Long‐term follow‐up of arrhythmogenic right ventricular cardiomyopathy patients with an implantable cardioverter‐defibrillator for prevention of sudden cardiac death

Abstract

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited cardiomyopathy with a high burden of ventricular arrhythmia, which is an important cause of sudden cardiac death (SCD). Implantable cardioverter‐defibrillator (ICD) is believed to be the most reliable management against SCD.

Hypothesis

Ventricular arrhythmia does not necessarily confer a poor prognosis in ARVC patients with an ICD.

Methods

A total of 39 ARVC patients (34 male) implanted with an ICD at our electrophysiology center and followed up continuously were included in this study. The mean age at diagnosis was 42.1 ± 14.8 years.

Results

Thirty‐three patients (84.6%) had suffered ventricular arrhythmia with hemodynamic compromise before ICD implantation. During a median follow‐up of 48.6 months (interquartile range, 32.3–73.3), 3 patients (7.7%) died, 1 of sudden death, 1 of heart failure, and 1 of cerebral infarction. Twenty‐eight patients (71.8%) experienced 540 appropriate ICD interventions. The first appropriate ICD intervention occurred more than 2 years after initial ICD implantation in 5 patients (12.8%). Twelve patients (30.8%) suffered from electrical storm. The event‐free period was significantly shorter in patients who did not have broad precordial T wave inversion ≥V1–V3 (hazard ratio = 0.39, 95% confidence interval: 0.16‐0.96). No significant difference was shown in antiarrhythmic drugs and radiofrequency catheter ablation before ICD implantation between patients with and without appropriate ICD therapies (P > 0.05).

Conclusions

Recurrence of sustained ventricular tachycardia/ventricular fibrillation is frequent in high‐risk patients with ARVC. The prognosis is favorable for ARVC patients treated with an ICD for prevention of SCD.

1. INTRODUCTION

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been determined as an inherited cardiomyopathy characterized pathologically by penetration of fibrofatty tissue into the right ventricular (RV) myocardium, sometimes compromising the left ventricle (LV), which consequently affects the electroactivity and pump function of the heart.1, 2, 3, 4 Symptoms range from palpitations and chest discomfort to syncope, heart failure, or even sudden cardiac death (SCD).3, 4, 5 The primary clinical manifestation and the progression of the disease may vary greatly and take on unique forms of presentation in different ethnic groups, probably due to its genetic heterogeneity and different forms of phenotypic expression.5, 6, 7, 8

The management of patients with ARVC should be individualized, and the main objective is to prevent arrhythmic SCD. Implantable cardioverter‐defibrillators (ICDs) are believed to be the most effective strategy against SCD.4, 5, 6, 9

The purpose of this study was to investigate the long‐term follow‐up of patients with ARVC who received ICDs for the prevention of SCD at our cardiac electrophysiology center.

2. METHODS

2.1. Patient population

A total of 42 patients with definitive diagnoses of ARVC received ICDs at Fuwai Hospital in Beijing, China, from December 1996 to September 2015. Thirty‐nine of these patients with continuous records of outpatient clinic follow‐up, readmission, or remote monitoring were included in this study. Patients were visited in the outpatient clinic or contacted by telephone from October 2015 to January 2016. Informed consent was obtained from all patients, and the study was approved by the ethics committee of our institution.

2.2. Diagnostic criteria

Clinical diagnosis of ARVC was established using the 1994 criteria proposed by the Task Force of the Working Group of 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.1 Revised criteria were adopted in 2010.2

The standard criteria can be classified into 6 categories representing structural, histologic, electrocardiographic (repolarization/depolarization), arrhythmic, and familial features of the disease, and then subdivided into major and minor criteria in each category according to their association with ARVC. Clinical diagnosis can be achieved if 2 major, 1 major plus 2 minor, or 4 minor criteria from different categories are fulfilled.

2.3. Implantable cardioverter‐defibrillators

All devices in this study are capable of providing antitachycardia and antibradycardia pacing. The devices also have the ability of storing diagnostic data and intracardiac electrograms for the triggering events, thus allowing for subsequent classification of arrhythmia events and the delivery of therapy.

Basic pacing rate, parameters used for detection and therapy, and other auxiliary functions were programmed individually by the patients’ attending physicians based upon their clinical histories and complications.

2.4. Follow‐up

Device interrogations were performed before discharge and every 3 to 6 months thereafter. Clinical follow‐up was required when patients experienced symptoms like syncope, presyncope, incessant palpitations, or an ICD therapy. The parameters of the ICD were changed whenever necessary as dictated by the attending physicians during each follow‐up. Intracardiac electrograms were retrieved and analyzed by at least 2 independent electrophysiologists to confirm the type of arrhythmia. When stored data were incomplete on a given patient, the team relied upon previous electrophysiologists’ interpretations of the ICD readings.

Ventricular fibrillation (VF) or ventricular flutter was defined as ventricular arrhythmia, with a cycle length of 272 ms or less (ie, ≥220 bpm), which was considered potentially fatal in the absence of an ICD. Regular (monomorphic) or irregular (polymorphic) ventricular arrhythmia with a cycle length of more than 272 ms was designated as ventricular tachycardia (VT). Electrical storm was defined as the occurrence of ventricular arrhythmia triggering 3 or more ICD interventions (shock and/or antitachycardia pacing) within a 24‐hour period. Nonsustained ventricular tachycardia (NSVT) was defined as 3 or more consecutive ventricular premature beats lasting <30 seconds without hemodynamic compromise.

All interventions were classified as appropriate or inappropriate on the basis of rate behavior, electrogram morphology, and the results of the interventions. Appropriate interventions were those delivered in response to ventricular tachyarrhythmia, and inappropriate interventions were defined as ICD discharges resulting from supraventricular tachycardia, sinus tachycardia, or a device malfunction.

SCD followed the definition of sudden unexpected death that occurred instantaneously or within 24 hours after the onset of acute symptoms or signs, as stipulated by the International Society of Cardiology and the American Heart Association.

2.5. Statistical analysis

Continuous variables are expressed as mean ± standard deviation or median (interquartile range). Comparison between continuous variables were performed using the Student t test or Wilcoxon rank test. Categorical variables were reported as frequency (%) and were compared using the Fisher exact test. The cumulative probability of survival and appropriate ICD intervention‐free rates were determined using the Kaplan‐Meier method, and the log‐rank test was used for the comparison of survival curves. Univariate and multivariate Cox regression models were used to identify the baseline variables associated with appropriate ICD therapy. A 2‐sided P value of <0.05 was considered indicative of statistical significance.

3. RESULTS

3.1. Patient characteristics

The patient population consisted of 39 patients with a median follow‐up of 48.6 (32.3–73.3) months. Patients’ clinical characteristics are summarized in Table 1. In 6 (15.4%) patients who had not experienced an episode of sustained VT/VF before ICD implantation, severe enlargement of the RV was observed in 5 (12.8%), NSVT was seen in 5 (12.8%), and LV dysfunction was present in 2 (5.1%), with left ventricular ejection fraction of 40% and 20%, respectively. None of these patients had a positive family history.

Table 1.

Baseline characteristics of patients with ARVC

	Total, n = 39		No Appropriate Therapy, n = 11		Appropriate Therapy, n = 28		P
Male	32	(82.1%)	9	(81.8%)	23	(82.1%)	1.00
Age at diagnosis, y	42.1	(14.8)	41.6	(17.9)	42.3	(13.8)	0.90
median, y	40.0	(32.0–54.0)	36.0	(23.0–59.0)	40.5	(32.0–52.5)
Main symptoms
Syncope	17	(43.6%)	4	(36.4%)	13	(46.4%)	0.72
Palpitations/chest discomfort	18	(46.2%)	6	(54.5%)	12	(42.9%)	1.00
Chest pain	2	(5.1%)	1	(9.1%)	1	(3.6%)	0.49
Fatigue	1	(2.6%)	0	(0%)	1	(3.6%)	—
Shortness of breath/edema	1	(2.6%)	0	(0%)	1	(3.6%)	—
Sustained VT/VF	33	(84.6%)	9	(81.8%)	24	(85.7%)	1.00
VT/VF occurred at first onset	14	(35.9%)	5	(45.5%)	9	(32.1%)	0.48
ECG
TWI (≥V1–V3)	31	(79.5%)	10	(90.9%)	21	(75.0%)	0.40
Epsilon	11	(28.2%)	4	(36.4%)	7	(25.0%)	0.69
Holter
Frequent PVC	29	(74.4%)	7	(63.6%)	22	(78.6%)	0.42
NSVT	14	(35.9%)	3	(27.3%)	11	(39.3%)	0.71
2‐dimensional echo
RV enlargement	34	(87.2%)	8	(72.7%)	26	(92.9%)	0.13
RV dyskinesia	27	(69.2%)	7	(63.6%)	20	(71.4%)	0.71
Aneurysms	4	(10.3%)	2	(18.2%)	2	(7.1%)	0.56
RV diameter, mm	34.8	(9.3)	36.5	(12.2)	34.2	(8.1)	0.50
LVEF, %	55.0	(15.3)	55.4	(17.7)	54.8	(14.7)	0.92
LV involvement	6	(15.4%)	1	(9.1%)	5	(17.9%)	0.65
MRI	29	(74.4%)	8	(72.7%)	21	(75.0%)	1.00
LGE	23	(79.3%)	6	(75.0%)	17	(81.0%)	1.00
RFCA before ICD	15	(38.5%)	4	(36.4%)	11	(39.3%)	1.00
AAD							1.00
Amiodarone	18	(46.2%)	6	(54.5%)	12	(42.9%)	0.72
Sotalol	11	(28.2%)	2	(18.2%)	9	(32.1%)	0.46
Mexiletine	1	(2.6%)	0	(0%)	1	(3.6%)	—
Propafenone	1	(2.6%)	1	(9.1%)	0	(0%)	—
β‐receptor antagonist	20	(51.3%)	7	(63.6%)	13	(46.4%)	0.48
Family history	4	(10.3%)	0	(0%)	4	(14.3%)	0.31
First symptom/sign to ICD, y	3.0	(1.0–7.0)	2.0	(1.0–6.0)	4.0	(1.0–8.5)	0.28
Follow‐up, d
Mean	1832.7		1215.7		2075.0		0.05
Median (interquartile range)	1481.0 (985.0–2237.0)		1273.0 (766.0–1935.0)		1684.0 (1065.5–2622.0)

Abbreviations: AAD, antiarrhythmic drug; ARVC, arrhythmogenic right ventricular cardiomyopathy; ECG, electrocardiogram; ICD, implantable cardioverter‐defibrillator; LGE, late gadolinium enhancement; LV, left ventricle; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; NSVT, nonsustained ventricular tachycardia; PVC, premature ventricular contraction; RFCA, radiofrequency catheter ablation; RV, right ventricle; TWI, T‐wave inversion; VT/VF, ventricular tachycardia/ventricular fibrillation.

3.2. Survival and appropriate ICD therapies

During follow‐up there were 3 deaths (7.7%). One patient died suddenly 6 years after the implantation of the ICD. This patient had received multiple appropriate ICD therapies and had experienced one ICD storm with radiofrequency catheter ablation to control ventricular arrhythmia thereafter. However, neither ICD interrogation nor autopsy was performed after this patient's death. The other 2 patients died of cerebral infarction and heart failure, respectively.

A total of 540 sustained VT/VF episodes were recorded for 28 (71.8%) of the study patients (Figure 1). The median of appropriate intervention episodes for these patients was 7 (range, 1–98). Malignant ventricular arrhythmia was not found to be rare even after 2 years of follow‐up, having occurred in 15 patients (38.5%) with a total number of 244, 36 VF in 10 patients (25.6%), and 207 VT in 12 patients. The median interval between ICD implantation and the first appropriate ICD therapy was 13.9 months. The interval was 2 years or longer in 5 patients (12.8%). Figure 2 shows the actual survival and the survival free of appropriate ICD therapy.

Figure 1.

Temporal distribution of (A) VT and (B) VF episodes treated by appropriate ICD therapy. Abbreviations: ICD, implantable cardioverter‐defibrillator; VT, ventricular tachycardia; VF, ventricular fibrillation.

Figure 2.

Kaplan‐Meier plot comparing actual survival probability with survival free of appropriate ICD therapy in these patients. Abbreviations: ICD, implantable cardioverter‐defibrillator.

Twelve patients (30.8%) suffered a total of 33 electrical storms. In 7 of these patients, the electrical storm occurred 2 or more years after ICD implantation. Six patients (15.4%) experienced inappropriate interventions, but all of them also had at least 1 episode of appropriate discharge. The reasons for inappropriate therapy were sinus tachycardia in 5 (12.8%) patients, atrial fibrillation in 1 (2.6%) patient, and electromagnetic interference in 1 (2.6%) patient. The median follow‐up time was significantly shorter for the 11 patients who did not experience any ICD firing events (41.7 months).

3.3. Predictors of appropriate ICD therapy

Univariate predictors of appropriate ICD intervention are listed in Table 2. None of these variables showed significant differences between patients who had experienced appropriate ICD therapies and those who had not (Table 1). However, the survival time without ICD firing was much longer in patients with T‐wave inversion (TWI) ≥ V1–V3 (hazard ratio = 0.39, 95% confidence interval [CI]: 0.16‐0.96, P = 0.04), and this remained as an independent predictor of survival time on multiple analysis (HR = 0.36, 95% CI: 0.14‐0.88, P = 0.03) (Figure 3).

Table 2.

Predictors of appropriate ICD interventions

Patient Characteristics	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P	HR	95% CI	P
Male gender	1.36	0.51‐3.62	0.53
Age ≤35 years	1.33	0.61‐2.89	0.47
Syncope	0.70	0.33‐1.51	0.37
Sustained VT	1.63	0.49‐5.43	0.43
RV enlargement	2.75	0.65‐11.71	0.17	3.07	0.72‐13.08	0.13
Epsilon	0.84	0.35‐1.99	0.69
TWI (≥V1–V3)	0.39	0.16‐0.96	0.04	0.36	0.14‐0.88	0.03
AAD	1.05	0.40‐2.79	0.92
RFCA before ICD	0.97	0.44‐2.12	0.93

Abbreviations: AAD, antiarrhythmic drug; CI, confidence interval; HR, hazard ratio; ICD, implantable cardioverter‐defibrillator; RFCA, radiofrequency catheter ablation; RV, right ventricle; TWI, T‐wave inversion; VT, ventricular tachycardia.

Figure 3.

Electrocardiograms of 2 patients with antiarrhythmic right ventricular cardiomyopathy. (A) A 35‐year‐old male patient with T‐wave inversion limited in V1. (B) A 54‐ year‐old female patient with T‐wave inversion extending from V1 to V6. Red arrows indicate T‐wave inversion.

3.4. ICD complications and exchanges

Complications occurred at the time of implantation in 3 patients (7.7%). A defibrillation threshold test (DFT) failed in 1 patient because sustained VT/VF could not be induced. Inadequate R‐wave amplitude was observed in 1patient (R = 1.6 mV); a second DFT was successfully achieved, and that patient's lead was not repositioned. One patient required lead repositioning due to dislocation within several days of the initial procedure. During the follow‐up, none of these patients experienced myocardial perforation, tamponade, infection, or lead malfunction. ICD replacement was performed in 6 patients (15.4%) due to battery depletion.

4. DISCUSSION

The outcomes of 39 patients with ARVC who had an ICD implanted for prevention of SCD were analyzed at our electrocardiology center. It was confirmed that, although the incidence of appropriate ICD intervention was high during the follow‐up, the expected survival time of ARVC patients with ICDs in situ was good. The natural history of ARVC is diverse; sustained VT/VF can occur at any time during the course of the disease. It was difficult to predict appropriate ICD therapy triggered through sustained VT/VF. Malignant ventricular arrhythmia was not rare even more than 2 years after ICD implantation. Patients without broad precordial TWI had a much shorter survival time without appropriate ICD intervention. These results have provided insight into the diagnosis, management, and long‐term clinical course of ARVC patients with a high risk of SCD in this geographic area, and complement the existing data concerning the important role of ICD in the treatment of ventricular tachyarrhythmia in ARVC.

4.1. Recurrence of ventricular arrhythmia

The recurrence of sustained VT/VF is frequent in ARVC patients complicated by ventricular tachyarrhythmia or apparent morphological changes in RV, and ICD can terminate these arrhythmia effectively. Previous studies have suggested that, during a mean follow‐up of 32 to 89 months, the rate of ICD therapy ranged from 40.4% to 78.6%.10, 11, 12, 13, 14 The incidence of appropriate ICD firing (71.8%) observed in the current study is consistent with previous data (median follow‐up 48.6 months).

Clinical presentation and progression of the disease may vary greatly among patients, causing differences in the time, frequency, and intensity of the recurrence of sustained VT/VF. One multicenter study carried out by Corrado et al demonstrated that the interval between ICD implantation and the first appropriate therapy ranged from 2 months to 8 years; 6.8% patients (9 patients) had their initial appropriate treatment at least 4 years after the implantation of an ICD.10 Roguin et al also reported that the first appropriate ICD therapy occurred in the range of 1 week to 66 months after the initial implantation procedure, and the interval without appropriate ICD intervention was 2 or more years in 19% of the patients in that study (8 patients).11 In the current study, 15.4% patients (6 patients) experienced their first appropriate ICD firing more than 2 years since implantation, and the VF episode that triggered the shock therapy was the first ventricular arrhythmia in 2 of these patients. As the follow‐up time was shorter for patients without appropriate ICD intervention, the occurrence of sustained VT/VF could not be precluded for these patients. All these data suggest that an ICD should be replaced promptly once the elective replacement indicator is reached for ARVC patients at high risk of ventricular arrhythmia.

TWI ≥ V1–V3 is an important sign used in diagnosis, reflecting abnormalities in ventricular repolarization.9, 15, 16 Previous studies have demonstrated that TWI in multiple precordial leads is an independent predictor of arrhythmic events in patients with ARVC.17, 18, 19 In the current study, no significant difference in the cumulative survival rate was seen between patients with TWI ≥ V1–V3 and those without. However, survival time free of appropriate ICD therapy was significantly reduced in patients with limited repolarization abnormalities, suggesting a much more unstable condition of cardiac muscle.

Previous studies have demonstrated that the extent of precordial T‐wave inversion might represent the progression of the disease.20, 21 Other studies have also suggested that disease‐causing mutations might influence the characteristics of an electrocardiogram.22 Thus, patients who do not have TWI in broad precordial leads but have suffered sustained VT/VF may be at the early stage of the disease or carrying specific disease‐causing genes. Further studies are needed to better understand the association between genotype, phenotype, and risk of SCD of this disease.

4.2. Limitations

This is an observational study, and some data were collected retrospectively. However, prospective randomized control studies are not practical because the prevalence of the disease is low and the risk of SCD is high. As the number of patients in the current study was small, and the follow‐up time for some of these patients was relatively short, this may confound the effect of our study. Furthermore, most of the participants in this study had an ICD implanted for secondary prevention of SCD, and this may indicate referral bias and add some limitation to our study. In addition, the patients acceptance of ICD implantation and other socioeconomic factors may influence the clinical decision making regarding ICD implantation.

5. CONCLUSION

The clinical courses of ARVC vary greatly among patients, and sustained VT/VF can occur at any time during the disease course. Long‐term prognosis tends to be favorable for high‐risk patients who receive ICDs for prevention of SCD.

Conflicts of Iinterest

The authors declare no potential conflict of interests.

Yin K, Ding L, Li Y and Hua W. Long‐term follow‐up of arrhythmogenic right ventricular cardiomyopathy patients with an implantable cardioverter‐defibrillator for prevention of sudden cardiac death, Clin Cardiol, 2017. doi: 10.1002/clc.22648