Outcome of catheter ablation of non-reentrant ventricular arrhythmias in patients with and without structural heart disease

Background Catheter ablation of non-reentrant, commonly termed “idiopathic” ventricular arrhythmias (VA) is highly effective in patients without structural heart disease (SHD). Meanwhile, the outcome of catheter ablation of these arrhythmias in patients with SHD remains unclear. This study sought to characterize the outcome of patients with and without SHD undergoing catheter ablation of non-reentrant VA. Methods In this single-centre study the acute and long-term outcome of 266 consecutive patients undergoing catheter ablation of non-reentrant VA was investigated. In 41.0% of patients a SHD was present (n = 109, 80.7% male, age 59.1 ± 14.7 years), 59.0% had no SHD (n = 157; 44.0% male, age 49.9 ± 16.5 years). Results Acute procedural success (absence of spontaneous or provoked VA at the end of procedure and within 48 h after the procedure) was achieved in 89.9% of patients with SHD vs. 94.3% without SHD (p = 0.238). During a mean follow-up of 34.7 ± 15.1 months a repeat catheter ablation was performed in 19.6% of patients with SHD vs. 13.0% without SHD (p = 0.179). Patients with dilated cardiomyopathy (DCM) were the most likely to require a repeat ablation procedure (32.0% of patients with DCM vs. 13.0% without SHD; p = 0.022). Periprocedural complications occurred in 5.5% of patients with SHD vs. 5.7% without SHD (p > 0.999). All complications were managed without sequelae. Conclusions The outcome of catheter ablation of non-reentrant VA in patients with SHD appears good and is comparable to patients without SHD. A slightly higher rate of repeat ablations was observed in patients with DCM.


Background
Catheter ablation of non-reentrant ventricular arrhythmias (VA) has been shown to be highly effective in the absence of structural heart disease (SHD) [1]. These VAs, commonly termed "idiopathic", originate frequently from the right and left ventricular outflow tracts, as well as aortic cusps and surrounding tissue including mitral annulus and papillary muscles [2,3]. They are generally accepted to be benign although rare fatal outcomes are reported [4,5]. By current international guidelines, catheter ablation in patients without SHD has a class I indication for VA originating from the outflow tracts [6]. While catheter ablation of non-reentrant VA is now well established in many electrophysiological laboratories, patients with an underlying SHD have been excluded from most studies addressing non-reentrant VA. Studies investigating outcome in patients with SHD are mainly restricted to reentrant VA related to an abnormal myocardial substrate. However, the prevalence of non-reentrant VA unrelated to abnormal myocardial substrate in patients with SHD presenting for catheter ablation has been found to be > 20%, while data on long-term outcome in these patients are sparse [7]. Therefore, we here present the short-and long-term outcome of catheter ablation of non-reentrant VA in a relatively large cohort of patients with SHD.

Patient selection
Case records from the University Heart and Vascular Center database were reviewed [8]. Between October 2012 and December 2015 387 patients with VA (ventricular tachycardia (VT) and/or premature ventricular contractions (PVC)) were referred to our institution for a catheter ablation. The present analysis includes all patients (n = 266) with non-reentrant VA originating from areas of structurally normal myocardium. Patients with and without SHD were included. Non-reentrant VA were defined as arrhythmias of presumably focal origin. They were distinguished from reentrant VA according to their mode of initiation, appearance in activation and entrainment mapping, their local electrogram characteristics (e.g. unipolar signal with QS pattern) and their response to overdrive pacing [7]. A definitive arrhythmia mechanism could not be defined for all VAs, though only patients with suspected focal mechanism were included into the study. Patients with evidence for a VA with reentry mechanism or non-reentrant VA originating from areas of structurally abnormal myocardium were excluded from further analysis.

Definition of structural heart disease
All patients were screened for SHD using echocardiography, cardiac magnetic resonance imaging and/or myocardial scintigraphy. SHD was defined according to the classification of cardiomyopathies in line with the current guidelines of the European Society of Cardiology [9,10]. Pathologic findings in the diagnostic workup including wall motion abnormalities, inhomogenicity of the myocardium, late gadolinium enhancement, perfusion defects, pathological Q-waves, and low-voltage areas in voltage mapping (> 1 cm 2 with a voltage < 1,5 mV) [11] were counted as a SHD [7]. Reduced left ventricular ejection fraction (LVEF) without other cardiac abnormalities that normalized after ablation (LVEF < 50% with improvement to > 50%) was defined as an arrhythmia induced cardiomyopathy and not counted as SHD [12].

Irrigated radiofrequency ablation
All patients underwent conscious sedation under spontaneous ventilation and continuous monitoring of oxygen saturation and blood pressure [13]. All antiarrhythmic drugs with exception of amiodarone had been discontinued for at least five half-lives. Access to the mapping region was gained through cannulation of the femoral vein or artery. In all patients cardiac anatomy was displayed using a three-dimensional electroanatomical mapping system (Carto ® 3 System, Biosense Webster Johnson and Johnson, Diamond Bar, CA, USA). Activation mapping and entrainment mapping were performed if possible. Whenever considered helpful, pace mapping was performed for identification of the PVC or VT origin site using the distal bipolar electrode of the mapping catheter at a pacing cycle length of 500 ms with the lowest stimulus amplitude (varying from 3 to 10 mA) and pulse width (1.0-2.0 ms) producing stable ventricular capture [8,13]. If no VA could be registered, programmed stimulation was performed with two different basic cycle lengths (510 and 440 ms) and up to three extra stimuli with a minimal coupling interval of 180 ms. In all cases incremental atrial and ventricular pacing was performed following the programmed stimulation. The induced VT was defined as the clinical VT when cycle length (within 20 ms) and morphology matched previous recordings. In the case of non-inducibility, the stimulation protocol was repeated during intravenous orciprenaline infusion (5 mg/500 mL NaCl 0.9%) with at least 20% increment of heart rate [14][15][16]. If the clinical VA could still not be induced, the patient was excluded from further analysis.
Ablations were performed using a 3.5-mm externally irrigated-tip ablation catheter (NaviStar ThermoCoolVR, Biosense Webster) after identification of the ablation site (earliest activation of at least − 20 ms before QRS-onset and/or perfect pace map). Radiofrequency applications were performed in a temperature-controlled mode with a maximum temperature of 48 °C. The maximum output chosen was 20-40 W depending on the location. When an acceleration or reduction of the cycle length of the VT or the frequency of the PVC was observed during the first 20 s of the application, the radio frequency energy delivery was continued for a maximum of 180 s. Otherwise the radio frequency delivery was terminated and the catheter was repositioned [8,13].

Procedure success and follow-up
Acute ablation success was defined as absence of spontaneous or provoked clinical VA at the end of the procedure, and absence of the targeted VA on 48-h electrocardiography (ECG) monitoring after ablation. VA burden was documented on Holter monitoring before and after ablation. Major complications were defined as complications leading to a prolonged hospital stay, permanent inconveniences or surgery. The follow-up was performed in our outpatient clinic or for some patients at the referring physician's office. Patients with insufficient follow-up data (n = 10) were excluded from the follow-up analysis.

Statistics
Continuous variables are expressed as mean ± standard deviation. Categorical variables are presented as frequencies and percentages. Independent samples t-tests were carried out to assess differences between patients with and without SHD in all continuous variables. Categorical variables were compared using Fisher's exact tests. We tested for significant mean change within each group using paired t-tests and compared mean change between groups by independent t-tests. Survival curves depicting the time to a repeat ablation procedure were estimated for each group, considered separately, using the Kaplan-Meier method and compared statistically using the log rank test. All of the models present available case analysis. A two-tailed p <0.05 was considered statistically significant. Statistical analyses were performed using the software GraphPad Prism 7.0 (GraphPad Software Inc., San Diego, CA, USA).

Patient characteristics
266 consecutive patients with non-reentrant, idiopathic VA were included into the study (  Table 2. A total of 15 periprocedural complications occurred in all 266 patients (5.6%). Ten of these were related to the vascular access, four were major complications ( Table 3). All adverse events were managed without sequelae.  Table 4).
Eight patients (six with SHD) died unrelated to the procedure or to arrhythmic events during the follow-up period. The causes of death were cancer (two patients), suicide (one patient) and terminal heart failure (five patients).
During the follow-up period 22.5% (23 out of 102) of patients with SHD and 15.6% (24 out of 154) of patients without SHD required a repeat ablation of VA (p = 0.189; Fig. 1a; Table 4). Specifically, 20 patients with SHD (19.6%) vs. 20 patients (13.0%) without SHD had a repeat ablation of the same recurring arrhythmia from the initial ablation (p = 0.179). In another three patients treatment with sodium channel blockers and in seven patients with amiodarone was initiated due to VA.
An analysis of subgroups showed that the reablation rate of VA with origin in the right ventricle and VA  originating from the left ventricle did not differ (12.9% vs. 17.9%, p = 0.304). Patients with DCM had the highest rate of repeat ablation procedures (32.0%), which was significantly higher than patients without SHD (p = 0.022; Table 5). The rate of repeat ablation procedures of the other subgroups (ICM, HCM, myocarditis, other cardiomyopathies) did not differ from patients without SHD (Fig. 1b). 42.9% of the VA in DCM patients originated from the right ventricular outflow tract, in comparison to 22.2% in all other SHD patients. The rate of repeat ablation procedures of VA from the right ventricular outflow tract was 27.6% in patients with SHD (27.0% in DCM) and 9.2% in patients without SHD (p = 0.027).

PVC burden and left ventricular function
The average PVC burden before ablation was 16.9 ± 13.8% in patients with SHD and 17.1 ± 13.2% in patients without SHD (p = 0.901). The postprocedural PVC burden significantly decreased in both groups (− 11,4 ± 15,5% vs. − 14,3 ± 13,4%), but remained higher in patients with SHD (5.5 ± 9.5% vs. 2.8 ± 6.4%; p = 0.005; Fig. 2). In neither group a significant change in the LVEF was observed. Yet some individuals experienced substantial increases in LVEF. All patients showing a relevant improvement of their LVEF had a decrease in PVC burden to values below 2%.

Discussion
The major findings of the present study are: 1. Symptomatic non-reentrant VA are common in patients with a wide variety of SHD.
2. Patients with SHD have a similar short-and longterm outcome following catheter ablation of nonreentrant VA to patients without SHD. The subgroup of patients with DCM has a higher rate of repeat ablations. 3. Patients with SHD have a slightly higher burden of PVC at follow-up.

Prevalence of idiopathic ventricular arrhythmias in patients with SHD
The first studies on radiofrequency energy ablation of VA in the late 1980s and early 1990s elegantly paved the way for catheter-based treatment of affected patients with and without SHD [17,18]. Meanwhile in patients with SHD the potential benefit of catheter ablation of reentrant VA has been established in multiple clinical studies [19]. Data on the treatment of non-reentrant VA in patients with SHD remain rare, since such patients have so far been excluded from most studies. However, the here reported analysis suggests that non-reentrant, so called "idiopathic" VA are more common in patients with SHD than previously described.

Outcome of catheter ablation
The present findings demonstrate a comparable outcome to recent relatively large studies investigating nonreentrant, idiopathic VA [20]. Patients with an otherwise healthy myocardium and idiopathic VA are known to have recurrence rates with up to 22% repeat ablation procedures in a recent multicentre study with 20.4 months follow-up [1]. Our findings suggest that this holds true irrespective of the fact whether a SHD is present or not. Rates of repeat ablation procedures appear comparable for both, patients with and without SHD presenting with non-reentrant VA during our follow-up period of 34.7 ± 15.1 months. SHD is often associated with several comorbidities including peripheral artery disease or chronic kidney  Fig. 1 Freedom from repeat ablations. a Patients with structural heart disease vs. patients without structural heart disease. The rate of repeat ablations of the initially ablated arrhythmia did not differ significantly between patients with and without structural heart disease. Patients are censored at the end of their follow-up period. SHD patients with structural heart disease. b Subgroups of patients with structural heart disease vs. Patients without structural heart disease. Patients with dilated cardiomyopathy had a higher repeat ablation rate than patients without structural heart disease. The other subgroups did not differ significantly. Patients are censored at the end of their follow-up period. *p < 0.05 was considered statistically significant. DCM dilated cardiomyopathy, HCM hypertrophic cardiomyopathy, ICM ischemic cardiomyopathy, SHD patients with structural heart disease disease. Those conditions are known to increase the risk of procedural complications [21]. A recent multicentre study including patients with different kinds of VA showed a risk of 11.9% for complications in patients with SHD and 4.4% for patients without SHD [22]. In contrast, in our collective comparing patients with non-reentrant VA the procedural safety was relatively high in both groups, patients with and without SHD, and comparable to other studies investigating patients without SHD.

Repeat ablation procedures in different types of SHD
Catheter ablation of VA is well known to be challenging in some patients with SHD. This especially holds true in non-ischemic causes (46-61% recurrences in patients with DCM) [23]. Aptly our data demonstrate a higher rate of repeat ablation procedures in patients with DCM in comparison to patients without SHD. As DCM patients in the present study had a high percentage of VA from the right ventricular outflow tractwhich generally had a good outcome-the higher repeat ablation rate does not seem to be caused by an anatomically hard-to-reach ablation target. An undetected substrate could have been responsible for the recurrences [24][25][26], though this seems unlikely as no

SHD No SHD
Before Ablation After Ablation Fig. 2 The impact of catheter ablation on the burden of premature ventricular contractions. A postprocedural reduction of the burden of premature ventricular contractions was observed in patients with and without structural heart disease. The burden at follow-up was higher in patients with structural heart disease. The bars show mean with standard deviation. *p < 0.05 was considered statistically significant. PVC premature ventricular contraction, SHD patients with structural heart disease