Long-Term Clinical Outcome After Alcohol Septal Ablation and Its Periprocedural Predictive Factors in Japan　― A Retrospective Observational Study ―

Abstract

Background: Evidence is limited regarding long-term clinical outcomes after alcohol septal ablation (ASA) for patients with hypertrophic obstructive cardiomyopathy and its periprocedural predictive factors in Japan.

Methods and Results: This retrospective observational study included 44 patients who underwent ASA between 1998 and 2022 in a single center. We evaluated the periprocedural change in variables and long-term clinical outcomes after the procedure. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. The secondary outcome was all-cause death. Using multivariable Poisson regression with robust error variance, we predicted underlying periprocedural factors related to primary outcome development. ASA decreased the median pressure gradient at the left ventricular outflow tract from 88 to 33 mmHg and reduced moderate or severe mitral regurgitation (MR), present in 53% of patients before ASA, to 16%. Over a median 6-year follow-up, the cumulative incidence of the primary outcome at 5 and 10 years was 16.5% and 25.6%, respectively. After multivariable analysis, moderate or severe MR after ASA was significantly associated with the primary outcome (relative risk 8.78; 95% confidence interval 1.34–57.3; P=0.024). All-cause mortality after ASA was 15.1% and 28.9% at 5 and 10 years, respectively.

Conclusions: This study presents long-term clinical outcomes after ASA in Japan. Moderate or severe MR after ASA was significantly associated with the composite of cardiovascular death or hospitalization for heart failure.

Patients with hypertrophic cardiomyopathy have left ventricular outflow tract (LVOT) obstruction of 30–50% at rest,^1,2 increasing to 70% with provocation by physiological exercise.³ For patients with hypertrophic obstructive cardiomyopathy (HOCM), medical management, including β-blockers, calcium channel blockers, and sodium channel blockers, can reduce pressure gradients at the LVOT and the related symptoms.^4,5 When the symptoms persist despite optimal medical therapy, septal reduction therapy is indicated. Surgical septal myectomy has been demonstrated to relieve LVOT obstruction, improving symptoms and survival rates.⁶ Percutaneous alcohol septal ablation (ASA) is an alternative treatment for septal reduction therapy in cases where surgical intervention is deemed unsuitable.^7–9 Meta-analysis has previously reported no significant difference between ASA and septal myectomy regarding improvement of symptoms, sudden cardiac death, or all-cause death.¹⁰

Editorial p 133

Long-term survival after ASA was reported to be favorable and did not differ significantly from that of the general population.^11,12 The largest multinational Euro-ASA registry (median follow-up 5.7 years) reported long-term clinical outcomes with mortality rates after ASA at 5 and 10 years of 11% and 23%, respectively.¹³ More recently, another multinational registry from overseas (median follow-up 6.4 years) reported a similar result, with a 26% mortality rate at 10 years after ASA.¹⁴ Clinical outcomes in Japan after ASA have also been reported, although only short-term follow-up data have been available thus far,^15,16 highlighting the insufficient evidence regarding long-term follow-up in Japan.

Against this background, we aimed to assess the long-term clinical outcomes after ASA for patients with HOCM in Japan. In addition, we investigated the potential periprocedural factors that serve as predictive indicators for subsequent clinical outcomes.

Methods

Study Population and Data Sources

This was a retrospective observational study of consecutive patients who underwent ASA at Kurashiki Central Hospital between 1998 and 2022. Patients who underwent ASA but were not injected with ethanol into the septal branch were excluded from the analysis. All data were collected from medical records. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Research Ethics Committee of Kurashiki Central Hospital (Reference no. 4156).

ASA Procedure

The ASA procedure was guided by transthoracic echocardiography in all cases. An angioplasty balloon was placed in the septal branch, and echocardiographic contrast was then injected. After confirming the possible contribution to ameliorating the LVOT obstruction, 100% ethanol was slowly injected into the targeted septal branch. We measured the LVOT pressure gradient before and after the procedure using a catheter. If necessary, additional ethanol was injected into the target septal branch. Patients without permanent pacemakers had temporary pacemakers placed during and after the procedure to manage potentially deteriorating atrioventricular blocks. The procedural endpoint was complete ablation of the targeted septal branch. In the present study, procedural success was defined as a reduction in the LVOT pressure gradient of >50%.¹⁶

Definition of Variables and Study Outcomes

Hypertension, dyslipidemia, and diabetes were defined in accordance with the use of respective medications before admission or the description in the medical records. All echocardiographic examinations were performed by experienced cardiologists or technicians at Kurashiki Central Hospital. Patients with a resting gradient ≤30 mmHg but >30 mmHg with provocation were considered to have latent obstruction.¹⁷ Velocity at the LVOT was measured using pulsed-wave Doppler from the apical view. The severity of mitral regurgitation (MR) was determined through a semiquantitative approach using color flow Doppler. The severity of systolic anterior motion (SAM) was graded as 0 (no SAM), 1 (brief anterior motion without septal contact), 2 (brief septal contact), or 3 (septal contact lasting >30% of the systolic period).¹⁸ The primary outcome of this study was a composite of cardiovascular (CV) death or hospitalization for heart failure, analyzed as the time to the first event after ASA. The secondary outcome was all-cause death. CV death was defined as death related to any CV disease, including stroke.¹³

Statistical Analysis

First, we compiled descriptive statistics for the study population. Categorical data are reported as numbers and percentages, and continuous data are reported as the mean±SD or median and interquartile range (IQR) according to data distribution. We also evaluated the periprocedural complications related to ASA. Next, we assessed the periprocedural change in variables, including laboratory and echocardiographic parameters. We determined the significance of differences using a paired-samples t-test or paired Wilcoxon test for continuous data, and the McNemar test for categorical data. We then evaluated the correlation between the grade of SAM and MR severity using the Pearson or Spearman correlation coefficient based on data distribution. The cumulative incidence of the outcomes was then calculated using Kaplan-Meier curves.

We performed multivariable-adjusted Poisson regression with robust error variance¹⁹ to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the primary outcome because the event rate was >10% in this cohort (odds ratios could not be interpreted as RRs). As covariate factors in the multivariable model, the following variables were selected based on their clinical relevance:^2,14,20 age, sex, β-blocker use (yes or no), atrial fibrillation (yes or no), and velocity at the LVOT after ASA. In addition, we incorporated the variables SAM grade after ASA and moderate or severe MR after ASA into the multivariable model because of their potential impact on the primary outcome, as well as their correlation (P<0.1) as identified through univariate analysis (Supplementary Table 1).

We used multiple imputations to account for the missing data values,²¹ whereby we constructed complete data sets regarding variables included as covariate factors in the multivariable model. We used the pooled 20 imputed datasets in the analyses. In the sensitivity analysis, we evaluated the periprocedural predictive factors using the same multivariable model without multiple imputations. All P values reported are 2-sided, and P<0.05 was considered statistically significant. We analyzed all data using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Of 46 patients who underwent ASA between 1998 and 2022, 2 did not receive ethanol injections, 1 because of a lack of valid septal area staining on contrast echocardiography and no improvement in pressure gradient by balloon occlusion, and the other because of anaphylactic shock caused by the contrast agent. After excluding these 2 cases, 44 patients were included in the analysis. Table 1 summarizes the baseline characteristics at the time of hospitalization for ASA. The mean age was 68.7 years, with female predominance (73%). Dyspnea was the most common symptom, followed by chest pain and syncope. Latent obstruction was observed in 5 patients. Approximately half the patients had hypertension, and atrial fibrillation was observed in 8 (18%) patients. Almost 90% of the patients were prescribed β-blockers.

Table 1.

Patient Characteristics

Characteristic	NA	Value
Age (years)	44	68.7±12.6
Female sex	44	32 (73)
BMI (kg/m2)	43	23.8±4.2
Symptoms
Dyspnea	37	28 (76)
Chest pain	37	11 (30)
Syncope	37	2 (5)
Latent HOCM	43	5 (12)
Current smoker	44	3 (7)
Hypertension	44	23 (52)
Diabetes	44	4 (9)
Dyslipidemia	44	18 (41)
Peripheral artery disease	44	1 (2)
Atrial fibrillation	44	8 (18)
Prior MI	44	0 (0)
Prior cerebral infarction	44	3 (7)
History of PCI	44	1 (2)
History of CABG	44	0 (0)
Medications
β-blockers	44	39 (89)
Ca channel blockers	44	30 (68)
Na channel blockers	44	10 (23)

Data are presented as mean±SD for continuous variables and as n (%) for each categorical variable. ^ANumber of non-missing values. BMI, body mass index; CABG, coronary artery bypass grafting; HOCM, hypertrophic obstructive cardiomyopathy; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Among 42 patients with available pressure data obtained by catheter during ASA, 38 had a reduction in the pressure gradient at the LVOT >50% (success rate 90%). The median total volume of ethanol injected was 1.0 mL (IQR 1.0–1.85 mL), and the median periprocedural peak creatine phosphokinase and creatine kinase-MB concentrations were 1,119 and 82 IU/L, respectively. Five (11%) patients required permanent pacemaker implantation during the index hospitalization, and 1 patient died 1 month after the procedure from multiple organ failure attributable to chordal rupture.

Table 2 presents changes in laboratory and echocardiographic parameters. Laboratory parameters, including hemoglobin and kidney function, were not significantly different before and after ASA. The echocardiographic evaluation after ASA (median 36 days; IQR 26–44 days) showed that the mean left ventricular end-systolic dimension increased significantly from 21.8 to 24.0 mm. The SAM grade improved significantly, with the percentage of patients with SAM grade 2 or higher decreasing from 45% to 16%. ASA reduced the peak velocity at the LVOT from 4.6 to 2.9 m/s, and the pressure gradient at the LVOT from a median of 88 to 33 mmHg. Moderate or severe MR observed in 53% of patients before ASA was present in only 16% of patients after the procedure (Supplementary Figure 1). Because the individuals in this study were basically presenting MR related to SAM, a strong correlation was observed between SAM grade and MR severity (before ASA, r_s 0.60, P<0.001; after ASA, r_s 0.70, P<0.001). Before ASA, the median New York Heart Association (NYHA) functional class was II (IQR II–III), which improved after ASA (median Class II; IQR Class I–II). The percentage of patients with NYHA Class III/IV decreased from 46% to 7%. Laboratory and echocardiographic parameters at 1, 5, and 10 years after ASA are presented in Supplementary Table 2.

Table 2.

Changes in Parameters From Before to After Alcohol Septal Ablation

	Before ASA		After ASA		P value
	NA	Value	NA	Value
Laboratory parameters
Hemoglobin (mg/dL)	39	13.0±1.8	34	12.8±1.8	0.327
Creatinine (mg/dL)	39	0.83 [0.69–1.00]	34	0.79 [0.65–1.05]	0.551
eGFR (mL/min/1.73 m2)	39	60.8 [51.6–71.3]	34	60.8 [48.4–70.5]	0.651
BNP (pg/mL)	31	326 [214–709]	27	278 [156–412]	<0.001
Echocardiographic parameters
End-diastolic anteroseptal wall thickness (mm)	33	15.8±3.0	31	15.0±3.1	0.134
End-diastolic posterior wall thickness (mm)	33	12.4±2.7	31	12.5±2.5	0.807
LV end-diastolic dimension (mm)	33	39.6±6.7	31	39.7±6.0	0.357
LV end-systolic dimension (mm)	33	21.8±4.4	31	24.0±4.9	0.014
Left atrial dimension (mm)	33	45.0±7.7	31	44.3±7.1	0.636
Left atrial volume index (mL)	32	68 [56–87]	31	59 [21–51]	0.022
SAM grade	33	1 [1–2]	31	1 [0–1]	<0.001
SAM grade ≥2	33	15 (45)	31	5 (16)	0.013
Peak velocity at LVOT (m/s)	35	4.6±1.1	32	2.9±1.2	<0.001
Pressure gradient at LVOT (mmHg)	34	88 [60–112]	31	33 [15–52]	<0.001
Moderate or severe MR	34	18 (53)	31	5 (16)	0.008

Continuous data are reported as the mean±SD or median [interquartile range] depending on data distribution and were compared using a paired-samples t-test and the paired Wilcoxon test, respectively. Categorical data are reported as n (%) and were compared using the McNemar test. ^ANumber of non-missing values. ASA, alcohol septal ablation; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; LV, left ventricle; LVOT, left ventricular outflow tract; MR, mitral regurgitation; SAM, systolic anterior motion.

Clinical Outcomes After ASA

Of 44 patients, over the median follow-up duration of 6.0 years (IQR 1.6–11.0 years), 10 developed the primary outcome. The cumulative incidence of the primary outcome at 5 and 10 years was 16.5% and 25.6%, respectively (Figure A). Figure B shows the Kaplan-Meier curve for the secondary outcome, with an all-cause mortality rate of 15.1% at 5 years and 28.9% at 10 years. Supplementary Table 3 summarizes the median and 95% CIs for the cumulative incidence of the primary and secondary outcomes, including their components. The cumulative incidence of CV death at 5 and 10 years was 7.1% and 11.8%, respectively. The corresponding rates of hospitalization for heart failure were 9.7% and 14.4%, respectively. During clinical follow-up, 2 patients had implantable cardioverter-defibrillators; 1 was performed as primary prevention 6 months after ASA, and the other was for ventricular tachycardia 6 years after ASA.

Figure.

Kaplan-Meier curves of (A) primary and (B) secondary outcomes representing the incidence of clinical outcomes after alcohol septal ablation (ASA). (A) Cumulative incidence of the composite of cardiovascular death or hospitalization for heart failure. (B) Cumulative incidence of all-cause death.

In the multivariable analysis, moderate or severe MR after ASA was significantly associated with the primary outcome (RR 8.78; 95% CI 1.34–57.3; P=0.024; Table 3). Patients who presented with moderate or severe MR after ASA developed the primary outcome significantly more frequently than those without such MR (Supplementary Figure 2). When the same multivariable model was substituted for the secondary outcome, moderate or severe MR after ASA was still significantly associated with all-cause death (RR 6.09; 95% CI 1.04–35.8; P=0.048; Table 4). In the sensitivity analysis, these results were consistently observed: the primary outcome was significantly associated with moderate or severe MR after ASA (RR 10.9; 95% CI 1.61–74.0; P=0.015; Supplementary Table 4).

Table 3.

RRs for the Primary Outcome

Variables	Univariable analysis		Multivariable analysis
	RR (95% CI)	P value	RR (95% CI)	P value
Age	0.99 (0.94–1.03)	0.538	1.00 (0.94–1.06)	0.882
Female sex	1.50 (0.37–6.08)	0.570	1.10 (0.19–6.51)	0.917
β-blockers use	0.51 (0.15–1.77)	0.291	0.45 (0.08–2.52)	0.364
Atrial fibrillation	1.13 (0.29–4.33)	0.864	1.12 (0.17–7.27)	0.907
SAM grade after ASA	1.13 (0.46–2.76)	0.794	0.63 (0.16–2.49)	0.510
Peak velocity at LVOT after ASA	1.19 (0.64–2.21)	0.582	1.06 (0.42–2.68)	0.900
Moderate or severe MR after ASA	3.79 (1.22–11.8)	0.022	8.78 (1.34–57.3)	0.024

A univariable and multivariable Poisson regression with robust error variance was used to estimate the relative risk (RR) and 95% confidence interval (CI) of the incidence of a composite of cardiovascular death or hospitalization for heart failure. In this model, we used multiple imputations to account for the missing data values. Abbreviations as in Table 2.

Table 4.

RRs for All-Cause Death

Variables	Univariable analysis		Multivariable analysis
	RR (95% CI)	P value	RR (95% CI)	P value
Age	1.00 (0.96–1.04)	0.973	1.01 (0.95–1.06)	0.799
Female sex	3.75 (0.54–26.2)	0.183	2.31 (0.22–24.0)	0.482
β-blockers use	0.34 (0.13–0.88)	0.026	0.38 (0.08–1.77)	0.218
Atrial fibrillation	2.57 (0.98–6.72)	0.054	2.26 (0.64–8.00)	0.206
SAM grade after ASA	0.83 (0.38–1.81)	0.634	0.72 (0.16–3.32)	0.674
Peak velocity at LVOT after ASA	0.82 (0.45–1.50)	0.517	0.86 (0.29–2.52)	0.785
Moderate or severe MR after ASA	2.27 (0.71–7.26)	0.167	6.09 (1.04–35.8)	0.048

A univariable and multivariable Poisson regression with robust error variance was used to estimate the RR and 95% CI of the incidence of all-cause death. In this model, we used multiple imputations to account for the missing data values. Abbreviations as in Tables 2,3.

The analysis focusing on the relationship between moderate or severe MR after ASA and preprocedural echocardiographic parameters is presented in Supplementary Table 5. In this analysis, end-diastolic anteroseptal wall thickness before ASA was significantly associated with postprocedural moderate or severe MR (RR 1.43; 95% CI 1.08–1.89; P=0.012).

Discussion

In the present study, with a median 6-year follow-up, the cumulative incidence of the composite of CV death or hospitalization for heart failure after ASA was 16.5% at 5 years and 25.6% at 10 years. We found that moderate or severe MR after ASA was significantly associated with this adverse outcome, even after adjusting for known risk factors.

Our study provides the first evaluation of the long-term clinical outcome after ASA in Japan. In our study, all-cause mortality rates at 1, 5, and 10 years after ASA were 5%, 15%, and 29%, respectively. Nakamura et al previously reported the short-term outcomes after ASA in Japan.¹⁶ They examined 58 patients (mean age 73 years) with a median follow-up of 1.4 years, observing all-cause mortality rates of 8% at 1 year and 15% at 5 years, which is largely consistent with our findings. In contrast, several reports other countries have explored longer-term outcomes after ASA. For example, Cui et al investigated 585 patients (median age 63.0 years) who underwent ASA with a median 6.4-year follow-up and reported an all-cause mortality rate of 26% at 10 years.¹⁴ Similarly, Veselka et al examined 1,275 patients (mean age 58 years) with a median follow-up of 5.7 years and reported all-cause mortality rates of 11% at 5 years and 23% at 10 years after ASA.¹³ Although the clinical outcomes after ASA may potentially present racial and ethnic disparities,²² the all-cause mortality rate after ASA in Japan appears to be comparable with that reported in other countries.

In the present study, we proposed the hypothesis that moderate or severe MR after ASA may contribute to subsequent unfavorable outcomes. This suggests that additional treatment options could be considered when moderate or severe MR is confirmed after the procedure. Transcatheter mitral intervention (MitraClip) is a potential therapeutic option for patients following unsuccessful procedures because it has been shown to reduce outflow obstruction and eventuate in symptomatic improvement by eliminating SAM and MR.^23,24 Previous studies have reported the association between septum wall thickness before ASA and subsequent CV mortality events.^20,25 Although in these reports there was no mention of a relationship with postprocedural MR, our study found preprocedural anteroseptal wall thickness to be a potential underlying factor of moderate or severe MR after the procedure. This finding suggests that septal wall thickness before ASA not only reflects disease severity, but may also be a potential factor in postprocedural MR. Although there are no randomized studies comparing ASA with other treatments, patients with greater anteroseptal wall thickness may be considered for alternative therapy options to ASA.

Our study has several limitations. First, because of its retrospective and observational nature, the conclusions that can be made may be limited. Although we used a multivariable-adjusted Poisson regression with robust error variance to reduce potential confounding, the adjustable variables in the multivariable analysis were restricted because of the sample size. Second, the assessment of clinical outcomes in our study relied on data obtained from medical records, which could lead to an underestimation of the incidence. However, the long-term clinical outcomes in our study were comparable with those reported in the literature. Third, we used multiple imputations to address missing data variables, potentially affecting the study results. Nevertheless, even when we performed analyses without multiple imputations, we obtained results that aligned with the main analysis. Finally, we analyzed a small sample size from a single center, which may not provide conclusive findings. Additional prospective studies will be necessary to establish definitive conclusions.

In conclusion, the present study reports long-term clinical outcomes after ASA in Japan. We found that the all-cause mortality rate after ASA in Japan may be comparable with that reported from other countries. We also demonstrated a significant association between moderate or severe MR after ASA and the subsequent occurrence of the composite of CV death or hospitalization for heart failure. It is crucial that clinicians determine the optimal management of patients who develop postprocedural moderate or severe MR to improve their prognosis after ASA.

Acknowledgments

The authors are grateful for the contributions of all the investigators. The authors thank Hugh McGonigle, from Edanz (https://www.jp.edanz.com/ac), for editing a draft of the manuscript.

Sources of Funding

None.

Disclosures

The authors declare no conflicts of interest associated with this manuscript.

IRB Information

The present study was approved by the Institutional Review Board of Kurashiki Central Hospital (Reference no. 4156).

Data Availability

The data underlying this article will be shared until March 2025 upon reasonable request from researchers who provide a methodologically sound proposal. After IRB approval, the data will be shared as Excel files via email for any kind of analysis.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0529

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