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Heart, Lung and Circulation

Catheter Ablation for Ventricular Tachycardia in Ischaemic Versus Non-Ischaemic Cardiomyopathy: A Systematic Review and Meta-Analysis

      Background

      There are differences in substrate and ablation approaches for ventricular tachycardia (VT) in ischaemic (ICM) and non-ischaemic cardiomyopathy (NICM).

      Objective

      To perform a systematic review and meta-analysis comparing clinical and procedural characteristics/outcomes of VT ablation in ICM versus NICM.

      Methods

      Electronic databases were searched for comparative studies reporting outcomes of VT ablation in patients with ICM and NICM. Primary outcomes were acute procedural success, VT recurrence and long-term mortality. Meta-analyses were performed using random-effects modelling.

      Results

      Thirty-one (31) studies (7,473 patients; 4,418 ICM and 3,055 NICM) were included. Patients with ICM were significantly older (67.0 vs 55.3 yrs), more commonly male (89% vs 79%), had lower left ventricular ejection fraction (29% vs 38%) were less likely to undergo epicardial access (11% vs 36%) and were more likely to require haemodynamic support during ablation (relative risk [RR] 1.30; 95% CI 1.01–1.69). Acute procedural success (i.e. non-inducibility of VT) was higher in the ICM cohort (RR 1.10, 95% CI 1.05–1.15). Recurrence of VT at follow-up was significantly lower in the ICM cohort (RR 0.77; 95% CI 0.70–0.84). Peri-procedural mortality, incidence of procedural complications and long-term mortality were not significantly different between the cohorts.

      Conclusions

      NICM and ICM patients undergoing VT ablation are fundamentally different in their clinical characteristics, ablation approaches, acute procedural outcomes and likelihood of VA recurrence. VT ablation in NICM has a lower likelihood of procedural success with increased risk of VA recurrence, consistent with known challenging arrhythmia substrate.

      Keywords

      Introduction

      Catheter ablation (CA) is recommended for the treatment of drug-refractory ventricular tachycardia (VT) [
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • Bryant W.J.
      • Callans D.J.
      • Curtis A.B.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      ,
      • Wong C.X.
      • Brown A.
      • Lau D.H.
      • Chugh S.S.
      • Albert C.M.
      • Kalman J.M.
      • et al.
      Epidemiology of sudden cardiac death: global and regional perspectives.
      ,
      • Sacher F.
      • Tedrow U.B.
      • Field M.E.
      • Raymond J.M.
      • Koplan B.A.
      • Epstein L.M.
      • et al.
      Ventricular tachycardia ablation: evolution of patients and procedures over 8 years.
      ]. CA, when compared to medical therapy, is associated with improved arrhythmia-free survival, reduces burden of arrhythmia and is associated with reduction or elimination in the use of anti-arrhythmic drug therapy. Ischaemic and non-ischaemic scar-related VT are fundamentally different in the distribution and topography of scar, mapping findings, ablation approaches and subsequent clinical outcomes in follow-up [
      • Bhaskaran A.
      • Tung R.
      • Stevenson W.G.
      • Kumar S.
      Catheter Ablation of VT in Non-ischaemic cardiomyopathies: endocardial, epicardial and intramural approaches.
      ]. These fundamental differences have been reported via several small individual studies over two decades. The past two decades have seen a growth in the number of catheter ablation procedures for VT [
      • Anderson R.D.
      • Lee G.
      • Prabhu M.
      • Patrick C.J.
      • Trivic I.
      • Campbell T.
      • et al.
      Ten-year trends in catheter ablation for ventricular tachycardia vs other interventional procedures in Australia.
      ] and a higher proportion of patients with non-ischaemic cardiomyopathy (NICM) undergoing VT ablation [
      • Sacher F.
      • Tedrow U.B.
      • Field M.E.
      • Raymond J.M.
      • Koplan B.A.
      • Epstein L.M.
      • et al.
      Ventricular tachycardia ablation: evolution of patients and procedures over 8 years.
      ]. Additionally, advances in epicardial mapping, multi-modality imaging for non-invasive delineation of arrhythmia substrate, advent of high density multi-electrode mapping, and improvements in ablation technologies have made VT ablation possible in a wider selection of patients. The purpose of this systematic review was to therefore: (i) synthesise over two decades of published literature on clinical characteristics, procedural approaches and outcomes after catheter ablation of VT in ischaemic cardiomyopathy (ICM) versus NICM and (ii) examine if ablation outcomes have improved over time.

      Methods

      The study was performed with Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic searches were performed on PubMed, EMBASE, Medline, Cochrane Central Register of Clinical Trials (CENTRAL), and Scopus databases from their date of inception to the 9 September 2021. The search terms used were (“catheter ablation” OR “radiofrequency catheter” OR “radiofrequency ablation”) AND (“Ventricular arrhythmias” OR “ventricular tachycardia”) AND (“Ischaemic cardiomyopathy” AND “Non-Ischaemic cardiomyopathy”). This was supplemented by hand searching the reference lists of key reviews and each of the selected articles to look for any other potentially relevant studies. Two (2) reviewers (T.P. and R.D.A) independently screened the title and abstract of records identified in the search. Full-text publications were subsequently reviewed separately if either reviewer considered the manuscript as being potentially eligible. Disagreements regarding final study inclusion were resolved by discussion and consensus. The meta-analysis was registered in the PROSPERO database
      Comparison of clinical outcomes after catheter ablation for ventricular arrhythmias in patients with ischemic versus non-ischemic cardiomyopathy [CRD42020159374]; National Institute for Health Research, University of York, York, United Kingdom).
      .

      Eligibility Criteria

      Studies were deemed eligible if they fulfilled the following criteria:
      • 1.
        Identification of ICM and NICM patients, that had received radiofrequency catheter ablation (RFA) for the management/treatment of ventricular tachycardia;
      • 2.
        Reported acute procedural success;
      • 3.
        Reported ventricular arrhythmia recurrence at follow-up.
      Data from abstracts, conference posters/presentations, case reports, case series of <3 patients, editorials, reviews, expert opinions and published papers that did not have an English translation were excluded in this review. If institutions published duplicate studies with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included. Patients with VT related to congenital heart disease were excluded.

      Patient and Public Involvement

      Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

      Data Extraction and Critical Appraisal

      All data was independently extracted from text, tables and figures by two investigators (T.P. and R.D.A). Discrepancies were resolved by discussion and consensus. For each study, the following information was extracted: study methodology (study design, duration, disease allocation, follow-up duration, loss to follow-up), participants (inclusion criteria, number of patients, baseline clinical and procedural characteristics) and outcomes (acute procedural success, peri-procedural mortality, procedural complications, VT recurrence at follow-up, mortality at follow-up). All included studies were critically appraised for risk of bias using the Newcastle-Ottawa Scale for case control and cohort studies. Studies were marked and divided into three grading scales: (1) 8 to 9 points (High quality); (2) 4 to 7 points (Medium quality); and (3) 0 to 3 points (Low quality) (Supplemental Table 1, 2).

      Endpoints

      The primary outcomes were acute procedural success, ventricular arrhythmia (VA) recurrence at follow-up, and long-term mortality. The secondary outcomes were peri-procedural mortality, incidence of procedural complications and procedural durations.

      Statistical Analysis

      The pooled incidence, mean difference (MD) or relative risk (RR) were used as summary statistics and reported with 95% confidence intervals (CI). Meta-analyses were performed using random-effects models to account for anticipated clinical and methodological diversity between studies. The I2 statistic was used to estimate the percentage of total variation across studies due to heterogeneity rather than chance, with values exceeding 50% indicative of considerable heterogeneity. For meta-analysis of continuous data, values presented as median and interquartile range were converted to mean and standard deviation using methods described previously [
      • Wan X.
      • Wang W.
      • Liu J.
      • Tong T.
      Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
      ]. Mixed-effects meta-regression models were formed by using publication year as a continuous moderator to assess its impact on the risk of recurrent VA and mortality at follow-up. Publication bias was assessed visually using funnel plots comparing log risk ratios with their standard error. Begg's rank correlation test was used to quantitatively assess for publication bias [
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      ]. Statistical analysis was conducted with Review Manager Version 5.3.5 (Cochrane Collaboration, Oxford, UK) and Comprehensive Meta-Analysis v3.0 (Biostat Inc, Englewood, NJ, US). A two-tailed p-value <0.05 was considered statistically significant.

      Results

      Overall, 3,663 articles were identified through the database and bibliographic searches. After screening of abstracts, review of full text articles, and review of reference lists of eligible articles, 31 studies were included in this review (Figure 1). A narrative review of included articles is shown in Supplemental Table 3.
      Figure thumbnail gr1
      Figure 1PRISMA flowchart summarising electronic search and study selection process.
      Abbreviations: OR, odds ratio; HR, hazards ratio.

      Baseline Characteristics

      In total, 7,473 patients were included (4,418 ICM and 3,055 NICM; Table 1). Ischaemic cardiomyopathy patients, compared to NICM, were significantly older (67.0±10.8 vs 55.3±14.6 yrs, p<0.001) and more likely to be male (89% vs 79%, p<0.001). At the time of ablation, patients with ICM had significantly worse left ventricular ejection fraction (29.3±11.8 vs 38.2±16.5, p<0.001) and a higher proportion had an implantable cardioverter defibrillator (ICD) in situ (89% vs 85%, p<0.001).
      Table 1Baseline clinical features and procedural characteristics of patients undergoing radiofrequency ablation of ventricular tachycardia
      ICM (n=4,418)NICM (n=3,055)P-value
      Clinical Characteristics
      Mean age (years)67.0±10.855.3±14.6<0.001
      Male gender (%)2,638/2,977 (89)1,449/1827 (79)<0.001
      Left ventricular ejection fraction29.3±11.838.2±16.5<0.001
      AICD in situ (%)2,305/2,479 (89)1,354/1538 (85)<0.001
      Procedural Characteristics
      No. of inducible VTs2.6±1.72.4±1.7<0.001
      Cycle length of inducible VTs391±98.6379±91.70.044
      Epicardial access356/3,128 (11)681/1,869 (36)<0.001
      Haemodynamic support required17.4% (95% CI 7.4–35.9)13.9% (95% CI 3.7–40.4)0.04
      Data presented as mean ± standard deviation or number/total (%).
      Abbreviations: ICM, ischaemic cardiomyopathy; NICM, non-ischaemic cardiomyopathy; SD, standard deviation; VT, ventricular tachycardia; AICD, automatic implantable cardioverter defibrillator.

      Procedural Details

      In patients with ICM, the mean number of inducible VTs per patient was higher (2.6±1.7 vs 2.4±1.7, p<0.001) and the mean cycle length of inducible VTs was longer (390.8±98.6 vs 379.4±91.7 ms, p<0.001). Epicardial access was employed in NICM in 36% of all cases, compared to only 11% of ICM cases (p<0.001).

      Procedural Outcomes

      Total procedure (MD 12.9 mins; 95% CI 3.3–22.5; I2 = 45%; p=0.008; Figure 2A) and fluoroscopy (MD 10.9 mins; 95% CI 3.5–18.4; I2 = 93%; p=0.004; Figure 2B) durations were significantly longer for NICM cases. However, RFA duration was significantly longer for ICM cases (MD 8.5 mins; 95% CI 7.0–10.0; I2 = 0%; p<0.001; Figure 2C). Patients with ICM were more likely to require haemodynamic support during ablation cases (RR for ICM 1.30; 95% CI 1.01–1.69; I2 = 0%; p=0.04).
      Figure thumbnail gr2
      Figure 2Forest plot displaying Mean Difference in total procedure [A], fluoroscopy [B] and ablation [C] durations for patients with ICM versus NICM cardiomyopathy undergoing ventricular tachycardia ablation.
      Abbreviations: ICM, ischaemic cardiomyopathy; NICM, non-ischaemic cardiomyopathy; MD, mean difference.
      Pooled rates of acute procedural success were 66.6% (95% CI 61.5–71.4) in patients with ICM compared to 55.6% (95% CI 51.6–61.4) in patients with NICM (Table 2). This difference was statistically significant (RR 1.10; 95% CI 1.05–1.15; I2 = 18%; p<0.001; Figure 3A).
      Table 2Summary of outcomes following ventricular tachycardia ablation in patients with ischaemic versus non-ischaemic cardiomyopathy.
      OutcomeCohortPooled Incidence (95% CI)Meta-Analysis of ICM vs NICMMeta-Regression
      RR (95% CI)P-valueCoefficient (95% CI)P-value
      Procedural
      Acute Procedural SuccessICM66.6% (61.5–71.4)1.10 (1.05–1.15)<0.001-0.02 (-0.06–0.03)0.40
      NICM56.6% (51.6–61.4)-0.02 (-0.06–0.03)0.42
      Peri-Procedural MortalityICM3.5% (2.7–4.4)1.07 (0.73–1.57)0.73-0.007 (-0.08–0.07)0.85
      NICM4.2% (2.7–6.5)-0.02 (-0.13–0.09)0.70
      Peri-Procedural ComplicationsICM10.0% (7.7–12.9)1.09 (0.85–1.40)0.48-0.009 (-0.07–0.05)0.77
      NICM9.3% (7.2–11.9)0.03 (-0.03–0.09)0.33
      Long-Term
      VT Recurrence at Follow-UpICM18.7/100 patient years (15.0–22.4)0.77 (0.70–0.84)<0.0010.005 (-0.002–0.01)0.16
      NICM26.3/100 patient years (21.3–31.3)0.004 (-0.007–0.02)0.48
      Mortality at Follow-UpICM10.1/100 patient years (7.6–12.7)1.03 (0.81–1.33)0.790.001 (-0.003–0.006)0.58
      NICM8.6/100 patient years (5.9–11.2)0.004 (0.001–0.008)0.008
      Abbreviations: CI, confidence intervals; ICM, ischaemic cardiomyopathy; NICM, non-ischaemic cardiomyopathy; RR, relative risk; VT, ventricular tachycardia.

      Peri-Procedural Mortality and Morbidity

      The pooled incidence of procedural complications was 10.0% (95% CI 7.7–12.9) in patients with ICM and 9.3% (95% CI 7.2–11.9) in patients with NICM. This difference was not statistically significant (RR 1.09; 95% CI 0.85–1.40; I2= 37%; p=0.48; Figure 3B). The pooled incidence of peri-procedural mortality was 3.5% (95% CI 2.7–4.4) in patients with ICM and 4.2% (95% CI 2.7–6.5) in patients with NICM, yielding no significant difference (RR 1.07; 95% CI 0.73–1.57; I2 = 0%; p=0.73; Figure 3C).

      Long-Term Outcomes

      The weighted mean follow-up duration for the aggregate study cohort was 23.5 months. The pooled incidence of VA recurrence at follow-up was 18.7 per 100 patient-years (95% CI 15.0–22.4) in the ICM cohort versus 26.3 per 100 patient-years (95% CI 21.3–31.3) in the NICM cohort. The risk of VA recurrence at follow-up was significantly lower in patients with ICM (RR 0.77; 95% CI 0.70–0.84; I2 = 36%; p<0.001; Figure 4A).
      Figure thumbnail gr4
      Figure 4Forest plot displaying RR for VA recurrence [A] and long-term mortality [B] in patients ICM versus NICM cardiomyopathy undergoing ventricular tachycardia ablation.
      Abbreviations: ICM, ischaemic cardiomyopathy; NICM, non-ischaemic cardiomyopathy; RR, relative risk; VA, ventricular arrhythmia.
      The pooled incidence of all-cause mortality at follow-up was 10.1 per 100 patient-years (95% CI 7.6–12.7) in the ICM cohort versus 8.6 per 100 patient-years (95% CI 5.9–11.2) in the NICM cohort. This difference was not statistically significant (RR 1.03; 95% CI 0.81–1.33; I2 = 75%; p=0.79; Figure 4B).

      Meta-Regression

      Meta-regression was employed in order to assess whether VA recurrence or mortality at follow-up varied with year of publication due to temporal effects of improvements in imaging integration, mapping and ablation technologies (Supplemental Figure 1). There was no significant change in VA recurrence in either the ICM (coefficient 0.005; 95% CI -0.002–0.01; p=0.16) or NICM (coefficient 0.004, 95% CI -0.007–0.02, p=0.48) cohorts. In the ICM cohort, publication date was not a significant moderator for long-term mortality (coefficient 0.001; 95% CI -0.003–0.006; p=0.58). In the NICM cohort, long-term mortality showed a small but statistically significant increase over time (coefficient 0.004; 95% CI 0.001–0.008; p=0.008).

      Quality Assessment

      Based on composite Newcastle-Ottawa Scale score, 22 of the included studies were assessed to be of “high quality” while nine were assessed to be of “medium quality.” None of the included studies were assessed to be of “low quality.” A complete summary of critical appraisal of included studies is displayed in Supplemental Tables 1–2.

      Publication Bias

      There was no evidence of significant publication bias for endpoints of long-term mortality (p=0.38), VA recurrence at follow-up (p=0.41) and acute procedural success (p=0.52). Funnel plots for these endpoints comparing precision and effect sizes of individual studies are displayed in Supplemental Figure 2.

      Discussion

      This study provides a summation of two decades of published data including 7,473 patients exploring the differences in clinical and procedural characteristics, acute procedural outcomes and outcomes in follow-up of arrhythmia recurrence and mortality in patients with ICM, compared to NICM aetiology presenting for catheter ablation. We identified the following key findings:
      • 1)
        ICM and NICM patients at baseline characteristics are uniquely distinct from one another. Patients with ICM were more likely to be male, older and have greater left ventricular ejection fraction (LVEF) impairment than patients with NICM.
      • 2)
        Acute procedural success was lower in NICM patients, despite longer procedural times, longer fluoroscopy times and higher rates of epicardial access. In contrast, ICM patients had longer RF ablation times and were more likely to require haemodynamic support.
      • 3)
        Ventricular arrhythmia recurrence post-ablation is greater in NICM patients compared to ICM patients, however peri-procedural long-term mortality did not statistically favour one specific aetiology.
      • 4)
        Meta-regression analysis showed no significant change over time in the incidence of VA recurrence at follow-up. Long-term mortality rates were not significantly moderated by publication year for ICM cohort but a marginal increase in mortality was seen in more recent publications for patients with NICM.

      Fundamental Differences in the Demographic Profile Between ICM and NICM

      Baseline clinical characteristics were significantly different between ICM and NICM patients. Patients with NICM were younger owing to the heterogenous nature of NICM, which encompasses various conditions, namely, genetic, inflammatory, toxic, and idiopathic aetiologies often recognised at an earlier age than in patients with ICM. Moreover, patients with NICM may have earlier recognition of their disease through both the utilisation of cardiac magnetic resonance imaging, which can non-invasively detect scar based on late gadolinium enhancement and tissue mapping (e.g. T1 and T2 mapping) and genetic testing in familial cardiomyopathies.
      Patients with ICM had worse LVEF at the time of ablation compared to NICM, due to infarct-related late ventricular remodelling, which results in proclivity to VA. In contrast, patients with NICM were often diagnosed having developed sustained VA before overt ventricular dysfunction. This is particularly apparent in genetic heart disease such as Lamin A/C cardiomyopathy or arrhythmogenic cardiomyopathy (selectively affecting the right ventricle more than the left ventricle, often with preservation of left ventricular function) and inflammatory conditions such cardiac sarcoidosis where focal inflammation and scarring create the substrates for VT before overt ventricular dysfunction.
      More males were present with ICM than NICM, however in both cohorts males comprised the majority of patients (≥80%). Females in general are less likely to suffer from cardiovascular diseases due to the cardioprotective features of oestrogen [
      • Bell J.R.
      • Bernasochi G.B.
      • Varma U.
      • Raaijmakers A.J.A.
      • Delbridge L.M.D.
      Sex and sex hormones in cardiac stress—mechanistic insights.
      ,
      • Kander M.C.
      • Cui Y.
      • Liu Z.
      Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases.
      ], explaining the clear difference in the sexes. Moreover, it has been noted that women are often under-represented in ablation procedures, owing to late presentation with disease, and a bias to not being offered invasive procedures as commonly as men [
      • Baldinger S.H.
      • Kumar S.
      • Romero J.
      • Fujii A.
      • Epstein L.M.
      • Michaud G.F.
      • et al.
      A Comparison of women and men undergoing catheter ablation for sustained monomorphic ventricular tachycardia.
      ,
      • Kentner A.C.
      • Grace S.L.
      Between mind and heart: sex-based cognitive bias in cardiovascular disease treatment.
      ]. The higher number of devices in-situ in ICM patients at the time of ablation is attributable to most patients qualifying for ICD implant based on guidelines for primary prevention of sudden cardiac death (LVEF≤35% at least 40 days post myocardial infarction, positive EPS findings for inducible VT/VF, or NYHA class II or III with LVEF≤35%) before spontaneous VT occurs. Occurrence of spontaneous VT in ICM is most often late after onset of overt progressive ventricular dysfunction as the structural and electrical remodelling facilitates the necessary substrate for re-entrant VT. In contrast, patients with NICM may initially present with spontaneous VT rather than ventricular dysfunction as their first presentation of the disease and are less likely to have an ICD in-situ, attributable to their preserved ventricular function and absence of heart failure symptoms.

      Differences in Procedural Characteristics Between the ICM and NICM Patients

      In ischaemic patients, scar is often subendocardial with variable transmural penetration, depending on duration of ischaemia, collateralisation and the effectiveness of revascularisation [
      • Soejima K.
      • Stevenson W.G.
      • Sapp J.L.
      • Selwyn A.P.
      • Couper G.
      • Epstein L.M.
      Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
      ,
      • Zaman S.
      • Deshmukh T.
      • Aslam A.
      • Martin C.
      • Kovoor P.
      Sex differences in electrophysiology, ventricular tachyarrhythmia, cardiac arrest and sudden cardiac death following acute myocardial infarction.
      ]. Patients with NICM have fundamentally different scar locations, scar topography, and scar properties that support VT compared to patients with ICM [
      • Nakahara S.
      • Tung R.
      • Ramirez R.J.
      • Michowitz Y.
      • Vaseghi M.
      • Buch E.
      • et al.
      Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia.
      ]. Scar in NICM can be patchy, perivalvular, intramural and epicardial, commonly involves the right ventricle and is often co-localised to critical structures [
      • Soejima K.
      • Stevenson W.G.
      • Sapp J.L.
      • Selwyn A.P.
      • Couper G.
      • Epstein L.M.
      Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
      ,
      • Nakahara S.
      • Tung R.
      • Ramirez R.J.
      • Michowitz Y.
      • Vaseghi M.
      • Buch E.
      • et al.
      Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia.
      ]. Frequent epicardial and intramural involvement makes ablation challenging, largely due to the difficulty in identifying critical isthmuses for re-entry (which may be intramural) and of the challenges faced by contemporary ablation technologies in the attempt to achieve sufficient lesion depth to interrupt the critical isthmuses; moreover the potential for collateral injury to the phrenic nerve, His bundle, and the coronary arteries may impede the operator’s ability to achieve VT cure [
      • Soejima K.
      • Stevenson W.G.
      • Sapp J.L.
      • Selwyn A.P.
      • Couper G.
      • Epstein L.M.
      Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
      ,
      • Schweikert R.A.
      • Saliba W.I.
      • Tomassoni G.
      • Marrouche N.F.
      • Cole C.R.
      • Dresing T.J.
      • et al.
      Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations.
      ,
      • Shirai Y.
      • Liang J.J.
      • Santangeli P.
      • Arkles J.S.
      • Schaller R.D.
      • Supple G.E.
      • et al.
      Comparison of the ventricular tachycardia circuit between patients with ischemic and nonischemic cardiomyopathies: detailed characterization by entrainment.
      ,
      • Fukuzawa K.
      • Yoshida A.
      • Kubo S.
      • Takano T.
      • Kiuchi K.
      • Kanda G.
      • et al.
      Endocardial substrate mapping for monomorphic ventricular tachycardia ablation in ischemic and non-ischemic cardiomyopathy.
      ].
      Due to these fundamental differences in scar topography and location, and its intramural location which can be difficult to target with contemporary ablation techniques, procedure time, fluoroscopy time are longer in NICM patients, as observed in this review [
      • Yu R.
      • Ma S.
      • Tung R.
      • Stevens S.
      • Macias C.
      • Bradfield J.
      • et al.
      Catheter ablation of scar-based ventricular tachycardia: Relationship of procedure duration to outcomes and hospital mortality.
      ]. Epicardial access is more frequently needed to access substrate in NICM, consistent with the findings of this review. Indeed epicardial access ablation for recurrent VT in NICM patients returning for repeat procedures has previously been reported as high as 75% [
      • Schmidt B.
      • Chun K.R.
      • Baensch D.
      • Antz M.
      • Koektuerk B.
      • Tilz R.R.
      • et al.
      Catheter ablation for ventricular tachycardia after failed endocardial ablation: epicardial substrate or inappropriate endocardial ablation?.
      ]. Lower ablation time in the NICM group in the present meta-analysis may be due to paucity of ablation targets such as bipolar low voltage and electrogram targets such as fractionated and late potentials and local abnormal ventricular activities, particularly in septal subtypes of NICM [
      • Soejima K.
      • Stevenson W.G.
      • Sapp J.L.
      • Selwyn A.P.
      • Couper G.
      • Epstein L.M.
      Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
      ,
      • Shirai Y.
      • Liang J.J.
      • Santangeli P.
      • Arkles J.S.
      • Schaller R.D.
      • Supple G.E.
      • et al.
      Comparison of the ventricular tachycardia circuit between patients with ischemic and nonischemic cardiomyopathies: detailed characterization by entrainment.
      ,
      • Schmidt B.
      • Chun K.R.
      • Baensch D.
      • Antz M.
      • Koektuerk B.
      • Tilz R.R.
      • et al.
      Catheter ablation for ventricular tachycardia after failed endocardial ablation: epicardial substrate or inappropriate endocardial ablation?.
      ]. In contrast, the longer ablation times observed in ICM patients in the present meta-analysis may be due to more visible targets for ablation such as larger areas of bipolar low voltage scar, increased incidence of identifiable fractionated and late potentials and local abnormal ventricular activities that facilitate the identification of conduction channels. Identification of areas of abnormal conduction allows for the application of sophisticated electrogram-based substrate mapping targets (e.g. decrement-evoked potential mapping, isochronal late activation mapping). Furthermore, ICM patients are more likely to receive greater amounts of ablation with complete scar homogenisation [
      • Nakahara S.
      • Tung R.
      • Ramirez R.J.
      • Michowitz Y.
      • Vaseghi M.
      • Buch E.
      • et al.
      Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia.
      ,
      • Marchlinski F.E.
      • Callans D.J.
      • Gottlieb C.D.
      • Zado E.
      Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy.
      ]. Ventricular tachycardia cycle length was significantly longer in our study patients with ICM, consistent with previous findings of VT being slower in ICM patients during conduction around scar compared to NICM patients [
      • Sacher F.
      • Tedrow U.B.
      • Field M.E.
      • Raymond J.M.
      • Koplan B.A.
      • Epstein L.M.
      • et al.
      Ventricular tachycardia ablation: evolution of patients and procedures over 8 years.
      ,
      • Zaman S.
      • Deshmukh T.
      • Aslam A.
      • Martin C.
      • Kovoor P.
      Sex differences in electrophysiology, ventricular tachyarrhythmia, cardiac arrest and sudden cardiac death following acute myocardial infarction.
      ].
      Patients with ICM are more likely to require haemodynamic support compared to NICM due to their reduced LVEF, and the presence of additional co-morbidities such as heart failure, renal failure, and lung disease. Prior studies have shown that haemodynamic support is more frequently employed in ICM ablation and can reduce time spent in intensive care, hospital stay and is linked to an overall reduction in complications [
      • Kumar S.
      • Fujii A.
      • Kapur S.
      • Romero J.
      • Mehta N.K.
      • Tanigawa S.
      • et al.
      Beyond the storm: comparison of clinical factors, arrhythmogenic substrate, and catheter ablation outcomes in structural heart disease patients with versus those without a history of ventricular tachycardia storm.
      ,
      • Aryana A.
      • Gearoid O'Neill P.
      • Gregory D.
      • Scotti D.
      • Bailey S.
      • Brunton S.
      • et al.
      Procedural and clinical outcomes after catheter ablation of unstable ventricular tachycardia supported by a percutaneous left ventricular assist device.
      ].

      Differences in Acute Procedural Success and Outcomes in ICM vs NICM Patients

      Given the complexity of substrate in NICM (epicardial, intramural, adjacency to critical structures), paucity of ablation targets, and limitations of radiofrequency ablation in producing adequate lesions within deep intramural substrate, acute procedural success was notably lower and VA recurrence higher in NICM, compared with ICM patients. The trend toward higher complications in ICM is likely attributed to the need for haemodynamic support, lower LVEF, and advanced age.
      Whilst not observed in this review, complications play a pivotal role in procedural success, peri-procedural mortality, VA recurrence, and long-term mortality [
      • Schweikert R.A.
      • Saliba W.I.
      • Tomassoni G.
      • Marrouche N.F.
      • Cole C.R.
      • Dresing T.J.
      • et al.
      Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations.
      ,
      • Borger Van Der Burg A.E.
      • De Groot N.M.S.
      • Van Erven L.
      • Bootsma M.
      • Van Der Wall E.E.
      • Schalij M.J.
      Long-term follow-up after radiofrequency catheter ablation of ventricular tachycardia: a successful approach?.
      ,
      • Di Biase L.
      • Santangeli P.
      • Astudillo V.
      • Conti S.
      • Mohanty P.
      • Mohanty M.
      • et al.
      Catheter ablation of ventricular arrhythmias with the remote magnetic navigation system and the 3.5 mm open irrigated magnetic catheter: results from a large single center series.
      ,
      • Della Bella P.
      • Baratto F.
      • Tsiachris D.
      • Trevisi N.
      • Vergara P.
      • Bisceglia C.
      • et al.
      Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: long-term outcome after ablation.
      ,
      • Deneke T.
      • Shin D.I.
      • Lawo T.
      • Bsche L.
      • Balta O.
      • Anders H.
      • et al.
      Catheter ablation of electrical storm in a collaborative hospital network.
      ]. We observed no statistical differences between ICM and NICM patients. This was most likely due to the heterogenous nature of definition of complications between included manuscripts. We found no difference in peri-procedural or long-term mortality between the groups. Kumar et al. previously demonstrated that whilst VA recurrence was higher in NICM, ICM had higher mortality than NICM [
      • Kumar S.
      • Romero J.
      • Mehta N.K.
      • Fujii A.
      • Kapur S.
      • Baldinger S.H.
      • et al.
      Long-term outcomes after catheter ablation of ventricular tachycardia in patients with and without structural heart disease.
      ]. That study had a median follow-up of 6 years, however in our analysis, the vast majority of included studies had shorter follow-up durations. It is plausible that similar findings could have been noted in our meta-analysis compared to that of Kumar et al. [
      • Kumar S.
      • Romero J.
      • Mehta N.K.
      • Fujii A.
      • Kapur S.
      • Baldinger S.H.
      • et al.
      Long-term outcomes after catheter ablation of ventricular tachycardia in patients with and without structural heart disease.
      ], if follow-up duration was longer.

      Trends in Outcomes on Meta-Regression Analysis

      Meta-regression analysis in our study was limited by the fact that only a small number of studies (n=31) were included in the meta-analysis. There was no change in VA recurrence over time in either the ICM or NICM cohorts, possibly because the impact of improved VT ablation techniques have been offset by increased complexity of cases being attempted. The marginal increase in mortality with publication year in NICM patients could be due to more high-risk patients with complex disease being referred for catheter ablation in recent years, enabled by improvements in mapping and ablation technologies.

      Study Limitations

      Our meta-analysis has several important limitations. Most papers were retrospective single centre studies, performed at tertiary referral centres with specialist expertise for VT ablation. There was an inherent referral bias in that patients with more advanced disease would be included in these studies. NICM patients with various disease aetiology were pooled together. This pooling may mask size of effect; for example more favourable outcomes have been noted in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), compared to cardiac sarcoidosis, which may have diluted our results [
      • Vaseghi M.
      • Hu T.Y.
      • Tung R.
      • Vergara P.
      • Frankel D.S.
      • Di Biase L.
      • et al.
      Outcomes of catheter ablation of ventricular tachycardia based on etiology in nonischemic heart disease: an international ventricular tachycardia ablation center collaborative study.
      ]. Follow-up durations varied considerably across included studies, contributing to significant heterogeneity. However, to account for this, pooled incidences for long-term outcomes (VA recurrence and mortality) were calculated as events per person-years.

      Conclusions

      Pooled data from 7,473 patients over two decades of published data comparing patients with ICM and NICM shows important clinical, procedural and outcome differences between the two groups. Whilst ICM patients are a cohort with generally more advanced disease, their acute procedural success is higher and arrhythmic outcomes more favourable in follow-up compared to NICM patients. NICM patients pose greater challenges to contemporary ablation strategies in the abolishment of arrhythmic substrate owing to the complex heterogeneity of NICM substrate and the limitations of contemporary ablation technologies in accessing arrhythmic substrate, resulting in lower acute procedural success and higher VA recurrence in follow-up.

      Acknowledgements

      Contributors

      SK conceived and designed the study. Material preparation, data collection and analysis were performed by AK, SV, TP and RA. SV performed the meta-analysis. All authors contributed to the interpretation of data. The manuscript was drafted by AK, SV, TP and SK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. AK and SV contributed equally to this work.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Competing Interests

      SK is a recipient of the NSW Health Early-Career Fellowship. TC is a former employee of Biosense Webster Inc.

      Supplementary Data

      Figure thumbnail figs1
      Supplemental Figure 1Meta-regression to assess (i) whether VA recurrence varied with year of publication in (A) ICM patients and (B) NICM patients and (ii) whether mortality varied with year of publication in (C) ICM patients and (D) NICM patients.
      Figure thumbnail figs2
      Supplemental Figure 2Funnel plots for the endpoints of (A) long-term mortality, (B) VA recurrence at follow-up and (C) acute procedural success.

      References

        • Al-Khatib S.M.
        • Stevenson W.G.
        • Ackerman M.J.
        • Bryant W.J.
        • Callans D.J.
        • Curtis A.B.
        • et al.
        2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
        Heart Rhythm. 2018; 15: e190-e252
        • Wong C.X.
        • Brown A.
        • Lau D.H.
        • Chugh S.S.
        • Albert C.M.
        • Kalman J.M.
        • et al.
        Epidemiology of sudden cardiac death: global and regional perspectives.
        Heart Lung Circ. 2019; 28: 6-14
        • Sacher F.
        • Tedrow U.B.
        • Field M.E.
        • Raymond J.M.
        • Koplan B.A.
        • Epstein L.M.
        • et al.
        Ventricular tachycardia ablation: evolution of patients and procedures over 8 years.
        Circ Arrhythm Electrophysiol. 2008; 1: 153-161
        • Bhaskaran A.
        • Tung R.
        • Stevenson W.G.
        • Kumar S.
        Catheter Ablation of VT in Non-ischaemic cardiomyopathies: endocardial, epicardial and intramural approaches.
        Heart Lung Circ. 2019; 28: 84-101
        • Anderson R.D.
        • Lee G.
        • Prabhu M.
        • Patrick C.J.
        • Trivic I.
        • Campbell T.
        • et al.
        Ten-year trends in catheter ablation for ventricular tachycardia vs other interventional procedures in Australia.
        J Cardiovasc Electrophysiol. 2019; 30: 2353-2361
        • Wan X.
        • Wang W.
        • Liu J.
        • Tong T.
        Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
        BMC Med Res Methodol. 2014; 14: 135
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Bell J.R.
        • Bernasochi G.B.
        • Varma U.
        • Raaijmakers A.J.A.
        • Delbridge L.M.D.
        Sex and sex hormones in cardiac stress—mechanistic insights.
        J Steroid Biochem Mol Biol. 2013; 137: 124-135
        • Kander M.C.
        • Cui Y.
        • Liu Z.
        Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases.
        J Cell Mol Med. 2017; 21: 1024-1032
        • Baldinger S.H.
        • Kumar S.
        • Romero J.
        • Fujii A.
        • Epstein L.M.
        • Michaud G.F.
        • et al.
        A Comparison of women and men undergoing catheter ablation for sustained monomorphic ventricular tachycardia.
        J Cardiovasc Electrophysiol. 2017; 28: 201-207
        • Kentner A.C.
        • Grace S.L.
        Between mind and heart: sex-based cognitive bias in cardiovascular disease treatment.
        Front Neuroendocrinol. 2017; 45: 18-24
        • Soejima K.
        • Stevenson W.G.
        • Sapp J.L.
        • Selwyn A.P.
        • Couper G.
        • Epstein L.M.
        Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
        J Am Coll Cardiol. 2004; 43: 1834-1842
        • Zaman S.
        • Deshmukh T.
        • Aslam A.
        • Martin C.
        • Kovoor P.
        Sex differences in electrophysiology, ventricular tachyarrhythmia, cardiac arrest and sudden cardiac death following acute myocardial infarction.
        Heart Lung Circ. 2020; 29: 1025-1031
        • Nakahara S.
        • Tung R.
        • Ramirez R.J.
        • Michowitz Y.
        • Vaseghi M.
        • Buch E.
        • et al.
        Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia.
        J Am Coll Cardiol. 2010; 55: 2355-2365
        • Schweikert R.A.
        • Saliba W.I.
        • Tomassoni G.
        • Marrouche N.F.
        • Cole C.R.
        • Dresing T.J.
        • et al.
        Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations.
        Circulation. 2003; 108: 1329-1335
        • Shirai Y.
        • Liang J.J.
        • Santangeli P.
        • Arkles J.S.
        • Schaller R.D.
        • Supple G.E.
        • et al.
        Comparison of the ventricular tachycardia circuit between patients with ischemic and nonischemic cardiomyopathies: detailed characterization by entrainment.
        Circ Arrhythm Electrophysiol. 2019; 12
        • Fukuzawa K.
        • Yoshida A.
        • Kubo S.
        • Takano T.
        • Kiuchi K.
        • Kanda G.
        • et al.
        Endocardial substrate mapping for monomorphic ventricular tachycardia ablation in ischemic and non-ischemic cardiomyopathy.
        Kobe J Med Sci. 2008; 54: E122-E135
        • Yu R.
        • Ma S.
        • Tung R.
        • Stevens S.
        • Macias C.
        • Bradfield J.
        • et al.
        Catheter ablation of scar-based ventricular tachycardia: Relationship of procedure duration to outcomes and hospital mortality.
        Heart Rhythm. 2015; 12: 86-94
        • Schmidt B.
        • Chun K.R.
        • Baensch D.
        • Antz M.
        • Koektuerk B.
        • Tilz R.R.
        • et al.
        Catheter ablation for ventricular tachycardia after failed endocardial ablation: epicardial substrate or inappropriate endocardial ablation?.
        Heart Rhythm. 2010; 7: 1746-1752
        • Marchlinski F.E.
        • Callans D.J.
        • Gottlieb C.D.
        • Zado E.
        Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy.
        Circulation. 2000; 101: 1288-1296
        • Kumar S.
        • Fujii A.
        • Kapur S.
        • Romero J.
        • Mehta N.K.
        • Tanigawa S.
        • et al.
        Beyond the storm: comparison of clinical factors, arrhythmogenic substrate, and catheter ablation outcomes in structural heart disease patients with versus those without a history of ventricular tachycardia storm.
        J Cardiovasc Electrophysiol. 2017; 28: 56-67
        • Aryana A.
        • Gearoid O'Neill P.
        • Gregory D.
        • Scotti D.
        • Bailey S.
        • Brunton S.
        • et al.
        Procedural and clinical outcomes after catheter ablation of unstable ventricular tachycardia supported by a percutaneous left ventricular assist device.
        Heart Rhythm. 2014; 11: 1122-1130
        • Borger Van Der Burg A.E.
        • De Groot N.M.S.
        • Van Erven L.
        • Bootsma M.
        • Van Der Wall E.E.
        • Schalij M.J.
        Long-term follow-up after radiofrequency catheter ablation of ventricular tachycardia: a successful approach?.
        J Cardiovasc Electrophysiol. 2002; 13: 417-423
        • Di Biase L.
        • Santangeli P.
        • Astudillo V.
        • Conti S.
        • Mohanty P.
        • Mohanty M.
        • et al.
        Catheter ablation of ventricular arrhythmias with the remote magnetic navigation system and the 3.5 mm open irrigated magnetic catheter: results from a large single center series.
        Eur Heart J. 2010; 31: 562
        • Della Bella P.
        • Baratto F.
        • Tsiachris D.
        • Trevisi N.
        • Vergara P.
        • Bisceglia C.
        • et al.
        Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: long-term outcome after ablation.
        Circulation. 2013; 127: 1359-1368
        • Deneke T.
        • Shin D.I.
        • Lawo T.
        • Bsche L.
        • Balta O.
        • Anders H.
        • et al.
        Catheter ablation of electrical storm in a collaborative hospital network.
        Am J Cardiol. 2011; 108: 233-239
        • Kumar S.
        • Romero J.
        • Mehta N.K.
        • Fujii A.
        • Kapur S.
        • Baldinger S.H.
        • et al.
        Long-term outcomes after catheter ablation of ventricular tachycardia in patients with and without structural heart disease.
        Heart Rhythm. 2016; 13: 1957-1963
        • Vaseghi M.
        • Hu T.Y.
        • Tung R.
        • Vergara P.
        • Frankel D.S.
        • Di Biase L.
        • et al.
        Outcomes of catheter ablation of ventricular tachycardia based on etiology in nonischemic heart disease: an international ventricular tachycardia ablation center collaborative study.
        JACC Clin Electrophysiol. 2018; 4: 1141-1150