RR interval variability in the evaluation of ventricular tachycardia and effects of implantable cardioverter defibrillator therapy

Abstract Background An implantable cardioverter defibrillator (ICD) is the most reliable therapeutic device for preventing sudden cardiac death in patients with sustained ventricular tachycardia (VT). Regarding its effectiveness, targeted VT is defined based on the tachyarrhythmia cycle length. However, variations in RR interval variability of VTs may occur. Few studies have reported on VT characteristics and effects of ICD therapy according to the RR interval variability. We aimed to identify the clinical characteristics of VTs and ICD therapy effects according to the RR interval variability. Methods We analyzed 821 VT episodes in 69 patients with ICDs or cardiac resynchronization therapy defibrillators. VTs were classified as irregular when the difference between two successive beats was >20 ms in at least one of 10 RR intervals; otherwise, they were classified as regular. We evaluated successful termination using anti‐tachycardia pacing (ATP)/shock therapy, spontaneous termination, and acceleration between regular and irregular VTs. The RR interval variability reproducibility rates were evaluated. Results Regular VT was significantly more successfully terminated than irregular VT by ATP. No significant difference was found in shock therapy or VT acceleration between the regular and irregular VTs. Spontaneous termination occurred significantly more often in irregular than in regular VT cases. The reproducibility rates of RR interval variability in each episode and in all episodes were 89% and 73%, respectively. Conclusions ATP therapy showed greater effectiveness for regular than for irregular VT. Spontaneous termination was more common in irregular than in regular VT. RR interval variability of VTs seems to be reproducible.


| INTRODUC TI ON
An implantable cardioverter defibrillator (ICD) is currently the most reliable therapy for preventing sudden death in patients with sustained ventricular tachycardia (VT) associated with organic heart disease. [1][2][3][4] ICDs can terminate life-threatening VTs by using electrical shocks, anti-tachycardia pacing (ATP), or both. Recent studies have shown that electrical shocks for ventricular tachyarrhythmia may lead to a worse prognosis, such as mortality or morbidity. 5,6 Therefore, it is essential to reduce the use of shock therapy to terminate VT. Although the effectiveness of ATP therapy has been extensively reported, [7][8][9] it occasionally induces VT acceleration 10,11 or progression to ventricular fibrillations (VFs). Many studies on the effectiveness of ICD therapy have reported that the cycle length defines the VTs that are best targeted by ICD therapy. However, in addition to the cycle length, the targeted VTs are characterized by RR interval variability ( Figure 1A). Variations in the RR interval in tachyarrhythmia distinguish VTs from supraventricular tachycardia, such as atrial fibrillation. 12 Concerning the RR interval variability in VT, few studies have reported on the clinical characteristics of VT or the effectiveness of ATP therapy.
This study aimed to evaluate the relationship between RR interval variability in VTs and clinical characteristics of VT, including the effects of ICD therapy.

| ME THODS
VTs per episode, recorded using an ICD or a cardiac resynchronization therapy defibrillator (CRT-D) device, were classified as regular or irregular according to the RR interval variability of the cycle length. Based on this variability, we evaluated the rates of VT termination using ATP or shock therapy, spontaneous termination, and acceleration. Additionally, the reproducibility rates of the RR interval variability of VTs (regular or irregular) in each episode and in all episodes were evaluated.

| Study design and population
This was a retrospective, multicenter, observational study.

Methods:
We analyzed 821 VT episodes in 69 patients with ICDs or cardiac resynchronization therapy defibrillators. VTs were classified as irregular when the difference between two successive beats was >20 ms in at least one of 10 RR intervals; otherwise, they were classified as regular. We evaluated successful termination using anti-tachycardia pacing (ATP)/shock therapy, spontaneous termination, and acceleration between regular and irregular VTs. The RR interval variability reproducibility rates were evaluated.
Results: Regular VT was significantly more successfully terminated than irregular VT by ATP. No significant difference was found in shock therapy or VT acceleration between the regular and irregular VTs. Spontaneous termination occurred significantly more often in irregular than in regular VT cases. The reproducibility rates of RR interval variability in each episode and in all episodes were 89% and 73%, respectively.
Conclusions: ATP therapy showed greater effectiveness for regular than for irregular VT. Spontaneous termination was more common in irregular than in regular VT. RR interval variability of VTs seems to be reproducible. Minneapolis, MN, USA). Patients whose device programing did not match the study requirements (Table S1) were unable to complete a 2-year follow-up period, or were unable to provide informed consent were excluded from this research. The recipients were followed up every 6 mo for up to 2 y after device implantation, by remote monitoring of their device or by presenting in the outpatient clinic. The devices were assessed at all scheduled and unscheduled follow-up visits. The DEFENSE trial revealed that, compared with the conventional algorithms, the SST discrimination algorithm significantly lowered the rate of inaccurate VT detection.

K E Y W O R D S
VT episodes were evaluated as follows: of the 185 patients initially enrolled, 69 experienced 821 episodes of ventricular arrhythmias (VT, fast VT, or VF); of the 821 episodes, 608 (74%) and 213 (26%) were judged as true ventricular tachyarrhythmia and as other episodes, respectively, including atrial fibrillation/atrial flutter (n = 26), sinus tachycardia or atrial tachycardia (AT) (n = 178), and T-wave oversensing (n = 9), leaving data from just 53 patients who exhibited true ventricular tachyarrhythmia. Each entire episode was reviewed by an independent adjudication committee to determine whether the diagnosis was appropriate.

| Analysis of the RR interval variability of VT
The DEFENSE trial guidelines recommended that the devices should have been programed to provide therapy for VTs with a cycle length <400 ms (Table S1). Of the aforementioned 608 true VT/VF episodes, only cycle lengths ≥240 ms were considered as VT episodes in this study.
VT cycle length variability was determined based on a previous report; 10 RR intervals, from 2 s after the onset of VT on intracardiac electrograms, were obtained by automatic reading of the devices, with an accuracy of 10 ms 12 VT was judged as irregular when any difference between two successive beats was >20 ms at least once in 10 RR intervals; otherwise, it was classified as regular. 12 When ATP was administered more than once in an episode, evaluation of the RR interval variability after the first therapy session was performed using the 10 RR intervals occurring immediately before any subsequent ATP therapy.

| VT termination
Episode termination was used to confirm the classification of success by ATP therapy. Termination occurring more than five beats after therapy was deemed unsuccessful and was classified as spontaneous termination after ATP delivery. 10 Furthermore, VTs that terminated naturally without ATP or shock therapy were defined as spontaneous termination without therapy.

| VT acceleration
Ventricular rhythm acceleration following ATP therapy was defined as a 10% decrease in the cycle length. 10

| Reproducibility of the RR interval variability of VT
We examined the reproducibility of the RR interval variability of VT from two perspectives: reproducibility in each episode (RE) and reproducibility in all episodes (RA).
RE was evaluated when there were two or more VTs in one episode (ie, ATP therapy was performed more than once in an episode). Of the VTs classified on the basis of the RR interval variability within an episode, the ratio of the larger number of VTs by type (ie, regular or irregular) was defined as RE ( Figure 1B). When the numbers of regular and irregular VTs were identical in an episode, the episode was assigned according to the variability of the first recorded VT in the episode.
RA was assessed in patients with multiple VT episodes. The ratio of the larger number of VTs by type to the number of total VT episodes in all episodes within an individual was defined as RA ( Figure 2).

| Statistical analysis
Continuous data are presented as means and standard deviations.
Univariate and multivariate odds ratios (ORs) for VT termination and acceleration were estimated. A multilevel logistic regression was ap- The level of statistical significance was set at P < .05.

| Study groups
In a study group of 53 patients with an ICD or CRT-D, cases of episodes with an unknown medication history (n = 77 in seven patients), a cycle length <240 ms (n = 8 in seven patients), and a starting point of ventricular tachyarrhythmia that could not be confirmed on intracardiac electrocardiogram (n = 58 in seven patients) were excluded. Consequently, the remaining 465 episodes in 43 patients were included in the present analyses ( Figure 3, Tables 1 and 2).

| VT termination
Among the 465 episodes in 43 patients, 290 were managed with ATP therapy, 10 with shock therapy without ATP (shock therapy was administered after ATP therapy in 17 episodes), and 165 without therapy.
The characteristics of ATP therapy are summarized in Table S2.
The first pacing program for ATP therapy was set as burst pacing in all cases. ATP therapy terminated 85% of VT episodes (n = 246) (regular VT, 94%; irregular VT, 66%), and shock therapy terminated   spontaneous termination was 5% (n = 24), and the spontaneous termination rate without therapy was 31% (n = 145). VT termination could not be confirmed using intracardiac electrocardiography (ie, episodes that were out of the VT zone without termination) in 5% of the episodes (n = 23).
Concerning the ATP therapy, regular VTs showed significantly more successful terminations than irregular VTs (P < .001; OR, 7.56).
No significant difference was found in VT termination using ATP therapy between ischemic and non-ischemic cardiomyopathies. In addition, VT episodes with a faster rate showed a lower termination rate (P = .002; OR, 0.97; Table 3). Spontaneous termination after ATP delivery occurred significantly more frequently in irregular than in regular VTs (P < .001; OR, 30.58; Table 4). The VT rate had no significant effect on spontaneous termination after ATP delivery. For episodes without therapy, spontaneous termination was more commonly observed in irregular than in regular VTs (P = .001; OR, 6.06).

| VT Acceleration
In 290 VT episodes of ATP therapies, occurrences of VT acceleration were significantly associated with faster than with slower VTs (P = .006; OR, 1.04; average VT heart rate of episodes including acceleration vs. no acceleration, 200 ± 21 vs. 178 ± 25 bpm). By contrast, no significant difference was observed in acceleration occurrence in other items (Table 5).

| D ISCUSS I ON
Based on the variability of the VT cycle length, the three important findings of this study were as follows: first, ATP therapy produced a significantly higher termination rate in regular than in irregular VTs. Second, spontaneous termination after ATP delivery or without therapy occurred significantly more frequently in irregular than in regular VT cases. Third, reproducibility of the RR interval variability of VT was high, both per episode and in all episodes.
The mechanism and properties of tachycardia, substrate, local electrophysiology, and stimulation site affect the success of ATP attempts in terminating VTs. 14 Although it may be difficult to capture all of this information in an ICD, focusing on RR interval variability may be important to improve the effectiveness of ATP treatment.
Three types of VT mechanisms are known to date-reentry, triggered activity, and automaticity. In general, regular heart rates are found in VT cases because of the reentry mechanism, and the irregular heart rate is a finding of non-reentrant VT. 15 According to previous reports, small changes in the VT cycle length suggested the increase in ATP effectiveness. 16 That evaluation used the percentage of variation, which was calculated by dividing the mean difference between each RR interval and the next one by the VT cycle length. Furthermore, ATP therapy is more effective for VTs that have smaller ventricular beat-to-beat morphologic variation on intracardiac recordings than for those that do not. 17 We evaluated the VT characteristics using a simple method, different from the one used in previous studies, to simply measure the variability of the VT cycle length.
In addition, ventricular tachyarrhythmia caused by a triggered activity or automaticity of the mechanism can be difficult to terminate using programed electrical stimulation with reproducibility.
By contrast, VT caused by the reentrant mechanism can result in successful termination using programed stimulation, without excluding triggered activity. 18 The efficacy of ATP in these VTs may be explained by the fact that the VT mechanisms were based on reentry and that VTs that demonstrate poor response to ATP therapy could result from the lack of organized reentry.

| VT termination
In our study, the successful VT termination rate using ATP was 85%, which is equivalent to those reported in previous studies. 19 Furthermore, no significant differences were found between patients with ischemic and non-ischemic cardiomyopathies with respect to VT termination using ATP therapy. Scar-related reentry is the most common cause of sustained VT in structural heart disease. 23 In patients with structural heart disease, myocardial infarction is most commonly associated with a damaged myocardium, which serves as a substrate for reentrant arrhythmias. However, scar-related VT also develops in other myocardial diseases, including dilated cardiomyopathy, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy, and after cardiac surgery for congenital heart disease or valve replacement. 17 The scar slows conduction and increases susceptibility to reentrant arrhythmias.

| Clinical implication of the RR interval variability of VT on ICD management
As VT regularity is highly reproducible in each episode or in all epi-

| Limitations
Our study has several limitations. First, the number of VT episodes per individual varied. Multilevel logistic regression was applied to estimate the ORs, as VT episodes were nested within individuals.
Second, the VT evaluation period was limited to 10 RR intervals of 2 s after the onset, to simplify the clinical usage. In some episodes, RR interval variations may have changed after the assessment. Third, we could not perform multivariate analyses for spontaneous termination without therapy, as the number of target episodes was small.
Fourth, these results may not be indicative for slow VT cases because the programing of VT detection for each monitor and therapy zone was set at approximately 150 bpm in most episodes.

| CON CLUS IONS
ATP therapy for VT termination is more effective for regular than for irregular VT cases, as determined by the VT cycle length variability.
Additionally, irregular VT has a higher rate of spontaneous termination than regular VT, and the VT cycle length variability is reproducible for an episode and an individual.

ACK N OWLED G M ENTS
None.

CO N FLI C T O F I NTE R E S T
This study was financially supported by Medtronic Japan. Dr Satoshi Higa is a consultant to Japan Life Line and Johnson & Johnson and received speaker's honoraria from Japan Life Line, Medtronic, Abbott, Bayer, Biotronik, Boehringer-Ingelheim, Bristol-Myers, Daiichi-Sankyo Pharmaceutical Company, and Pfizer.

E TH I C A L A PPROVA L
The study protocol was approved by the institutional review board of each participating center. Written informed consent was obtained from the patients for obtaining the data.