Author + information
- Received April 6, 2011
- Revision received June 9, 2011
- Accepted June 27, 2011
- Published online September 27, 2011.
- Aditya Bhonsale, MD,
- Cynthia A. James, PhD,
- Crystal Tichnell, MS,
- Brittney Murray, MS,
- Dmitri Gagarin, MD,
- Binu Philips, MD,
- Darshan Dalal, MD,
- Ryan Tedford, MD,
- Stuart D. Russell, MD,
- Theodore Abraham, MD,
- Harikrishna Tandri, MD,
- Daniel P. Judge, MD and
- Hugh Calkins, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Hugh Calkins, Carnegie 530, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287
Objectives The purpose of this study was to define the incidence and predictors of implantable cardioverter-defibrillator (ICD) therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) after placement of an ICD for primary prevention.
Background Patients with a diagnosis of ARVD/C often receive an ICD for prevention of sudden cardiac death.
Methods Patients (n = 84) from the Johns Hopkins registry with definite or probable ARVD/C who underwent ICD implantation for primary prevention were studied. Detailed phenotypic, genotype, and ICD event information was obtained and appropriate ICD therapies were adjudicated based on intracardiac electrograms.
Results Over a mean follow-up of 4.7 ± 3.4 years, appropriate ICD therapy was seen in 40 patients (48%), of whom 16 (19%) received interventions for potentially fatal ventricular fibrillation/flutter episodes. Proband status (p < 0.001), inducibility at electrophysiologic study (p = 0.005), presence of nonsustained ventricular tachycardia (p < 0 .001), and Holter premature ventricular complex count >1,000/24 h (p = 0.024) were identified as significant predictors of appropriate ICD therapy. The 5-year survival free of appropriate ICD therapy for patients with 1, 2, 3, and 4 risk factors was 100%, 83%, 21%, and 15%, respectively. Inducibility at electrophysiologic study (hazard ratio: 4.5, 95% confidence interval: 1.4 to 15, p = 0.013) and nonsustained ventricular tachycardia (hazard ratio: 10.5, 95% confidence interval: 2.4 to 46.2, p = 0.002) remained as significant predictors on multivariable analysis.
Conclusions Nearly one-half of the ARVD/C patients with primary prevention ICD implantation experience appropriate ICD interventions. Inducibility at electrophysiologic study and nonsustained ventricular tachycardia are independent strong predictors of appropriate ICD therapy. An increase in ventricular ectopy burden was associated with progressively lower event-free (appropriate ICD interventions) survival. Incremental risk of ventricular arrhythmias and ICD therapy was observed with the presence of multiple risk factors.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized predominantly by ventricular arrhythmias, increased risk of sudden cardiac death (SCD), and right ventricular dysfunction (1–3). After a diagnosis of ARVD/C is established, the most important management decision is whether to implant an implantable cardioverter-defibrillator (ICD) for treatment of sustained ventricular arrhythmias and prevention of SCD. This is a critically important decision because these are young patients with few or no symptoms who are expected to live many years with a device that is not complication free. It is now standard practice for ARVD/C patients presenting with sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) to undergo placement of an ICD because of a high risk of recurrent VT and/or SCD (4–6). In contrast, there is much more uncertainty regarding which patients who have not had a previous sustained ventricular arrhythmia should have an ICD placed for primary prevention (7).
The objectives of this study were 3-fold. First, we sought to better define the incidence of appropriate ICD therapy as well as potential lifesaving therapy against VF/ventricular flutter (VFL) in patients with definite or probable ARVD/C undergoing ICD implantation for primary prevention. Second, we sought to identify which clinical and electrophysiologic factors best identify patients at highest risk of sustained VT or sudden death. Third, we sought to identify a subgroup of patients with definite or probable ARVD/C who are at sufficiently low risk that placement of an ICD as part of a primary prevention strategy may not be needed. We relied on the 2010 Task Force Criteria (TFC) (8) to establish the diagnosis of ARVD/C. Particular attention was focused on determining the influence of genotype, incremental role of multiple risk factors, as well as the relative risk of probands versus family members in the development of sustained ventricular arrhythmia.
Patient population and follow-up
The Johns Hopkins ARVD/C Program was established in 1995 to provide clinical care for patients with ARVD/C and to study this disease. All those in the registry who had implantation of an ICD for primary prevention of sudden death, a follow-up period of at least 2 months after implantation of the device, and documentation of clinical outcomes were included in the study. All subjects gave written informed consent to participate in this study, which was approved by The Johns Hopkins School of Medicine Institutional Review Board. Detailed clinical information regarding demographics, symptoms, electrocardiographic abnormalities on a 12-lead electrocardiogram, signal-averaged electrocardiographic testing, 24-h Holter monitoring, exercise stress testing, and arrhythmia occurrence was obtained for each patient. Echocardiographic and magnetic resonance imaging reports were obtained, and images were reviewed for structural abnormalities to determine the severity and extent of right ventricular dysfunction. Right ventricular angiography and/or endomyocardial biopsy were performed per the discretion of the managing cardiologist. Programmed ventricular stimulation was performed according to each referring institution's protocol. Electrophysiologic study (EPS) was deemed inducible if a sustained ventricular tachyarrhythmia—VT or VF that lasted >30 s or required termination because of hemodynamic compromise was induced. A detailed family history was obtained through patient interview for pedigree analysis, and comprehensive desmosomal mutation testing was performed for those patients whose DNA sample was available (9).
Patients were followed at yearly intervals as part of the Johns Hopkins registry, and data including invasive and noninvasive investigations, pedigree, device interrogation, and stored electrograms were obtained from referring institutions and individual patients throughout the duration of follow-up. In patients without an ICD intervention, follow-up was to the date of death, transplantation, or most recent follow-up evaluation, whichever came first. Of the 84 study patients, 28 were included in an earlier investigation (10) and are reported with extended follow–up.
Diagnosis of ARVD/C
The diagnosis of ARVD/C is based on the presence of major and minor diagnostic criteria according to the 2010 revised TFC (8). The patients were classified as having a diagnosis of definite ARVD/C when they met the full criteria (2 major criteria or 1 major criterion plus 2 minor criteria or 4 minor criteria). Probable ARVD/C was considered present when only partial fulfillment of the criteria was met (i.e., 1 major and 1 minor or 3 minor). Each of the patients with probable ARVD/C in this study had received an ICD after diagnosis of ARVD/C by their primary cardiologist and/or electrophysiologist.
ICDs and classification of discharges
All patients received multifunctional third- or fourth-generation ICDs between May 1995 and June 2010. Decisions regarding ICD implantation were made by the managing cardiovascular specialists. Stored intracardiac electrograms were analyzed to classify arrhythmias responsible for precipitating defibrillator discharges, according to following definitions (11). VF or VFL was defined as an irregular or regular tachycardia with a mean cycle length (CL) of ≤240 ms. VT was defined as a regular tachycardia with mean CL >240 ms. Defibrillator shocks were considered appropriate versus inappropriate on the basis of standard criteria (2). When complete ICD interrogation information was not available, ICD interrogation interpretation by the outside referring electrophysiologist was used to classify arrhythmic events.
Syncope was defined as a transient loss of consciousness and postural tone with spontaneous recovery. For purposes of our analysis, the term syncope was not used if the clinical characteristics of a patient's syncopal episode were suggestive of reflex-mediated or vasodepressor syncope. Although we considered referring to this type of syncope as cardiac syncope, we preferred to use the term syncope and clarify this important distinction in the definitions section. Nonsustained ventricular tachycardia (NSVT) was defined as ≥3 consecutive ventricular premature beats with a rate >100 beats/min, lasting <30 s, which was documented during exercise testing, loop monitoring, or 24-h Holter monitoring. Electrical or VT storm was defined as the occurrence of VT or VF that resulted in ≥3 ICD interventions (shock or antitachycardia pacing) in a 24-h period (12).
Survival data and statistical analyses
Continuous variables are summarized as either mean ± SD or median (interquartile range) and compared across groups using a t test or Mann-Whitney U test. Categorical variables are reported as frequency (percentage) and compared between groups by the chi-square or Fisher exact test. The cumulative probability of survival free of appropriate ICD intervention was determined by the Kaplan-Meier method, and differences in survival between groups evaluated with the log-rank test. Univariate Cox regression analysis identified baseline variables that were significantly associated with appropriate ICD therapy. Significantly associated variables (p < 0.15) were integrated into multivariable analysis using the Cox proportional hazard model to identify independent predictors of appropriate ICD intervention. All analyses were performed using PASW statistics version 18.0 (SPSS Inc., Chicago, Illinois). A p value <0.05 was considered significant.
The patient population consisted of 84 ARVD/C patients who received an ICD for primary prevention of SCD. Seventy patients met the revised TFC (8) for ARVD/C and received a diagnosis of definite ARVD/C, and 14 patients received a diagnosis of probable ARVD/C. The mean age at presentation was 31.9 ± 11.9 years (range 11 to 59 years) (Table 1), with two thirds of the cohort being younger than 40 years at initial evaluation. Thirty-nine patients (46%) were males. Fifty-four patients (64%) were probands (an affected person ascertained independently of family history of ARVD/C), whereas the rest were family members (affected individuals ascertained through family screening).
Genetic testing was performed in 63 patients, and pathogenic desmosomal mutations were detected in 36 (43%). An EPS was performed in 72 patients before ICD implantation, and inducibility of sustained VT/VF was observed in 40 patients (48%). The mean CL of the induced VT was 257 ± 54 ms (range 170 to 404 ms). Holter monitoring was performed in 65 patients and >1,000 premature ventricular complexes (PVCs)/24 h were seen in 39 (60%). NSVT on exercise stress testing, Holter monitoring, or loop monitors was seen in 41 patients (49%). At the time of ICD implantation, one third of the patients were using beta-blockers with 3 (4%) receiving antiarrhythmic agents (Table 2). No significant phenotypic or outcome differences were observed between those with and without the testing (Online Tables 1 to 3).
A single-chamber device was implanted in 56 patients (67%) and a dual-chamber device in 28 patients (33%). The mean age at ICD implantation was 35.1 ± 11.4 years (range 13 to 59 years) (Fig. 1A). The mean R-wave amplitude was 9.4 ± 4.9 mV (range 3 to 30 mV), with 12 patients exhibiting R-wave amplitudes <5 mV (range 3 to 4.8 mV). Appropriate sensing was achieved in all patients at the time of device implantation. The mean defibrillation threshold was 15.7 ± 6.5 J (range 5 to 35 J). Twenty patients (24%) had device-related complications during long-term follow-up including pocket hematoma (n = 2), pocket infection (n = 1), lead dislodgment (n = 2), subclavian vein occlusion (n = 2), lead fracture (n = 1), lead revision (n = 4), lead recall (n = 3), lead replacement due to sensing problem (n = 3), generator explantation due to infection (n = 1), and dual-chamber upgrade due to conduction abnormalities (n = 1).
ICD therapy and follow-up
Over a mean follow-up of 4.7 ± 3.4 years, 40 (48%) of the 84 patients with definite or probable ARVD/C had received appropriate ICD therapy. The mean CL of the arrhythmia at the first appropriate event was 265 ± 35 ms (range 210 to 360 ms). Patients with a diagnosis of probable ARVD/C experienced appropriate ICD interventions in comparable proportion to those with a definite diagnosis (8) (46% vs. 57%; p = 0.434). The median time from ICD implantation to first appropriate therapy was 0.54 years (range 0.02 to 5.4 years). The majority (55%) of appropriate interventions occurred within 1 year of ICD implantation; however, 6 patients (7%) had initial therapy 3 or more years after implantation (Fig. 1B). The median number of appropriate ICD intervention during follow-up was 5.5 (range 1 to 72), with 1 patient receiving >50 interventions (Fig. 1C). Twenty-five patients (63%) were engaged in exertional or recreational activity at the time of first appropriate shock, whereas 10 (25%) were sedentary. VT storms were seen in 16 patients (19%) with 10 (12%) having 1 VT storm, 4 (5%) having 2 episodes, and 2 (2%) experiencing 3 storm episodes. The mean duration from ICD implantation to the first VT storm was 3.4 ± 2.6 years (range 0.18 to 10.6 years).
Overall, the cumulative survival free of appropriate ICD therapy was 73%, 64%, 42%, and 37%, respectively at 1, 2, 5, and 10 years of follow-up (Fig. 2A). The average yearly rate of appropriate ICD interventions for the overall population was 10%. Probands demonstrated a higher event rate (13%/year) compared with family members (3.4%/year). On Kaplan-Meier analysis, no significant event-free survival difference was detected between definite and probable patients. Patients with appropriate ICD interventions had significantly longer follow-up (5.9 ± 3.5 years vs. 3.6 ± 2.9 years; p = 0.001), were more often symptomatic at presentation (90% vs. 64%; p = 0.005), and had a higher median PVC burden on Holter monitoring (4,397 vs. 1,027; p = 0.001). Inappropriate shocks were seen in 20 patients (24%). The median time to first inappropriate shock was 1.3 years (range 0.09 to 9.13 years). One third of these events occurred within 1 year of ICD implantation, with 89% occurring within 5 years of implantation. The inappropriate discharges were due to sinus tachycardia (n = 8), another type of supraventricular arrhythmia (n = 5), and electrical noise (n = 2) due to lead problems.
An appropriate ICD intervention for VF/VFL was seen in 16 patients (19%), of whom probands constituted 15 (94%) and 1 patient was a family member (p < 0.001). The mean CL of the first VF/VFL episode was 222 ± 13 ms (range 200 to 240 ms), and the median duration between implantation and first ICD intervention triggered by VF/VFL was 1.5 years (range 0.05 to 7 years). The cumulative survival free of appropriate ICD therapy for VF/VFL was 93%, 87%, 79%, and 68% at 1, 2, 5, and 10 years, respectively (Fig. 2B). The average rate of ICD interventions for VF/VFL was 4%/year. The estimated mortality reduction at 1, 5, and 10 years of follow-up was 6%, 18%, and 29% (i.e., the difference between actual patient survival rate of 99%, 97%, and 97%, respectively, at those times and comparable VF/VFL-free survival).
Forty-four patients (52%) had no ICD interventions. At last follow-up, 82 patients (98%) were alive, 1 patient died of a brain tumor, and another died of complications after a heart transplantation. Seven patients underwent heart transplantation due to progressive heart failure and/or incessant arrhythmias. The mean duration from ICD implantation to transplantation was 6.8 ± 4.1 years (range 1.5 to 13.2 years).
Predictors of appropriate ICD therapy
Shown in Table 3 are the variables analyzed as potential predictors of appropriate ICD interventions. Univariate predictors of appropriate ICD therapy were proband status (hazard ratio [HR]: 6.4; 95% confidence interval [CI]: 2.3 to 18.2; p < 0.001), the presence of NSVT (HR: 3.8; 95% CI: 1.9 to 7.6; p < 0.001), inducibility at EPS (HR: 3.1; 95% CI: 1.4 to 6.9; p = 0.005), and Holter PVC count >1,000/24 h (HR: 3.1; 95% CI: 1.1 to 8.3; p = 0.024). NSVT (HR: 10.54; 95% CI: 2.40 to 46.18; p = 0.002) and inducibility at EPS (HR: 4.5; 95% CI: 1.37 to 14.96; p = 0.013) alone remained as significant predictors of appropriate ICD interventions on multivariable analysis. Shown in Figure 3 is the Kaplan-Meier analysis of freedom from any appropriate ICD intervention stratified by inducibility at EPS, NSVT, PVCs >1,000 on 24-h Holter monitoring, and proband status. The positive predictive value (PPV) and the negative predictive value (NPV) of EPS inducibility were 65% and 75%, respectively, for appropriate ICD therapy. In probands, the PPV increased to 73%, whereas in family members, an NPV of 88% was seen. Also, the cumulative survival rate free of appropriate ICD therapy at 10 years was significantly higher (64%) in those noninducible at EPS compared with those inducible (23%). Among inducible patients, 10 (25%) experienced appropriate ICD interventions for VF/VFL, whereas only 1 of the 32 noninducible patients (3%) had such ICD therapy for VF/VFL, providing a high NPV of 97%. None of the 18 family members with negative findings on EPS in our study experienced a VF/VFL episode.
The presence of NSVT had a sensitivity, specificity, PPV, and NPV of 70%, 70%, 68%, and 72%, respectively, for appropriate ICD therapy. Among family members, the NPV was 95%, with only 1 of the 20 patients without NSVT experiencing an appropriate shock. None of the 13 family members with a PVC count <1,000/24 h received appropriate ICD therapy, providing this criterion with an NPV of 100%. As shown in Figure 4, a higher PVC burden on Holter monitoring was associated with an increasing proportion of patients experiencing appropriate ICD interventions and a lower cumulative event-free survival rate.
Relationship between the number of risk factors and appropriate ICD therapy
Fifty-four patients had evaluation of all 4 major risk factors identified (inducibility at EPS, NSVT, Holter monitoring PVC count >1,000/ 24 h, and proband status). The numbers of patients with 0, 1, 2, 3, and 4 risk factors were 7 (8%), 8 (10%), 13 (16%), 17 (20%), and 9 (11%), respectively. Appropriate ICD therapy occurred in 0 (0%), 0 (0%), 3 (23%), 11 (65%), and 7 (78%) patients in each group, respectively. Patients with no or 1 risk factor had no events, and patients with multiple risk factors had a substantially increased risk of appropriate ICD therapy (Fig. 5). The 5-year survival rate free of appropriate ICD therapy for patients with 1, 2, 3, and 4 risk factors was 100%, 83%, 21%, and 15%, respectively.
This study reports the outcome of a large North American cohort of 84 patients with definite or probable ARVD/C who received ICD implantation for primary prevention of SCD. This study has 4 main findings. First, the results of this study reveal a high rate of appropriate ICD therapy in this patient population. Nearly one-half of the patients experienced appropriate ICD therapy with one fifth receiving potentially lifesaving therapy for VF/VFL during an average of 4.7 years of follow-up. Second, our study identifies clinical variables: inducibility at EPS, the presence of NSVT, proband status, and Holter monitoring PVC count >1,000/24 h as significant predictors of appropriate ICD therapy. Third, the results of this study show that the presence of multiple risk factors incrementally increases the likelihood of appropriate ICD therapy with mutation status, electrocardiographic and major structural abnormalities not affecting this risk. Patients, especially family members with none of these markers, appear to be at low risk of life-threatening ventricular arrhythmias. Finally, this investigation reveals that an increase in ventricular ectopy burden is associated with progressively increasing risk of appropriate ICD interventions and a lower event-free survival rate.
ARVD/C is an uncommon but important cause of SCD because most of these individuals are young. It is estimated that it accounts for one fifth of all episodes of SCD that occur in patients younger than the age of 35 years (13). During the past decade, 4 studies, predominantly in patients with sustained VT/VF, have demonstrated the efficacy of ICD therapy and its impact on SCD prevention. These studies have included, in varying proportions (7% to 73%), primary prevention patients with overall rates of ICD therapy ranging from 48% to 70% (4–6,14). Similar rates of appropriate (14) and lifesaving therapy (10) in patients receiving ICDs for primary and secondary prevention indications have been reported, underscoring the considerable potential arrhythmic risk among recipients of prophylactic ICD. Only 1 recent study of largely European patients examined the role of prophylactic ICD therapy in primary prevention of SCD (15). In this study by Corrado et al. (15), 106 ARVD/C patients without previous sustained VT or VF were studied over a mean follow-up of 58 months. Twenty-five patients (24%) had appropriate ICD interventions, and 17 (16%) experienced shocks for life-threatening VF or VFL, with syncope emerging as the sole predictor of ICD therapy. Taken together, these studies suggest that ICD therapy has an important role in the primary prevention of SCD in patients with ARVD/C.
VT/VF in ARVD/C
The results of the present study confirm and extend the results of these previous investigations. In our study, over approximately 5 years of follow-up, appropriate ICD therapy was observed in nearly one-half of the study patients. This high cumulative incidence of appropriate ICD interventions likely reflects the clinical characteristics of the population (probands vs. family members), minimal prophylactic use of antiarrhythmic agents and beta-blockers, and the intrinsic arrhythmic potential among ARVD/C patients. As in the study by Corrado et al. (15), the estimate of the potential survival benefit of ICD was limited to appropriate ICD therapies for episodes of VF/VFL. In our study, appropriate therapy for VF/VFL was seen in nearly one-fifth of the patients, with an estimated survival benefit of 19% seen at 5 years of follow-up. This was similar to the 23% reduction seen by Corrado et al. (15) and comparable to that observed in large ICD primary prevention studies for CAD like the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial) (16) (28%, 2 years) and SCD-Heft (Sudden Cardiac Death in Heart Failure Trial) (16) (23%, 5 years). The annual rate of appropriate therapy for VF/VFL in our study was 4%, which is remarkably similar to the 3.3% rate seen by Corrado et al. (15), confirming the lifesaving efficacy of prophylactic ICD therapy.
Predictors of appropriate ICD therapy
Inducibility at EPS
The results of our study show that inducibility at EPS is a significant, strong predictor of appropriate ICD therapy in primary prevention ARVD/C patients with a significantly worse event-free survival rate in those inducible. Additionally, its NPV is considerable, especially in family members. In contrast, in the study by Corrado et al. (15), EPS inducibility did not seem to affect the risk in the survival analysis and provided a 35% PPV and a 70% NPV. A higher event rate among our study population as well as population characteristics unique to each study could potentially explain this difference. We do recognize that the predictive value (both positive and negative) of this test is not perfect and that a certain proportion experienced ICD interventions even with a test with negative findings. However, our study shows that multiple factors contribute to the occurrence of arrhythmias in ARVD/C patients and that EPS inducibility contributes to their overall risk assessment. Most importantly, EPS inducibility when used in conjunction with other risk factors and as part of an additive scheme as proposed in this paper can provide considerable prognostic information for the physician.
In the study by Corrado et al. (15), asymptomatic patients with NSVT presented a trend toward an increased arrhythmic risk and NSVT reached borderline significance as a predictor of appropriate ICD therapy. They had an overall rate of appropriate ICD intervention of 3.7%/year and a rate of appropriate ICD intervention against VF/VFL of 1.48%/year. In our study, NSVT was identified as an independent predictor of appropriate ICD therapy. Patients with NSVT had somewhat higher (6%/year) appropriate discharge rate and a 2%/year VF/VFL rate. The presence of NSVT was associated with a higher cumulative appropriate shock rate in both probands (p = 0.034) and family members (p = 0.009) and in both older (older than 30 years; p = 0.006) and younger (younger than 30 years; p = 0.002) patients, implying a comprehensive prognostic role for the presence of NSVT in clinical situations. In nonischemic as well as ischemic cardiomyopathies, NSVT has similarly been seen to be an independent predictor of appropriate ICD therapy (17). In hypertrophic cardiomyopathy, NSVT has also proved to be a significant independent risk factor for SCD, especially in the young (18).
In our study, proband status was a predictor of appropriate ICD therapy. Thirty-six probands (90%) had appropriate ICD intervention compared with only 4 family members (9%) who received ICD therapy. Of the 4 family members with appropriate ICD therapy, 1 had EPS inducibility, whereas the other 3 had the presence of NSVT and/or PVC count >1,000/24 h on Holter monitoring. All had pathogenic mutations and were phenotyped definite per new TFC (8). Only 1 family member experienced appropriate therapy for VF/VFL during the follow-up. This was a 45-year-old asymptomatic Caucasian male with PKP-2 mutation who had an ICD implanted due to family history of ARVD/C in his brother and abnormal findings on magnetic resonance imaging demonstrating major structural abnormalities with NSVT and substantial PVCs (2,505) on 24-h Holter monitoring. Within 6 months of ICD implantation, he experienced an appropriate shock (CL 240 ms) while exercising. This observation is consistent with the recent finding by Corrado et al. (15) and previous large family studies (19) in which probands have shown considerable arrhythmic and symptom manifestation, whereas the majority of affected ARVD/C relatives are likely to have a benign course. In our study, no family member experienced any VT storm, underwent cardiac transplantation, or died.
Our study identified that a Holter monitoring PVC count >1,000/24 h was significantly associated with higher cumulative ICD therapy. Uniquely, the proportion of patients receiving appropriate ICD therapy increased progressively with increasing PVC burden. Patients with a higher PVC count had a significantly lower event-free survival rate and increased probability of appropriate ICD therapy. The prognostic role of frequent ventricular ectopy in predicting SCD although a new concept in ARVD/C, has been seen in large coronary artery disease trials and nonischemic cardiomyopathy as well, providing evidence of its potential role (20). Our data suggest that this frequent manifestation of ARVD/C may be a marker for electrical instability culminating in more malignant ventricular arrhythmias over time.
The role of clinical and electrophysiologic characteristics in predicting appropriate ICD interventions in ARVD/C patients has been unclear. As a result, the criteria for optimal selection of ARVD/C patients who will benefit from prophylactic ICD implantation are undefined. The results of the present study provide new insight into risk stratification of ARVD/C patients before ICD implantation for primary prevention of SCD. The presence a proband status, >1,000 PVCs, NSVT, and inducible VT at EPS identified ARVD/C individuals at high risk of appropriate therapy. Assuming our findings are confirmed by others, we propose that these risk factors be referred to as the PONI (Proband status, more than One thousand extrasystoles, Nonsustained VT and Inducible VT at EPS) risk stratification scheme. Our study demonstrates for the first time that a combination of these 4 risk factors portends incremental risk and can be used to risk-stratify patients. The presence of 2, 3, or 4 risk factors is associated with an escalating ICD event rate. On the other hand, ARVD/C patients with no or 1 risk factor did not receive any appropriate ICD intervention during follow-up and appear to be at very low risk of the development of a sustained ventricular arrhythmia or SCD. Therefore, given the concomitant risk of inappropriate shocks and lead-related complications, these patients may not be candidates for prophylactic ICD implantation. This additive risk factor scheme is particularly significant for clinical management and arrhythmic risk stratification of asymptomatic ARVD/C relatives and genotype-positive family members who may only manifest ventricular ectopy with minimal ARVD/C phenotype.
In contrast to the study by Corrado et al. (15), a history of syncope was seen less often (27% vs. 39%) in our cohort. Also, unlike that study, the majority (75%) of patients receiving appropriate ICD therapy did not have a history of syncope. Despite these differences, nearly one-half of the patients with syncope in our study experienced appropriate ICD therapy at a comparably high rate (9%/year). Importantly, significantly more patients with recent unexplained syncope (<6 months before ICD implantation) experienced ICD interventions than those with remote syncope (63% vs. 20%; p = 0.046), none of whom experienced potentially fatal VF/VFL. Our data suggest that absence of syncope does not confer protection from the risk of appropriate ICD therapy due to the presence of multiple other risk factors. Furthermore, it did not emerge as an independent predictor of ICD therapy. On the other hand, the presence of syncope was associated with similar high rates of appropriate ICD therapy, as seen in the study by Corrado et al. (15). More importantly, a history of recent syncope suggests a higher risk of ventricular arrhythmias and should prompt consideration for ICD therapy.
There are several limitations to consider when interpreting the results of this study. The survival benefit of ICD therapy was assessed by assuming that VF/VFL would have been fatal in all cases without shock therapy. Because even very rapid ventricular tachyarrhythmia may self-terminate before death, the use of appropriate ICD shocks for VF/VFL as a surrogate for SCD may have led to an overestimation of survival benefit from ICD. These patients were clinically judged to have a high arrhythmic risk to warrant prophylactic ICD therapy. Therefore, the reported rate of arrhythmic events does not necessarily correspond to the true arrhythmic risk of an unselected general cohort of ARVD/C patients, which is likely characterized by lower mortality rates (3,19). Second, we did not have complete information on the CL of treated arrhythmias in all patients. When intracardiac tracing were unavailable for review, we relied on the interpretation of the treating electrophysiologist with regard to the appropriateness of the ICD intervention. Third, not all patients had EPS or Holter monitoring performed before ICD implantation. This could potentially introduce bias due to missing data and affect the precision of the HR estimates with resultant wide CIs due to a reduced number during multivariable modeling. Nonetheless, we believe that our study results and analysis indicate important clinically relevant associations for arrhythmic risk stratification and management of ARVD/C patients. Fourth, decisions about device programming including VT detection were made at the discretion of the patient's clinical electrophysiologist. Last, potentially lethal arrhythmic manifestations of ARVD/C are often unpredictable, and a mean follow-up of half a decade may not be enough to generalize predictions regarding the low-risk nature of certain ARVD/C patients to their entire lifetime. However, the observation that appropriate ICD therapy is received early after implantation in high-risk ARVD/C patients coupled with electrical quiescence of the low-risk group during this period makes it plausible that this reflects their long-term course.
This study represents an important step in understanding the incidence of ICD interventions, identifying predictors of appropriate ICD therapy, and developing a risk stratification scheme in ARVD/C patients undergoing primary prevention ICD implantation. Patients receiving ICD implantation for primary prevention of SCD experience a considerable amount of appropriate ICD interventions with an appreciable estimated survival benefit. Probands are more often symptomatic and are at higher arrhythmic risk than family members, the majority of whom are asymptomatic and at low risk of ICD therapy. Inducibility at EPS and the presence of NSVT are independent predictors of appropriate ICD therapy in this population. These markers coupled with proband status and a high ventricular ectopy burden on 24-h Holter monitoring can be used to risk-stratify ARVD/C patients before ICD implantation. Patients with multiple risk factors are at considerable risk of future appropriate ICD therapy and benefit from ICD implantation, whereas those with no or 1 risk factor may not be candidates. The results of this study combined with the results of recently published study (15) add to the growing evidence of ICD therapy in primary prevention of SCD in ARVD/C patients. There exists a need for larger prospective studies of arrhythmic outcomes among ARVD/C patients with prophylactic ICD to determine the long-term validity of these predictive markers.
The authors are grateful to the ARVD/C patients and families who have made this work possible.
For supplemental tables, please see the online version of this article.
Funding for this study has been received from the National Heart, Lung, and Blood Institute (K23HL093350 to Dr. Tandri), the St. Jude Medical Foundation, Medtronic Inc., and Boston Scientific Corp. The Johns Hopkins ARVD/C Program is supported by the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, and Wilmerding Endowments, and the Dr. Francis P. Chiaramonte Private Foundation. Dr. Dalal is an employee of Genentech Inc. Dr. Tedford has received a Fellow's Travel Grant from Medtronic. Dr. Calkins receives research support from Boston Scientific Corp., Medtronic Inc., and St. Jude Medical Foundation and is a consultant for Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
- confidence interval
- cycle length
- electrophysiologic study
- hazard ratio
- implantable cardioverter-defibrillator
- negative predictive value
- nonsustained ventricular tachycardia
- positive predictive value
- premature ventricular complex
- sudden cardiac death
- Task Force Criteria
- ventricular fibrillation
- ventricular flutter
- ventricular tachycardia
- Received April 6, 2011.
- Revision received June 9, 2011.
- Accepted June 27, 2011.
- American College of Cardiology Foundation
- Marcus F.I.,
- Fontaine G.H.,
- Guiraudon G.,
- et al.
- Blomstrom-Lundqvist C.,
- Sabel K.G.,
- Olsson S.B.
- Wichter T.,
- Paul M.,
- Wollmann C.,
- et al.
- Corrado D.,
- Leoni L.,
- Link M.S.,
- et al.
- Roguin A.,
- Bomma C.S.,
- Nasir K.,
- et al.
- Wichter T.,
- Breithardt G.
- Marcus F.I.,
- McKenna W.J.,
- Sherrill D.,
- et al.
- den Haan A.D.,
- Tan B.Y.,
- Zikusoka M.N.,
- et al.
- Credner S.C.,
- Klingenheben T.,
- Mauss O.,
- Sticherling C.,
- Hohnloser S.H.
- Calkins H.,
- Marcus F.
- Hodgkinson K.A.,
- Parfrey P.S.,
- Bassett A.S.,
- et al.
- Corrado D.,
- Calkins H.,
- Link M.S.,
- et al.
- Monserrat L.,
- Elliott P.M.,
- Gimeno J.R.,
- Sharma S.,
- Penas-Lado M.,
- McKenna W.J.
- Nava A.,
- Bauce B.,
- Basso C.,
- et al.
- Maggioni A.P.,
- Zuanetti G.,
- Franzosi M.G.,
- et al.