Efficacy and safety of radiofrequency ablation for hypertrophic obstructive cardiomyopathy: A systematic review and meta-analysis.

Abstract Background Although radiofrequency ablation is widely used in the treatment of arrhythmias, its role in septal reduction therapy of hypertrophic obstructive cardiomyopathy (HOCM) is unclear. This meta‐analysis aimed to assess the efficacy and safety of radiofrequency septal ablation for HOCM. Hypothesis Radiofrequency septal ablation is effective and safe for relieving obstruction and improving exercise capacity in patients with HOCM. Methods A systematic review of eligible studies that reported outcomes of patients with HOCM who underwent radiofrequency septal ablation was performed using PubMed, Embase, Cochrane, ProQuest, Scopus, ScienceDirect, and Web of Science database. Pooled estimates were calculated using random‐effects meta‐analysis. Methodological quality was assessed using the Newcastle‐Ottawa scale. Publication bias and sensitivity analyses were also performed. Results Eight studies with 91 patients (mean follow‐up 11.6 months) were included. The left ventricular outflow tract (LVOT) gradient at rest decreased significantly after radiofrequency septal ablation (pooled reduction: −58.8 mmHg; 95% confidence interval [CI] −64.3 to −53.5). A reduction was also found in the provoked LVOT gradient with a pooled reduction of −97.6 mmHg (95% CI: −124.4 to −87.1). An improvement of the New York Heart Association classification (mean: −1.4; 95% CI: −1.6 to −1.2) was found during follow‐up. The change in septal thickness was minimal and not statistically significant. Two procedure‐related deaths were documented, and complete heart block occurred in eight patients. Conclusions Radiofrequency septal ablation is effective and safe for relieving LVOT obstruction and improving exercise capacity in patients with HOCM.


| INTRODUCTION
Hypertrophic obstructive cardiomyopathy (HOCM) could lead to symptoms of dyspnea, chest pain, and syncope due to left ventricular outflow tract (LVOT) obstruction. Population-based studies estimated that the prevalence of HOCM was 0.02% to 0.23% in adults. 1 The morbidity and mortality were higher in a population with LVOT obstruction than in that without. [2][3][4] An increased LVOT gradient, which is defined as a peak gradient ≥30 mmHg, was present in 20% to 30% and 70% of hypertrophic cardiomyopathy patients at rest and with exercise provocation, respectively. The key causes of an increased LVOT gradient were septal hypertrophy and systolic anterior motion (SAM) of the mitral valve. 1,5 For decades, myectomy has been the golden standard therapy for symptomatic drug-resistant HOCM because of its excellent outcome. 6 Moreover, alcohol septal ablation (ASA) has been an appealing alternative approach in the treatment of HOCM because it effectively reduced symptoms with less trauma and shorter hospital stay than myectomy.
Nevertheless, the use of ASA is limited by coronary anatomy, which means that 5% to15% of patients are unsuitable to undergo ASA. 7,8 Radiofrequency catheter ablation has been a well-accepted treatment of cardiac arrhythmia for many decades. This technique has been also used to relieve LVOT obstruction without restriction of the coronary anatomy. 9 However, the efficacy and safety of radiofrequency septal ablation have not been clear, as only small studies on this topic were conducted. Therefore, in the current study, we aimed to perform a systematic review and meta-analysis of the short-term efficacy and safety of radiofrequency ablation for HOCM.

| Search strategy
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-analysis of Observational Studies in Epidemiology statement. 10,11 We searched PubMed, Embase, Cochrane, ProQuest, Scopus, ScienceDirect, and Web of Science database from January 1979 to July 2019 using the medical subject heading (MeSH) terms and all synonyms for hypertrophic cardiomyopathy in combination with the MeSH term and all synonyms for radiofrequency ablation (Supporting Information). In order to achieve maximum sensitivity and identify all relevant studies, we applied no language restrictions, and conference abstracts were considered. References to all identified publications were entered into reference-managing software (Endnote, version X9; Clarivate Analytics, Philadelphia, Pennsylvania).

| Study election and data extraction
Clinical studies that reported patients with typical HOCM who underwent radiofrequency ablation for HOCM were screened for inclusion. Typical HOCM was defined as LVOT gradient ≥50 mmHg (at rest or after provocation) and symptomatic despite adequate medical therapy. Exclusion criteria were as follows: studies that included myectomy and ASA, studies without a definite diagnosis, studies without a measurement of the LVOT gradient before or after radiofrequency ablation, reviews, case reports, editorials, and commentary articles. Two independent reviewers reviewed the study titles and abstracts according to the inclusion and exclusion criteria. Studies that satisfied the inclusion criterion were retrieved for full-text assessment. Because of a lack of randomized controlled trial, we included only observational studies in the analysis.
The outcomes were as follows: change in the resting and provoked LVOT gradient, septal thickness, and New York Heart Association (NYHA) functional classification between baseline and postprocedure. We extracted the following data from each selected study: the total number of participants, age, sex, duration of follow-up, ablation site, and major complications. We also collected baseline and post-procedure resting LVOT gradient values, provoked LVOT gradient value, NYHA class, and septal thickness.

| Assessment of study quality
The Newcastle-Ottawa scale (NOS) 12 was used to assess the quality of each study, and included the selection of cases, comparability of cases and controls, and ascertainment of exposure to risks. Furthermore, a sensitivity analysis was considered as an essential part of the quality assessment. 10 The quality of each study was assessed independently by two reviewers. Disagreements between the reviewers were resolved through discussion by the research group until a consensus was reached.

| Statistical analysis
The LVOT gradient, septal thickness, and NYHA class were analyzed as continuous variables (mean ± SD). Pooled estimates of the mean difference in resting and provocation LVOT gradients were calculated by using a random-effect model to describe the effect of radiofrequency septal ablation. We also calculated the pooled estimate of the mean difference in improvement of the septal thickness and NYHA class with a random-effect model.
Heterogeneity of the included studies was examined by using the Cochran Q test, with P < .1 regarded as being statistically significant between-study heterogeneity. The I 2 test was also utilized to assess the magnitude of heterogeneity between the studies; values >50% were regarded as indicating a moderate to high level heterogeneity. 11 Further, sensitivity analyses were conducted by excluding one study sequentially, and the impact of removing each of the studies was evaluated on the basis of the pooled results and between-study heterogeneity. The results were determined as credible when the pooled results and between-study heterogeneity were not substantially different in the sensitivity analyses.
Additionally, publication bias was examined by constructing a funnel plot, and Begg's test and Egger's test were used to assess the funnel plot asymmetry. Statistical analysis of this meta-analysis was conducted in Stata 15.0 (StataCorp, College Station, Texas). includes two studies that treated children ( Table 1). All studies measured the LVOT gradient at rest (mean 77.8 mmHg). Each patient enrolled in these studies was diagnosed as having typical HOCM with an LVOT gradient ≥50 mmHg at rest or after provocation (Table 2). Four studies measured the provoked LVOT gradient before and after the procedure. Five studies reported septal thickness measured by echocardiography before the procedure, and four of them reported septal thickness post-procedure. The NYHA class was reported in six studies that assessed the resolution of symptoms after radiofrequency septal ablation. All studies except one used a left-sided approach (Table 3). Unlike other studies, Liu et al 20 conducted percutaneous intramyocardial septal radiofrequency ablation in which the radiofrequency needle was inserted through the left ventricular apex.

| Quality assessment of included studies
All studies were assessed by NOS in which two studies 13,19 received seven scores, four studies [14][15][16]20 received eight scores and two studies 17,18 received nine scores. It represented moderate to high methodological quality.

| Clinical efficacy and safety of radiofrequency ablation
Patients' mean resting LVOT gradient was reported to be significantly

| Complications associated with radiofrequency ablation
Major complications were documented in six clinical studies, whereas the others did not document complications or only documented a mild F I G U R E 1 Flow diagram of study selection process complication. Two procedure-related deaths due to retroperitoneal hemorrhage and paradoxical increase in the LVOT gradient caused by tissue edema after ablation were documented among 91 participants.
Complete heart block occurred in eight (8.8%) patients with permanent pacemaker dependency, and three patients developed ventricular fibrillation requiring cardioversion.

| Sensitivity analysis and publication bias
As most studies did not measure septal thickness before or after the procedure, pooled analysis of septal thickness included only three studies, which led to severe heterogeneity. Sensitivity analyses found that the corresponding pooled results and heterogeneity were not significantly different in all analyses, except for the pooled analysis of the change in septal thickness after ablation. When Liu et al's study 20 was excluded from the analysis, the pooled mean differences of septal thickness and heterogeneity were reduced significantly (I 2 test: 93-0%, X 2 test: P < .01 to P = .87). Thus, the final pooled analysis of change in septal thickness did not include the study conducted by Liu et al. 20 No publication bias was evident for any of the pooled analyses. An example of Begg's test funnel plot for resting LVOT gradient is shown in Figure 3.

| DISCUSSION
Septal reduction therapy is essential when optimal medication therapy cannot relieve patients' symptoms. Although the benefits of radiofrequency ablation have been widely accepted in the treatment of cardiac arrhythmias, such as ventricular tachycardia and atrial fibrillation, it is still a novel technique in patients with HOCM.  could be up to 5 to 6 mm in ASA and more than 8 mm in myectomy, [26][27][28] there was minimal change in septal thickness after radiofrequency ablation, with only two studies that reported a reduction <2 mm. The SAM of the mitral valve contacting the hypertrophied septum in mid-systole was the key mechanism of LVOT obstruction. 29 Moreover, this SAM-septal feedback mechanism would produce a >30 mmHg pressure gradient at rest or after provocation. Thus, in theory, septal reduction, which stopped the SAMseptal feedback mechanism, could reduce the LVOT gradients. With the electroanatomical mapping system, the advantage of radiofrequency septal ablation was accuracy in targeting the SAM-septal contact area, independent of the coronary anatomy. Studies 15,17 proved that a small amount of damage accurately delivered through radiofrequency ablation did interrupt the SAM-septal feedback mechanism and reduced the LVOT gradient as effectively as ASA, with a minimal change in septal thickness.
Although it has been more than 20 years since the first introduction of ASA, there is still concern about its safety, especially the complete heart block risk. A meta-analysis 25 reported that the periprocedural mortalities were 1.3% for ASA and 2.5% for myectomy.
Although lower mortality was observed after ASA, the proportion of permanent pacemaker dependency after ASA was 10% compared with 4.4% after myectomy. 25 In this review, we found that the incidence of permanent pacemaker implantation was 8.8%, which was not higher than that of ASA. However, clinical studies of radiofrequency ablation conducted in recent years reported a lower incidence of pacemaker dependency because of use of the electroanatomical mapping system. [16][17][18] The His conduction tissue, left bundle, and left anterior and posterior fascicles were directly mapped during radiofrequency ablation, which helped to preserve atrioventricular conduction and was a potential benefit of radiofrequency ablation. Nevertheless, more clinical studies are expected to support that radiofrequency septal ablation is beneficial. Periprocedural mortality (2.2%) in this meta-analysis was similar when compared with that of ASA and myectomy. Two cases of paradoxical increase in the LVOT gradient after the procedure were reported among 91 patients, and one of those cases resulted in death.
Employing dexamethasone peri-procedurally may reduce tissue edema at the ablation site, although more clinical studies are needed to assess the efficacy of this drug. 17 There were three limitations to our meta-analysis. One limitation is that only observational studies were included. controlled trial comparing radiofrequency septal ablation with ASA or myectomy is needed to further assess the efficacy and safety of radiofrequency ablation for patients with HOCM.

| CONCLUSIONS
Radiofrequency septal ablation allows significant reduction in the LOVT gradient and symptomatic improvement of patients with HOCM. Although further study is required, this novel technique is safe and effective, which makes it a promising alternative approach in the treatment of patients who are unsuitable for undergoing myectomy or ASA.