There are no conflicts of interest involved other than research grants to the institution from Medtronic, Biotronik, St. Jude and Boston Scientific not directly related to this project. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: PS FD. Analyzed the data: PS CB FT RJ TL FD. Wrote the paper: PS LH AS TW CB NC. Data acquisition, statistics: PS.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC.
A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation.
Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy.
In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable cardiomyopathy with typically autosomal dominant inheritance pathologically characterized by progressive fibrofatty replacement of the right ventricular myocardium. This type of cardiomyopathy is a major cause of sudden cardiac death in young adults and athletes
Implantable cardioverter defibrillators (ICD) are increasingly utilized in patients with ARVC who have survived SCD or have developed ventricular tachyarrhythmias associated with syncope
Patients who were diagnosed with ARVC at the University Hospital of Zurich (Switzerland) based on the Task Force Criteria and in whom an ICD was implanted were enrolled in the study
The presence and nature of symptoms were collected at the time of ARVC diagnosis. In addition, patient charts were meticulously screened for past history of heart failure, which was defined by the presence of the following clinical features: symptoms of heart failure described typically by shortness of breath according to the New York Heart Association (NYHA) functional classification and/or fatigue; physical signs of fluid retention, such as pulmonary congestion or ankle swelling; and objective evidence of a structural or functional cardiac abnormality as cardiomegaly, third heart sound, abnormality on the echocardiogram, and elevated natriuretic peptide concentration.
Transthoracic echocardiograms were performed by an experienced operator in a standard fashion by two dimensional and Doppler echocardiography and M-mode measurements
A cardioversion/defibrillation therapy or anti-tachycardia pacing for a ventricular arrhythmia faster than the programmed detection rate and accurately detected by the ICD, and confirmed by an experienced electrophysiologist at the University Hospital Zurich, was categorized as an appropriate ICD therapy (
A sustained monomorphic ventricular tachycardia with a rate of 250 beats/min is appropriately detected by he device and terminated by an appropriate shock (30.3 Joule).
A standardized ventricular stimulation protocol was performed in 16 patients out of 26 patients (62%) in the absence of antiarrhythmic drugs. The protocol consists in the delivery of up to three extrastimuli at three different basic drive train cycle lengths and ventricular burst pacing at two right ventricular sites (right ventricular apex and right ventricular outflow tract). Sustained ventricular tachycardia (VT) was defined as tachycardia of ventricular origin with a duration of more than 30 seconds or ventricular tachycardia leading to hemodynamic compromise.
Continuous variables were summarized as median (range or interquartile range, as stated) since these mostly had skew distributions. Logistic models were used to estimate the odds associated with ICD therapy. Odds ratios are presented with 95% confidence intervals. Where there were zero events in some cells, the odds ratios and confidence intervals were estimated by adding 0.5 to each cell and Fishers exact testing used to assess significance. For skew data, the significance levels were also estimated using Mann-Whitney U-test between the two ICD groups.
Clinical data were collected in a total of 26 patients with ARVC (median age of 40 years at time of diagnosis, 21 males and 5 females) in whom an ICD was implanted.
Patients characteristics | Number or Median (Inter-quartile range) |
(n = 26, unless stated otherwise) | |
Men | 21 |
Family history of ARVC | 4 |
Age at diagnosis (years) | 39.5 (35.75, 48.50) |
Symptoms at time of ARVC diagnosis | |
- aborted SCD | 4 |
- syncope | 12 (n = 24) |
- heart failure | 1 (n = 25) |
- VT | 19 (n = 25) |
History of heart failure | 4 |
Arrhythmia | |
- atrial fibrillation or flutter | 3 |
- VT | 19 (n = 25) |
- others (WPW, AVNRT) | 3 |
Drug therapy | |
- betablocker | 14 |
- Amiodarone | 5 |
- ACEI or ARB | 5 |
ICD implantation | |
- primary prevention | 1 |
- secondary prevention | 25 |
- age at ICD implantation | 43.5 (36.75, 56.25) |
- time period from ARVC diagnosis to ICD | 1.5 months (2.5 days, 6.5 years) |
- Implantation | |
ICD therapy | |
- appropriate therapy | 12 |
- time from ICD implantation to first appropriate ICD therapy | 9 months (3.6, 54 months) |
(
12 out of the 26 patients (46%) received appropriate ICD therapy. The majority of the patients (n = 9) experienced the first appropriate therapy within the first 2 years after device implantation. Two patients received the first shock after 4 years, and one patient 8 years after device implantation. The median time period between the implantation of the ICD and the first appropriate ICD therapy was 9 months (range 2 months; 8 years). Multiple ICD therapies occurred in one patient due to pacing-induced ventricular proarrhythmia, which could be successfully prevented by device reprogramming.
The mean age at time of ARVC diagnosis was similar for patients with appropriate ICD therapy and patients without appropriate ICD therapy.
Clinical characteristics | ICD therapy | No ICD | Odds ration | p-value |
n = 12 | therapy n = 14 | (95% CI) | ||
Men | 11 | 10 | 4.4 (0.42, 46.3) | 0.217 |
Family history of ARVC | 1 | 3 | 0.33 (0.03, 3.72) | 0.372 |
Age at diagnosis (years) | 39.5 | 39.5 | 1.00 (0.94, 1.06) | 0.968 |
(35.0, 54.0) | (36.8, 48.5) | |||
Follow-up duration (years) | 14±10 | 9.8±9.7 | 1.01 (0.99, 1.02) | 0.202 |
Symptoms at time of | ||||
ARVC diagnosis | ||||
- aborted SCD | 3 | 1 | 4.0 (0.36, 45.1) | 0.262 |
- syncope | 3 | 9 | 0.11 (0.018, 0.7) | 0.020 |
- heart failure | 1 | 0 | 0.28 | 0.48 |
(0.01, 7.67)fis |
||||
- VT | 10 | 9 | 2.22 (0.33, 15.18) | 0.415 |
History of heart failure | 4 | 0 | 15.35 | 0.033 |
(0.73, 321.60) |
||||
Arrhythmia | ||||
- AFib or flutter | 2 | 1 | 0.60 (0.047, 7.63) | 0.694 |
- VT | 8 | 7 | 0.667 (0.13, 3.35) | 0.622 |
- Other (WPW, AVNRT) | 2 | 1 | 0.60 (0.047, 7.63) | 0.694 |
Drug therapy | ||||
- betablocker | 9 | 5 | 0.397 (0.08, 1.94) | 0.253 |
- Amiodarone | 3 | 2 | 0.227 (0.022, 2.4) | 0.217 |
- ACEI or ARB | 4 | 1 | 0.227 (0.022, 2.4) | 0.217 |
ICD | ||||
- primary prevention (vs | 0 | 2 | 2.78 (0.1, 74.7) | 0.99 |
secondary) | ||||
- time from ARVC | 3.25 | 0.06 | 0.90 (0.76, 1.06) | 0.19 (0.067 M–W) |
diagnosis to ICD | (0.06, 21.5) | (0.004, 1.23) | ||
implantation (years) | ||||
- age at time of | 52 | 39 | 1.075 | 0.063(0.053 M–W) |
implantation | (39.3, 60.5) | (34.8, 50.5) | (0.996, 1.16) |
p-values based on Fishers exact testing.
Summaries within groups are given as number with the feature for categoric variables and median (inter-quartile range) for numeric data.
(
Four patients (33%) having received ICD therapy had a previous history of heart failure, whereas none of the patients without ICD therapy during follow-up had a history of heart failure. Using Fishers exact test this difference is significant (p = 0.033) and using exact methods to create a confidence interval for the difference (4.3%, 60.9%) also excludes compatibility with zero difference. The time period elapsed between ARVC diagnosis was made and ICD implantation was different for both groups: In patients who received an appropriate ICD therapy during follow-up the ICD was implanted a median time of 3.25 years after diagnosis, while patients who did not require an ICD therapy which had the ICD inserted after a median of 3 weeks (p = 0.19; n.s.). During follow-up two patients died (due to infective endocarditis and end-stage heart failure after heart transplantation). One patient required an external biventricular assist device because of severe heart failure and one patient was lost to follow-up.
The transthoracic echocardiography revealed left ventricular involvement in 12 patients: 8 (67%) patients out of the patient group with appropriate ICD therapy compared to 4 (29%) in the group without appropriate ICD therapy (p = 0.059). The right ventricle most commonly showed the typical sites of disease predilection, which are the right ventricular apex, the inflow and outflow tracts, the so-called “triangle of dysplasia”
Echocardiographic | ICD therapy | No ICD | Odds ration | p-value |
parameters | n = 12 | therapy n = 14 | (95% CI) | |
LV involvement | 8/12 | 4/14 | 5.00 | 0.059 |
(0.942, 26.53) | ||||
LA dilatation | 3/11 | 3/11 | 1.00 | 0.99 |
(0.153, 6.531) | ||||
RA dilatation | 6/11 | 7/12 | 0.857 | 0.855 |
(0.164, 4.467) | ||||
RV aneurysm | 12/12 | 11/13 | 0.307 | 0.6513 |
(0.0054, 4.624) | ||||
RV dilatation | 7/11 | 4/13 | 3.937 | 0.114 |
(0.718, 21.594) | ||||
RV systolic function | 1/12 | 5/13 | 0.16 | 0.125 |
impairment | (0.015, 1.66) | |||
RV area (cm2) | 29.5 (20.8, | 22.0 | 1.104 | 0.189 |
36.5) n = 10 | (17.5, 27.0)n = 5 | (0.952, 1.279) | (0.193 M–W) | |
RV fac (%) | 32 (25, 46) | 25 | 1.067 | 0.173 |
n = 9 | (23, 35.5) n = 8 | (0.972, 1.172) | (0.173 M–W) | |
RV TAPSE (mm) | 18 (16.25, 22) | 17 (10.25, | 1.094 | 0.326 |
n = 8 | 21.5) n = 8 | (0.914, 1.309) | (0.544 M–W) | |
|
||||
EP study performed | 9/12 | 7/14 | 3.0 (0.56,16.01) | 0.20 |
QRS >120 msec | 7/10 | 4/12 | 4.67 (0.77,28.5) | 0.10 |
PR >200 msec | 3/10 | 2/13 | 2.36 (0.31,17.8) | 0.41 |
(
Summaries within groups are given as number with the feature for categorical variables and median (inter-quartile range) for numeric data.
No significant differences in both groups were observed with respect to PR prolongation (>200 ms) or QRS duration (>120 ms).
The procedure was performed in 9 patients of patients with appropriate ICD therapy, and 7 patients without ICD therapy. Sustained ventricular tachycardia could be induced in 8 (89%) patients of the first group, and in 7 (100%) patients without shocks. Catheter ablation for a sustained monomorphic ventricular tachycardia was performed in one patient of each group.
No early (<30 days after ICD implantation) complications occurred in our patient population. Two late complications related to the lead were observed: A 51-year-old physically active man who performed Nordic walking on a regular basis and never required an ICD therapy developed electrode dysfunction with signal undersensing due to insulation failure 12 years after the implantation. The second patient was a 61-year-old man who presented with bacterial endocarditis with vegetations on the ICD lead one year after implantation requiring explantation of the lead and the generator. Subsequently, this patient died as a consequence of acute low output failure due to electrical storm which was refractory to drug therapy and external shocks. Another patient died due to progressive congestive heart failure three years after heart transplantation without replacing the ICD.
Among all clinical variables analyzed, the presence of the history of heart failure was identified as a predictor of a subsequent appropriate ICD therapy. LV involvement and the age at implantation were borderline significant predictors in our patient cohort. The presence of syncope at the time of diagnosis was more likely to be found in patients who were not shocked (p = 0.022). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy.
The clinical course of ARVC varies considerably. Cardiac electrical instability may lead to life-threatening ventricular arrhythmias and SCD. Therefore, ARVC patients are often considered for ICD implantation after a survived SCD or after a presentation with syncope related to ventricular tachyarrhythmias
During a median follow-up duration of 10.7 years, 12 patients (46%) with ARVC received appropriate ICD therapy, 9 of whom within the first two years after device implantation. Other studies with a considerably shorter observation period documented similar rates of appropriate ICD therapy. Corrado et al showed appropriate ICD therapies in 64 patients out of 132 patients (48%) during a follow-up period of 3.3±2.3 years
In the present single-center patient cohort, history of heart failure was a significant predictor of appropriate ICD therapy during long-term follow-up. Left ventricular disease involvement and time between ARVC diagnosis and ICD implantation were of borderline significance. Invasive electrophysiological testing did not predict appropriate ICD therapy. The findings of this study are consistent with the results of the previously published report from our group, in which we were able to demonstrate that congestive heart failure and left ventricular involvement were independently associated with adverse outcome in 61 patients with ARVC, including 24 patients who were implanted with an ICD
Besides a left ventricular involvement, the echocardiographic evaluation revealed no major differences between patients with or without appropriate ICD therapy. Indeed, right ventricular dimension and function were similar between the two groups. However, two-dimensional echocardiography for right ventricular evaluation is limited by the complexity of the right ventricular anatomy not resembling simple geometrical shapes and this may have confounded the study result. In addition, since left ventricular involvement is often associated with regional echocardiographic anomalies, the assessment of the ejection fraction using the biplane area-length method may have failed to demonstrate such abnormalities
Previous studies investigating the predictive value of syncope for appropriate ICD therapy have yielded conflicting results
Another explanation may be that syncope may not be of arrhythmic origin in some patients and linked to hemodynamic factors.
In the majority of our patients ventricular tachycardia or fibrillation could be induced during electrophysiological stimulation. However, arrhythmia inducibility was not significantly associated with appropriate ICD therapy, although the confidence intervals were wide and we cannot exclude odds ratios of over three for VT and over seven for the other two components due to the small patient number. Nevertheless, these findings are in accordance with those of Piccini et al.
This is an observational study, and hence, it is not possible to ascribe causality. Although the study cohort was relatively large, given the rarity of ARVC in the population at large, and the follow-up period important for an ARVC population of a single-center, the major weaknesses of this report are those inherent to observational trials in general. Another limitation might have been the concomitant use of antiarrhythmic medication that can impact on the rate of appropriate ICD therapy
History of heart failure is a significant predictor of appropriate ICD therapy in patients with ARVC. Therefore, close clinical monitoring of these patients is important and signs of heart failure should alert the treating physician. More long-term studies on clinical variables influencing the outcome of patients with ARVC in larger multicenter cohorts currently developed are warranted in the future.