 (73)	<0.001
Symptomatic at presentation	15 (26)	7 (64)	0.014
Syncope	7 (12)	2 (18)	NS
Presyncope	4 (7)	2 (18)	NS
Palpitations	10 (17)	6 (55)	0.007
Chest pain	2 (3)	1 (9)	NS
ECG abnormal	29 (50)	10 (91)	0.012
Negative T waves V1-2	6 (10)	1 (9)	NS
Negative T waves V1-3 or beyond	19 (33)	9 (82)	0.002
Epsilon waves	0 (0)	1 (9)	0.021
Terminal activation duration ≥55ms	9 (16)	4 (36)	NS
Holter abnormal*	10/49 (20)	4/5 (80)	0.004
> 500 PVC / 24 hours	9/49 (18)	4/5 (80)	0.002
Non-sustained VT recorded	6/49 (12)	3/5 (60)	0.006
Fulfillment of TFC for CMR	10 (17)	11 (100)	<0.001
Major TFC	6 (10)	11 (100)	<0.001
Minor TFC	4 (7)	0 (0)	NS
RV EDV/BSA (ml/m2)	80.9 ± 19.2	109.9 ± 20.7	<0.001
LV EDV/BSA (ml/m2)	78.6 ± 13.9	87.7 ± 17.6	NS
RV EF (%)	49.3 ± 9.2	32.6 ± 6.8	<0.001
LV EF (%)	55.2 ± 6.0	45.8 ± 4.9	<0.001
RV wall motion abnormalities	14 (24)	11 (100)	<0.001
RV fatty infiltration	7 (12)	2 (20)	NS
RV delayed enhancement†	0/52 (0)	2/9 (22)	0.001
LV wall motion abnormalities	4 (7)	2 (18)	NS
LV fatty infiltration	7 (12)	6 (55)	0.001
LV delayed enhancement†	5/52 (10)	2/9 (22)	NS
RV involvement only	8 (14)	4 (36)	NS
LV involvement only	3 (5)	0 (0)	NS
Biventricular involvement	8 (14)	7 (64)	<0.001

^*54 patients underwent Holter

^†For 61 patients, delayed enhancement images were available.

Abbreviations: BSA: body surface area, ECG: electrocardiography, EDV: end-diastolic volume, EF: ejection fraction, LV: left ventricular, NS: non significant, PVC: premature ventricular complex, RV: right ventricular, TFC: Task Force Criteria.

All patients with arrhythmic events presented with electrical abnormalities (Figure 2). Time between presentation and the arrhythmic event was 4.5 ± 4.3 years (range 0.2-14.0 years). For both ECG and Holter monitoring separately, event free survival was significantly lower in patients with abnormal test results compared to patients with normal test results (p=0.001 and p=0.002, respectively). Overall, event free survival in patients with any electrical abnormality (on ECG and/or Holter monitor) was significantly lower than survival in patients without electrical abnormalities (p=0.001). Among patients with electrical abnormalities, cumulative survival free form arrhythmic events after 1, 5 and 10 years was 95% (95% CI 87-100%), 76% (95% CI 60-92%) and 66% (95% CI 46-86%), respectively.

Figure 2. Risk of Sustained Ventricular Arrhythmias Based on ECG and Holter monitoring.

Cumulative survival free from sustained ventricular arrhythmias among patients stratified according to ECG (A) and Holter monitoring (B) results. Event free survival in ARVD/C mutation carriers who fulfill at least a minor Task Force Crtierion for ARVD/C on ECG and/or Holter is significantly lower than survival in patients without electrical abnormalities (C). Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, ECG: electrocardiogram

Sustained ventricular arrhythmias occurred exclusively in patients with an abnormal CMR (Figure 3). All patients with arrhythmic events fulfilled a major TFC for CMR. Biventricular involvement was seen in 7 (64%) of 11 patients experiencing a sustained tachyarrhythmia. Compared to patients with electrical abnormalities in isolation (n=22), patients with both electrical and CMR abnormalities (n=20) had a significantly higher propensity towards ventricular arrhythmia (p<0.001). In this group, cumulative survival free from arrhythmic events after 1, 5 and 10 years was 89% (95% CI 75-100%), 54% (95% CI 29-79%) and 36% (95% CI 9-63%), respectively.

Figure 3. Incremental Risk of Sustained Ventricular Arrhythmias with Abnormal CMR.

Mutation carriers who meet both electrical (ECG and/or Holter) and CMR criteria for ARVD/C have significantly higher arrhythmic propensity compared to patients with abnormal ECG and/or Holter monitor in isolation. Abbreviations: ARVD/C: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, CMR: cardiac magnetic resonance.

Discussion

During the past decade, the understanding of the genetic basis of ARVD/C has evolved greatly (3-7). Genetic screening of patients with ARVD/C identifies a pathogenic mutation in approximately half of individuals (8-10,25-27). Once a pathogenic mutation is identified in a proband, downstream genetic testing of family members is recommended (12,26). Although many studies have assessed non-invasive modalities for risk stratification in ARVD/C patients (13,14,16,28-30), several uncertainties remain both in the evaluation and management of these patients. For example, it is unclear what minimum initial testing should be performed in mutation positive patients. Although conventional wisdom suggests that patients at risk of developing ARVD/C based on the presence of a pathogenic mutation should undergo complete ARVD/C screening including CMR at regular intervals, there is little objective evidence to demonstrate the necessity of this approach. Also, with regard to CMR, it is important to recognize that many imaging centers have little or no experience with clinical evaluation of ARVD/C, and that nonspecific findings such as fatty infiltration alone or minor wall motion abnormalities are often over-interpreted as providing evidence of ARVD/C (17,31-34). Our study provides data that help address some of the clinically important questions relating to ARVD/C mutation carriers without a history of prior arrhythmic events.

Electrical abnormalities on ECG and Holter

An important finding of this study is that ARVD/C mutation carriers who lack electrical abnormalities based on ECG and Holter monitor evaluation have a very low risk of arrhythmia during a mean follow up of 7 years. These data suggest that the presence of a mutation itself does not necessarily confer risk of arrhythmia in these patients. These data are also in alignment with prior retrospective studies, which have shown that ECG (13-15) and Holter monitoring (16) are useful tools in risk stratification of ARVD/C patients. Although included in the revised TFC, we did not use signal averaged ECG to define electrical abnormalities. In our cohort, signal averaged ECG data were available in only a subset of patients, in whom it did not add to the risk stratification paradigm.

We determined electrical abnormalities based on ECG and Holter examination closest to presentation. It is possible that some of the patients with normal ECG and Holter monitor at presentation developed electrical changes during their clinical course; however, this was not specifically investigated in our study. This leads to two possibilities: 1) ARVD/C mutation carriers without electrical abnormalities at baseline do not have disease expression and therefore have no long-term risk of arrhythmia, or 2) the more likely possibility that ARVD/C mutation carriers without electrical abnormalities are in the concealed phase of the disease prior to overt disease manifestation. The fact that none of the patients without electrical abnormalities developed a sustained ventricular arrhythmia during almost 6 years of follow-up suggests that there may be a long latent concealed phase in most patients. It is important to note in this regard that we routinely advise mutation carriers to give up high-level athletics. It is certainly possible that absence of arrhythmic events in patients with an initially negative electrical and CMR evaluation may not be applicable to ARVD/C mutation carriers who do not restrict athletic activity.

Correlation of ECG and Holter monitoring with CMR

The second important result of our study is the very low incidence of abnormal CMR in patients with normal ECG and Holter monitor at baseline. Interestingly, only 1 patient in the cohort fulfilled a minor TFC for CMR in the absence of electrical abnormalities at presentation. It is important to note that the ECG in this patient was abnormal with T-wave inversion in leads V1 and V3, but not V2. Because T-wave inversion was not seen in consecutive precordial leads, TFC for ARVD/C were not fulfilled, and ECG was classified as normal. It is also important to note that this patient, with an atypical ECG pattern and minor CMR abnormalities, did not experience an arrhythmic event during follow-up. These data lead us to believe that electrical abnormalities precede detectable structural changes in ARVD/C, and that evaluation of cardiac structure and function using CMR may not be necessary in the absence of baseline electrical abnormalities. New CMR sequences such as high-resolution T1 mapping are promising tools to detect early, subtle changes in the RV.

Arrhythmic events

The final important result of our study is that arrhythmic events occurred exclusively in patients who met both electrical (ECG and/or Holter monitoring) and structural (CMR) criteria for ARVD/C, suggesting that both an abnormal electrical and structural substrate is required for arrhythmic occurrence. Our observation that patients with electrical abnormalities in isolation had a low risk of arrhythmic events in our study during 6 years of follow-up opens the path for the strategic implementation of CMR in patients with abnormal electrical baseline tests. This insight is critically important, as CMR might be able to identify those who may benefit from intensive screening, further clinical investigation, and consideration of prophylactic ICD implantation.

Strategic use of CMR

Our study reveals the potential of CMR to identify desmosomal mutation carriers at high risk of arrhythmias, when used strategically in conjunction with results of ECG and Holter monitoring. Prior work by our group has demonstrated the utility of ECG and Holter monitoring in risk stratification of mutation carriers and highlighted the increased arrhythmic risk of probands as compared to family members detected through cascade screening (15). In the present study, 8 (73%) of 11 patients experiencing an arrhythmic event were probands, similar to prior findings. The current study builds on this risk stratification paradigm and suggests a strategy for optimizing use of CMR to evaluate mutation carriers presenting without a history of arrhythmic events. Based on our results, the optimal approach would be to use CMR in patients with abnormal ECG and/or 24-hours Holter monitoring at initial evaluation. Evaluation of cardiac structure and function using CMR may be able to be deferred in the absence of baseline electrical abnormalities, at least among asymptomatic family members detected through cascade screening. The clinical follow-up evaluation of patients who have no electrical abnormalities at baseline and those who meet electrical criteria but do not have CMR abnormalities remains to be determined. While further studies are needed to validate our data, these results suggest a strategy to optimize use of CMR to detect ARVD/C-associated mutation carriers who are at significant risk of arrhythmic events, while limiting use of this second line test among those who are unlikely to derive benefit from its results.

Study limitations

Rate cut-off for therapy during ICD programming was not uniform. However, ICD programming was not different between ICD carriers with and without interventions, and ICD discharges were adjudicated as appropriate based on ECG analyses. Studies on ARVD/C, in particular involving CMR, are typically small in size. Larger studies are needed to validate our findings and to determine optimal clinical follow-up recommendations for these high-risk patients. Also, our study sample was underpowered to assess independent prognostic value of specific parameters. However, to our knowledge, we studied the largest cohort of asymptomatic ARVD/C mutation carriers using an integrated approach of both electrical and CMR investigations. This provided us with the unique possibility to assess the optimal role of CMR within the prognostic work-up of these patients. The only imaging modality we employed to define structural and/or functional abnormalities was CMR. Yet, as CMR offers the unique possibility to assess cardiac morphology, function and tissue characteristics in a single investigation, it is frequently used in the prognostic evaluation of ARVD/C mutation carriers. In our study, CMR was not performed at time of initial presentation for all study participants. This represents clinical practice where CMR is often not considered a first line test for ARVD/C. Our study results actually favor this approach, as all events occurred in patients with abnormalities detected on their electrical baseline testing and electrical abnormalities appear to precede abnormal CMR. It would be interesting to see whether similar results can be obtained using echocardiography or angiography.

Conclusion

In this prospective cohort of 69 ARVD/C associated pathogenic mutation carriers without prior sustained ventricular arrhythmias, we demonstrate that there is a strong association between electrical baseline abnormalities on the ECG and Holter monitor and structural and functional abnormalities detected by CMR. Importantly, we showed that CMR is a valuable tool to identify patients at high risk of ventricular arrhythmias, especially when used strategically in patients with abnormal electrical baseline tests.

Abbreviations list

ARVD/C

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

BSA

Body surface area

CI

Confidence interval

CMR

Cardiac magnetic resonance

ECG

Electrocardiography

ICD

Implantable cardioverter-defibrillator

LV

Left ventricle

PVC

Premature ventricular complex

RV

Right ventricle

SCD

Sudden cardiac death

TFC

Task Force Criteria

VT

Ventricular tachycardia

VF

Ventricular fibrillation