Clinical and Laboratory Predictors of Long-Term Outcomes after Catheter Ablation for a Ventricular Electrical Storm

Background Ventricular electrical storm (VES) is characterized by the occurrence of multiple episodes of sustained ventricular arrhythmias (VA) over a short period of time. Radiofrequency ablation (RFA) has been reported as an effective treatment in patients with ventricular tachycardia (VT). Objective The aim of the present study was to indicate the short-term and long-term predictors of recurrent VA after RFA was performed due to VES. Methods A retrospective, single-centre study included patients, who had undergone RFA due to VT between 2012 and 2021. In terms of the short-term (at the end of RFA) effectiveness of RFA, the following scenarios were distinguished: complete success: inability to induce any VT; partial success: absence of clinical VT; failure: inducible clinical VT. In terms of the long-term (12 months) effectiveness of RFA, the following scenarios were distinguished: effective ablation: no recurrence of any VT; partially successful ablation: VT recurrence; ineffective ablation: VES recurrence. Results The study included 62 patients. Complete short-term RFA success was obtained in 77.4% of patients. The estimated cumulative VT-free survival and VES-free survival were, respectively, 28% and 33% at the 12-month follow-up. Ischemic cardiomyopathy and complete short-term RFA success were predictors of long-term RFA efficacy. Neutrophil to lymphocyte ratio (NLR) and GFR <60 mL/min/1.73 m2 were associated with VES recurrence. NLR ≥2.95 predicted VT and/or VES recurrence with a sensitivity of 66.7% and specificity of 72.2%. Conclusion Ischemic cardiomyopathy and short-term complete success of RFA were predictors of no VES recurrence during the 12-month follow-up, while NLR and GFR <60 ml/min/1.73 m2 were associated with VES relapse.


Introduction
Ventricular electrical storm (VES) is a clinical situation characterized by three or more episodes of sustained ventricular tachycardia (sVT) occurring within 24 hours [1].Te triad of a susceptible electrophysiological substrate, triggers, and autonomic dysregulation take part in the pathogenesis of VES [2].Treatment includes correction of the underlying abnormalities (electrolyte disturbances, coronary angioplasty of the artery responsible for myocardial ischemia), antiarrhythmic drugs, sedative medications, and in some patients also catheter ablation.Radiofrequency ablation (RFA) has been reported as an efective treatment in patients with ventricular tachycardia (VT).Terapy of ventricular tachycardia difers depending on whether we are dealing with monomorphic ventricular tachycardia (an important role of transcatheter ablation) or with polymorphic ventricular tachycardia (the dominant role of coronary revascularization, correction of electrolyte disturbances, and correction of current pharmacotherapy, avoiding drugs that prolong QTc interval; programming a correspondingly high basic rate in the case of patients with an implanted pacemaker/implantable cardioverter-defbrillator).It should be emphasized, however, that also in the case of polymorphic arrhythmias, with confrmation of the trigger (repetitive, monomorphic ventricular premature complexes), it is possible to perform effective transcatheter ablation.When present, substrate ablation targeting scar is also a reasonable option even if premature ventricular complexes are absent [3,4].Tere are several studies on the prognostic factors for recurrent VTafter the RFA procedure.However, there is little research on the laboratory parameters in predicting recurrent ventricular arrhythmias (VA).Te aim of the present study was to indicate the short-term and long-term predictors of recurrent VA after RFA was performed due to VES, with particular emphasis on the laboratory biomarkers.

Study Design and Population.
Our retrospective study included all patients, who had undergone radiofrequency ablation (RFA) due to VT between 2012 and 2021 at the Department of Cardiology and Electrotherapy Medical University of Gdańsk in Poland.Ten, among them, we selected patients, who underwent RFA due to VES.
In patients with implantable cardioverter-defbrillator (ICD), the ventricular electrical storm was recognized when three or more episodes of sustained VT (sVT) occurred in 24 hours, requiring therapy, i.e., antitachycardia pacing (ATP) or shocks, and with at least 5 minutes between these episodes.In patients without implanted ICDs, VES is recognized in the case of at least three separate episodes of sVT in 24 hours [2,[5][6][7][8].
Te analysis included patients' demographic data, underlying heart disease, concomitant diseases, pharmacological treatment, and selected laboratory parameters obtained from peripheral blood samples at the time of RFA.Te neutrophil to lymphocyte ratio (NLR) was calculated by dividing the number of neutrophils by the number of lymphocytes.Chronic renal disease was diagnosed when the glomerular fltration rate (GFR) was <60 mL/min/1.73m 2 in two examinations performed within the last 3 months.Te CKD-EPI creatinine equation was used to estimate GFR.

Radiofrequency Ablation Procedure.
Prior to RFA, potential reversible causes of VES were excluded, including coronary angiography in patients with ischemic cardiomyopathy and elevated troponin levels.Endocardial access was obtained to the right ventricle using a transvenous approach and to the left ventricle using a transseptal or retrograde transaortic approach.In all procedures involving left-sided access, the systemic anticoagulation was achieved with heparin with an initial bolus of 5000 U administered intravenously, followed by infusion of 1000-2000 U/hour or based on ACT >300 s).Endocardial electrogram and surface ECG were recorded using the CardioLab EP recording system (General Electric, Houston, TX, USA).Electrical stimulation was delivered using an external stimulator (Qubic Stim Cardiac Stimulator, Biotronik, Berlin, Germany).
In the case of hemodynamically stable VT or in the absence of availability of 12-lead ECG (only IEGM recordings), conventional mapping strategies such as activation and entrainment mapping were used.Te goal was to identify the critical isthmus.Substrate-based strategies were applicable to hemodynamically unstable VT and included ablation of late potentials and scar homogenization/local abnormal ventricular activity (LAVA) elimination.
Programmed ventricular stimulation was used to induce VT, with a basal pacing cycle length of 600 ms and 400 ms, and with up to three extrastimuli.Voltage mapping was performed during sinus or paced rhythm from an inserted catheter, using a three-dimensional electro-anatomic navigation system CARTO 3 (Biosense Webster, Diamond Bar, CA).Endocardial areas with bipolar electrogram amplitudes of <0.5 mV were defned as zones of dense scar tissue, areas with amplitudes of 0.5 to 1.5 mV corresponded with scar border zone, and areas >1.5 mV delineated normal endocardial tissue [9].Sites with fractionated electrograms or late potentials within or adjacent to areas of the scar were also identifed and tagged.Pacemapping was performed in areas with abnormal electrograms and in the sites in which the VT exit (reentry mechanism) or VT origin (focal mechanism) was suspected on the base of the 12-lead ECGs of VT.Te target for ablation was defned as all areas potentially involved in the arrhythmia mechanism based on the mapping technique described above [10][11][12][13].
Radiofrequency current was delivered with a 3.5-mm open irrigated catheter using power settings of 30 to 40 W up to 60 seconds or an ablation index of 500-600 (ablations performed in 2020-2021).Te ablation index (AI) is an index that incorporates contact force, time, and radiofrequency power simultaneously and is able to predict lesion size and outcomes in RFA.Te ablation index was used in some patients as an additional marker of application time, especially in spots when adequate contact force (>10 g) was not achieved.In those applications, RF delivery was prolonged above 60 seconds if the ablation index was <500-600.According to our knowledge, there is only one ongoing clinical trial to assess the value of AI in VT ablation (ClinicalTrials.govIdentifer: NCT03437408).Te value of 500-600 used in our study was established arbitrarily based on the assumption that it should be higher than used in pulmonary vein isolation (400-550) and based on our observations that AI � 500-600 is the value reached during 60 seconds application of 30−40 W in spots with good contact (>10 g).
Tere are reports in the literature that the ablation index value during ablation may be a predictor of the efectiveness of ablation of ventricular premature complexes.Te maximum and mean AI values were statistically higher in the RFA success group (median of the maximum AI 630 (IQR 561-742); median of the mean AI 489 (IQR 411-560)), in which authors assessed RFA efcacy in premature ventricular complex ablation [14].It should be emphasized that AI was only an additional parameter monitored during the RFA.It has a limited value for guiding VT ablation, which may be related to small proportional signifcance of application duration and complex tissue architecture [15].
After ablation, right ventricular programmed stimulation was performed to assess the efect of catheter ablation.In some patients, the bipolar remap of the ablation area was 2 Journal of Interventional Cardiology made to assess late/fragmented potentials abolition or pacing from inside the lesion was performed to check failure to capture the ventricle.

Study Endpoints.
Te endpoints assessed in the study were divided into two types: in terms of short-term efectiveness of RFA and in terms of long-term efectiveness of RFA.Short-term efcacy was assessed immediately after the completion of ablation and consisted in assessing the possibility of induction of VT with the protocol as before ablation.Tere were three scenarios available at that time.
Complete short-term RFA success was defned as the inability to induce any VT (clinical or other) at the end of the RFA procedure, while partial success was defned as the absence of clinical VT.RFA failure was recognized when the clinical VT has been induced after the RFA procedure.
Long-term efcacy was assessed 12 months after RFA based on an outpatient clinic visit.Routine follow-up of patients after RFA in our centre includes a visit to the hospital outpatient clinic and control of the cardiac implantable electronic device (CIED) at 3, 6, and 12 months after RFA.All VA episodes recorded by the CIED were analyzed in this study, and those lasting >30 sec or terminated by the CIED were taken into account.
In terms of the long-term efectiveness of RFA, the following scenarios were distinguished: ( Te study was retrospective in nature, it did not require the participation of patients, and therefore, the consent of the bioethics committee was not required for its conduct.

Results
Te study included 56 men (90.3%) and 6 women (9.7%) with a mean age of 65.7 years at the time of RFA.Te baseline characteristics of the study population are shown in Table 1.Ischemic cardiomyopathy was recognized in 73% (n � 45), while dilated cardiomyopathy in 19.4% (n � 12) of patients.Arrhythmogenic right ventricular cardiomyopathy (ARVC) and left ventricular noncompaction (LVNC) were less common (3 and 2 patients, respectively).Te majority of patients were diagnosed with heart failure with reduced ejection fraction (HFrEF): 54 (87.1%), while the mean left ventricular EF in the study group was 28.4% ± 9.7%.32 (51.6%) patients were taking amiodarone at the time of RFA.Amiodarone was continued in all patients who had received this drug prior to RFA.During the follow-up period, there were no complications related to the use of this type of treatment.60 patients (97%) had an ICD implanted.
Te mean rate of clinical VT was 151 ± 29 bpm.Te mean RFA procedure duration was 218 ± 60 min.During the electrophysiological study (EPS), the median number of diferent types of VT induced was 2. Two patients underwent both, the endo-and epicardial RFA.Among the patients requiring LV RFA, retroaortic access was used in 44% of patients, while transseptal access was used in 56%.Two patients underwent RFA in general anesthesia, and these were patients with long-term inefective RFA, moreover, patients who died during the follow-up.
Te majority (69.4%) of induced clinical VTs were hemodynamically stable.All VTs qualifed for RFA were monomorphic arrhythmias.Serious complications of RFA occurred in 6 patients (9.7%).It was a permanent (2 cases) or transient third-degree atrioventricular block (1 case), ischemic stroke (1 case), pulmonary oedema requiring respiratory therapy ended in death in the mechanism of pulseless electrical activity (1 case), and aorto-atrial fstula (1 case).Aortoatrial fstula was a complication found in a 69-year-old patient with ischemic cardiomyopathy, dextrocardia, and visceral inversion (Supplementary Figure 1).During the ablation, the right atrial wall was punctured into the aortic root.Transesophageal echocardiography did not reveal any fuid in the pericardium, but a slight leak from the aorta into the right atrium was observed (three mm diameter), which was confrmed in the subsequent examination two days later.After a cardiac surgery consultation, it was decided to implement conservative treatment.Nine days after ablation, a computed tomography of the aorta was performed, which confrmed the closure of the fstula.Te clinical characteristics of patients with serious RFA complications are presented in Table 2.

Short-Term Outcomes.
Complete RFA success was obtained in 48 (77.4%) patients, while in 12 (19.4%)patients, it was a partial success.Only in 2 (3.2%) patients, RFA failure was noted.Among the assessed laboratory parameters, only a signifcantly higher concentration of ALT was found in patients with RFA failure (p � 0.005), as shown in Table 3. Due to the small size of the subgroup with an RFA failure, the logistic regression analysis was not performed in determining predictors of RFA failure.

Long-Term
Outcomes.Median follow-up was 14 months (range, 1 to 100 months); however, in 15 patients (24%), data on the long-term outcomes of the RFA were not obtained because they did not come for the control visits to our centre, and contact with them was lost.Terefore, the fnal analysis of the long-term results of RFA included data from 47 patients.In the remaining patients, there were no recurrences of VT or VES in 19 (40.4%) patients (efective ablation).In 15 (31.9%) patients, VT recurrences were recorded but without electrical storm (partially successful ablation), and only 13 patients (27.7%) had a recurrence of VES (inefective ablation).Te median time to recurrence of VT was 3.2 months, and it was 3.4 months in the case of VES  Journal of Interventional Cardiology During the follow-up, 10 from 62 (16.1%) patients died.Among the causes of death, end-stage, severe heart failure dominated (n � 8), and in the remaining cases, it was gastrointestinal obstruction and septic shock.Figure 4 shows the Kaplan-Meier curve representing all-cause mortality in the studied population.Among the assessed laboratory parameters, only the concentration of hsTnI before ablation correlated signifcantly with the risk of death (HR 1.31; CI 1.06-1.6;p � 0.04).

Discussion
In the present study, we examined short-term and long-term outcomes of RFA performed in patients with VES, with particular emphasis on predictors of ventricular arrhythmia recurrence after RFA.We found that (1) lack of complete short-term RFA success and ischemic cardiomyopathy (vs.others) were independent predictors of VES recurrence during the 12-month follow-up; (2) among laboratory parameters, the independent predictors also increased neutrophil to lymphocyte ratio and GFR < 60 ml/min/1.73m 2 ; (3) there was a signifcant correlation between the baseline hsTnI concentration and the risk of death in patients undergoing RFA due to VES.
In a retrospective study, the short-term efcacy of RFA due to electric storm was assessed in 62 patients, while the long-term efcacy was assessed in 47 patients (15 patients were lost to follow-up).Te size of the population covered by the study is not large; although due to the relatively rare occurrence of this disease and thus the rare performance of RF ablation in ES, there are reports in the literature on similar groups of patients [16][17][18][19] and only several publications on larger groups [20,21].
Te clinical characteristics of patients in our group were similar to those reported by other authors.As in the study by Carbucicchio et al. [22], men were more frequently referred for RFA due to VES (90.3% of our patients vs. 86.7% in the Cabucicchio group), the underlying disease was mainly ischemic cardiomyopathy (70.9% vs. 76%, respectively), and patients presented with decreased left ventricular systolic function (mean LVEF 28.4% vs. 36%, respectively) and moderately fast ventricular tachycardia (151 bpm vs. 157 bpm respectively).
Te duration of the ablation procedure (218 min vs. 260 min) and the median number of induced VTs (2 vs. 2) were also similar to those reported by other authors [22].
Unfortunately, due to the retrospective nature of study, we did not have information on more detailed characteristics of RFA procedures.Tis is important because, in Te VISTA Randomized Multicenter Trial, an extensive substrate-based ablation approach is superior to ablation targeting only clinical and stable VTs in patients with ischemic cardiomyopathy (who constituted most of our material) presenting with well-tolerated VT [23].Ablation performed due to VES is associated with a relatively low number of serious complications, especially considering the usually severe condition of the patients undergoing this procedure.In our group, we reported serious complications in 9.7% of patients treated with RFA, which was higher than in other studies: 3-6.2% [24][25][26].However, unlike other authors, we considered a transient complete atrioventricular block as a serious (not minor) complication.We have not recorded any deaths related to the RFA procedure.Fortunately, this fatal complication is very rare, as documented in other studies [27,28].Regarding the short-term results of the RFA, it has been reported in patients with ICM that complete RFA success was achieved in 60-80% of patients, partial success in 15-25%, and failure was reported in 0-10% of patients [29].As the majority of our study group participants were patients with ICM, we obtained similar results (77.4%, 19.4%, and 9.68%, respectively).
In the long-term assessment of the RFA efect, most of the authors reported that the complete success of the procedure was 62%-100% [25,[30][31][32][33][34].However, in the study by Kozeluhova et al., it was 48% [35].In our whole group, RFA was efective in 40% of patients, but unfortunately, we did not have data on this subject in 15 patients who did not come to our centre for postoperative follow-up.On the other hand, the percentage of patients with recurrence of VES was 28%, and in other studies, it was 0-35% [25,[35][36][37].It should be emphasized that ablation performed due to VES is  Journal of Interventional Cardiology a complex procedure, and the relatively high VT or recurrence refects the presence of a large myocardial substrate and difculties in its modifcation, as suggested by some authors [27].However, with a low risk of serious complications and often high efectiveness, the RFA procedure is performed in patients with implantable cardioverter-defbrillator (ICD) and recurrent VT.Sapp et al. reported that in patients with ischemic cardiomyopathy and an ICD who had VT despite antiarrhythmic drug therapy, the primary composite outcome of death, VES, or appropriate ICD shock occurred signifcantly less frequently if they underwent RF ablation, compared to an escalation of antiarrhythmic drug therapy [38].An interesting option may be stereotactic arrhythmia radioablation (STAR).It is an alternative for patients who, despite optimal pharmacotherapy and the applied RF ablation, still have recurrences of VT/VES [39].
Analyzing the clinical parameters of our patients at the time of RFA, we showed on the basis of a multivariate analysis that ischemic cardiomyopathy as the underlying disease and short-term complete success of RFA were independent predictors of the lack of VES recurrence in the 12-month follow-up.Tese data confrm the fndings from other authors [22] who also reported a higher risk of VES recurrence in patients with nonischemic cardiomyopathy and in those with the unfavorable early efect of RFA.However, it should be underlined that the prognosis of patients with nonischemic cardiomyopathy has improved signifcantly since the introduction of epicardial ablations, as reported in more recent multicentre studies.On their basis, it is clearly visible that the diferences in the frequency of VES relapses disappear among patients with ischemic and nonischemic cardiomyopathy when using both endo-and epicardial ablations [40].Other reported clinical predictors of recurrent ventricular arrhythmias after RFA due to VES are older age, more severe left ventricular dysfunction, higher NYHA class, amiodarone treatment prior (or according to other authors post) to ablation, poorly tolerated VT, the greater number of diferent inducible VTs, and a history of atrial fbrillation [27,[41][42][43].
Te analysis of laboratory parameters in our patients at the time of RFA indicated the increased NLR and GFR <60/ mL/min/1.73m 2 as the independent predictors of VES relapse within the 12-month follow-up after RFA.Laboratory biomarkers have been rarely evaluated in terms of the longterm efcacy of RFA performed in the VES therapy.Kozeluhova et al. reported on renal insufciency as a predictor of the adverse outcome within the 6-month observation after catheter ablation for VES [35].Also, Özcan et al. indicated the increased creatinine concentration as the risk factor for the recurrence of VES in patients with ischemic cardiomyopathy [44].However, these observations have not been confrmed in newer, multicentre studies involving larger numbers of patients.Also, the I-VT score developed and validated by Vergara et al. in its fnal form did not contain chronic kidney disease as a predictor of the recurrence of an electric storm following RFA [45,46].In the abovementioned predictive scale of VT recurrence after RFA, one of the key predictors of VT/VES recurrence turned out to be LVEF.In our case, in the multivariate analysis, this parameter was not statistically signifcant, although there was a trend in lower LVEF values among patients with longterm partially successful ablation and long-term inefective ablation, compared to patients with long-term efective ablation (p � 0.071).
Our study is the frst to indicate that NLR can be a predictor of inefective ablation due to VES.NLR is a hematological parameter for systemic infammation and stress.Tere is a lot of evidence in the literature supporting the role of infammation in the pathogenesis of cardiovascular diseases.Te studies conducted so far confrm the relationship between NLR and the severity of atherosclerosis [47].Higher NLR has been reported as an independent predictor of mortality in patients undergoing angiography or cardiac revascularization and in acute decompensated heart failure [48].Correlations between NLR and acute coronary syndrome risk prediction models such as SYN-TAX, GRACE, and GENSINI have been established.Te prognostic value of NLR in valvular disease and in patients undergoing valve replacement procedures has been indicated [49].Based on a meta-analysis, Angkananard et al. showed the association of NLR with coronary artery disease, acute coronary syndromes, stroke, and other composed cardiovascular events [50].Tere are several explanations for the relationship between increased NLR and the risk of cardiovascular events.First of all, neutrophils secrete infammatory mediators that may lead to the degeneration of the vascular wall [51].On the other hand, lymphocytes are responsible for the regulation of the infammatory response, in which regulatory T lymphocytes may inhibit atherosclerosis [52].NLR was found a predictor of incidence, treatment success, recurrence, and thromboembolic complications in patients with atrial fbrillation [53].In the prospective study on paroxysmal atrial fbrillation (AF), Trivedi et al. indicated that NLR ≥3.08 in patients undergoing catheter ablation due to AF was a predictor of AF recurrence, with a sensitivity of 72.5% and a specifcity of 78.6% [54].
NLR is a simple, widely available, and inexpensive biomarker that provides information on both the infammatory status and the stress response (high neutrophil count refects subclinical infammation, while reduced lymphocyte count refects physiological stress) [55].In addition, accumulating neutrophils can contribute to atrial remodeling through the release of proinfammatory mediators [56].Te fndings from the studies indicating that preablation NLR levels were signifcantly associated with the ablation outcomes support observations that infammation plays a role in AF recurrence.Our results may indicate a similar relationship in patients undergoing RFA due to VES.It seems that the accompanying infammation is primarily conducive to early relapses of arrhythmias after ablations, while in the midterm and long-term perspective in the case of atrial fbrillation, nonpulmonary vein triggers and pulmonary vein reconnections are of key importance.Terefore, it may be worth revisiting the concept of steroids' use for a short time after the RFA procedure for VES, as was performed in some studies after AF ablations studies [57].However, this concept is a topic for a separate study.

Study Limitations.
A relatively small sample size is the study as as the lack of follow-up in 15 patients from our group.It makes some statistical calculations difcult and the conclusions drawn should be treated with caution.Our fndings are based on a retrospective analysis of patients undergoing ablation in one centre; however, increased experience in performing RFA, as well as the advances in the technical feasibility of RFA procedure over 9 years, should be taken into account.In order to establish a real statistical link between long-term VES/VT recurrence after RFA, it should be persistent/recurrent infammation with permanently elevated NLR values, and due to the retrospective nature of the study, these data are not provided by the current study.
Another limitation of the study is the signifcant heterogeneity of the analyzed group of patients, mainly due to the multiple etiologies of cardiomyopathy.Additionally, patients undergoing RFA for nearly 10 years were included in the analysis, and it was a time of intensive development of electrophysiology (ablation index, epicardial ablations) and cardiology (new drugs: angiotensin receptor-neprilysin inhibitor); all this may also be refected in the obtained results.
Te last limitation of the study is the relatively small amount of data on the RFA methodology in our patient group, due to the retrospective nature of the study and reliance on postablation protocols, which often did not include data such as the amount of ablation, low voltage areas, or size of the ablation area covered.

Conclusions
RF ablation performed for the ventricular electrical storm is a procedure characterized by a relatively low incidence of serious complications.Ischemic cardiomyopathy and shortterm complete success of RFA were independent predictors of no VES recurrence during the 12-month follow-up, while neutrophil to lymphocyte ratio and GFR <60 ml/min/ 1.73 m 2 were independently associated with VES relapse.Baseline hsTnI concentration, assessed before the ablation, correlated signifcantly with the overall mortality among patients undergoing RFA for VES.

Figure 1 :Figure 2 :
Figure 1: Patients free from ventricular tachycardia (VT) recurrence (Kaplan-Meier curve) during the 12-month follow-up after the radiofrequency ablation performed due to ventricular electrical storm (N � 47).

Figure 3 :Figure 4 :
Figure3: Treshold of the preablation neutrophil to lymphocyte ratio (NLR) that determined an increased risk of ventricular tachycardia (VT) and/or ventricular electrical storm (VES) recurrence after the radiofrequency ablation performed for VES.

Table 1 :
Baseline characteristics of the studied population and in relation to the long-term outcome of the radiofrequency ablation (RFA) performed due to ventricular electrical storm.

Table 2 :
Clinical characteristics of patients with serious complications of the radiofrequency ablation (RFA) performed due to ventricular electrical storm.

Table 3 :
Laboratory parameters before radiofrequency ablation (RFA) for ventricular electrical storm depending on the short-term ablation result.

Table 4 :
Laboratory parameters before radiofrequency ablation for ventricular electrical storm depending on the long-term ablation result.