Relationship Between Procedural Right Bundle Branch Block and 1-Year Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy　― A Retrospective Study ―

Junya Matsuda; Hitoshi Takano; Masaki Morooka; Yoichi Imori; Jun Nakata; Mitsunobu Kitamura; Shuhei Tara; Yukichi Tokita; Takeshi Yamamoto; Morimasa Takayama; Wataru Shimizu

doi:10.1253/circj.CJ-20-1191

Abstract

Background: Alcohol septal ablation (ASA) is a treatment option in patients with drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). In many patients, right bundle branch block (RBBB) develops during ASA because septal branches supply the right bundle branch. However, the clinical significance of procedural RBBB is uncertain.

Methods and Results: We retrospectively reviewed 184 consecutive patients with HOCM who underwent ASA. We excluded 40 patients with pre-existing RBBB (n=10), prior pacemaker implantation (n=15), mid-ventricular obstruction type (n=10), and those lost to follow-up (n=5), leaving 144 patients for analysis. Patients were divided into 2 groups according to the development (n=95) or not (n=49) of procedural RBBB. ASA conferred significant decreases in the left ventricular pressure gradient (LVPG) in both the RBBB and no-RBBB group (from 74±48 to 27±27 mmHg [P<0.001] and from 75±45 to 31±33 mmHg [P<0.001], respectively). None of the RBBB patients developed further conduction system disturbances. The percentage reduction in LVPG at 1 year after the procedure was significantly greater in the RBBB than no-RBBB group (66±24% vs. 49±45%; P=0.035). Procedural RBBB was not associated with pacemaker implantation after ASA, but was associated with reduction in repeat ASA (odds ratio 0.34; 95% confidence interval 0.13–0.92; P=0.045).

Conclusions: Although RBBB frequently occurs during the ASA procedure, it does not adversely affect clinical outcomes.

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease characterized by cardiac hypertrophy in the absence of hypertension and aortic valve disease. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients.¹^,² Alcohol septal ablation (ASA) is a treatment option for hypertrophic obstructive cardiomyopathy (HOCM) refractory to optimal medical therapy:³^–⁷ to reduce symptoms and the left ventricular pressure gradient (LVPG), pure ethanol is injected into septal branches that supply the hypertrophic septal myocardium constituting LVOT obstruction. In recent years, long-term reductions in LVOT obstruction and associated reductions in symptoms after ASA have been well documented.⁴^,⁸^,⁹

Editorial p 1492

Disturbance of the atrioventricular (AV) conduction system is a well-known adverse effect of ASA, with an approximate 10% risk of requiring permanent pacing due to complete atrioventricular (AV) block after ASA.⁷^,¹⁰^,¹¹ In addition to complete AV block, right bundle branch block (RBBB) has been reported to develop in approximately 39–68% of patients.⁷^,¹¹ However, insufficient ablation for fear of such conduction system disturbances may possibly lead to failure of LVPG reduction and symptom improvement.¹^,²^,¹²^,¹³

The relationship between procedural RBBB and (1) subsequent development of AV block requiring pacemaker implantation, (2) reductions in symptomatic severity, pressure gradient, left ventricular (LV) mass, and LV diastolic dysfunction, and (3) requirements for repeat ASA are unclear. Therefore, the aim of the present study was to evaluate the relevance of therapeutic outcomes, post-ASA complications, and the requirement for repeat ASA with and without RBBB during the first ASA.

Methods

Ethics Statement

Ethics approval for the study was obtained from the Review Committee of Nippon Medical School (Approval no. 28-07-615), and written informed consent was obtained from all patients, in accordance with the principles of the Declaration of Helsinki.

Study Design and Population

We performed 217 ASA procedures in 184 patients with drug-refractory HOCM at Nippon Medical School Hospital between January 1998 and January 2017. Patients with pre-existing RBBB (n=10), dual-chamber pacing therapy before ASA (n=15), isolated mid-ventricular obstruction type of HOCM (n=10), and those lost to follow-up (n=5) were excluded from the study. After applying the exclusion criteria, 144 patients were finally enrolled in the present retrospective study (Figure 1), and their clinical course after ASA was evaluated over a 1-year follow-up period. The study population was divided into 2 groups: the RBBB (n=95; 66%) and no-RBBB (n=49; 34%) groups. Patients were assigned to the RBBB group if they had developed RBBB within 24 h of the ASA procedure. Patients who had RBBB and transient complete AV block after ASA were included in the RBBB group. Three patients who had left bundle branch block (LBBB) after ASA were included in the no-RBBB group. Clinical examinations, electrocardiography (ECG), and echocardiography were performed at baseline and 3 months and 1 year after ASA. Data for all patients who underwent ASA were consecutively recorded in the institutional registry database.

Figure 1.

Study flowchart. Overall, 184 patients who were diagnosed with drug-refractory hypertrophic obstructive cardiomyopathy (HOCM) underwent alcohol septal ablation (ASA) between 1998 and 2007. Patients were excluded if they had pre-existing right bundle branch block (RBBB), underwent dual chamber DDD pacemaker therapy before ASA, underwent ASA for mid-ventricular obstruction-type HOCM, or were lost to follow-up of the clinical course over a 1-year period after ASA. Thus, 144 patients were finally enrolled in this study (RBBB, n=95; no-RBBB, n=49).

Diagnosis of HCM and HOCM

The diagnosis of HCM was established using transthoracic echocardiography. The definition of HCM was based on the presence of a maximum LV wall thickness of >15 mm on transthoracic echocardiography or cardiac magnetic resonance imaging and the absence of other conditions that may explain left ventricular hypertrophy (LVH) during a patient’s clinical course. HOCM was diagnosed in patients with defined HCM and an intraventricular velocity of >2.7 m/s on echocardiography (or a gradient of >30 mmHg on a direct simultaneous recording) at rest or on provocation. Patients who exhibited only a sigmoid septum but not significant hypertrophy were excluded from the study. Systolic anterior motion of the anterior mitral leaflet was not considered essential for a diagnosis of muscular obstruction at the mid-ventricular level.

ECG Evaluation

Standard 12-lead ECG (10 mm=1 mV, 25 mm/s) was performed with patients in the supine position during quiet respiration. ECGs were obtained at each clinical point (i.e., at baseline and 3 months and 1 year after ASA). We evaluated heart rate, the PR interval, QRS duration, and QTc interval. RBBB was defined by the following: (1) QRS duration ≥110 ms in adults; (2) rsr′, rsR′, or rsR′ in Leads V1 or V2 (the R′ or r′ deflection is usually wider than the initial R wave); (3) an S wave duration greater than that of the R wave or >40 ms in Leads I and V6 in adults; and (4) normal R peak time in Leads V5 and V6 but >50 ms in Lead V1. Of these criteria, the first 3 should be present to make a diagnosis of RBBB. When a pure dominant R wave with or without a notch is present in V1, only Criterion 4 needs to be met.¹⁴ ECGs were interpreted by 2 experienced cardiologists (J.M. and Y.I.) who were blinded to patient information.

Follow-up Study and Echocardiography

A 1-year follow-up study was conducted to evaluate the changes in clinical findings. Clinical examination of symptoms, ECG, and echocardiography were performed at 3 months and 1 year after ASA. In the echocardiographic study, interventricular septal thickness (IVST), posterior wall thickness (PWT), LV end-diastolic diameter, LV end-systolic diameter (LVDs), left atrial (LA) diameter, left arterial area (LAA), LA volume index (LAVI), and LV mass index (LVMI) were measured in accordance with the American Society of Echocardiography recommendations.¹⁵ To evaluate LVH regression, we compared LV diastolic parameters (E wave velocity, E/A, e′, and E/e′) at baseline to those at 1 year after ASA.

Candidates and Procedural Details of ASA

Patients were considered candidates for ASA if their symptoms were life-limiting after optimization of medication and a resting or provoked gradient of >30 mmHg was confirmed by at least 1 method during simultaneous pressure recordings. Life-limiting symptoms were categorized in accordance with New York Heat Association (NYHA) functional classes (FC). Patients with an NYHA functional class of II were stratified into 2 groups based on physical activity limitations: those with slight (Class IIs) and those with moderate (Class IIm) limitations.¹⁶ From the potential candidates, we carefully excluded patients with subaortic membranous stenosis, abnormal insertion of the papillary muscle or tendon, and large apical aneurysms. To identify the target septal perforator branch, coronary angiography and left ventriculography were performed simultaneously. A temporary pacemaker was placed into the right ventricle to prepare for a trifascicular block during the procedure. Using a 6- to 7-Fr guiding catheter and a 4- or 5-Fr specially designed pigtail catheter, a small over-the-wire balloon (diameter 1.25–2.5 mm, length 8–10 mm) was dilated on the target branch and selective angiography was performed to confirm isolation of the left anterior descending artery. Myocardial contrast echocardiography was performed during all procedures to avoid misplacement of alcohol to the free wall of the right ventricle and papillary muscle, and to accomplish sufficient ablation of the septal myocardium subject to obstruction. A small amount of alcohol (1.0–2.0 mL for a single branch) was a slowly injected (0.3 mL/min) via the lumen of the balloon.

After the procedure, all patients were admitted to the cardiac care unit and fitted with a temporary pacemaker for at least 48 h as a prophylactic measure for late-onset heart block. Repeat ASA was indicated for patients with residual symptoms related to intraventricular obstruction after the index procedure for up to 12 months because of the gradual regression of the pressure gradient due to slow regression of LV thickness. The presence of the target septal branch was needed to ablate the culprit septal myocardium.

Statistical Analysis

Normally distributed continuous variables are presented as the mean±SD, whereas continuous variables that were not normally distributed are presented as the median with interquartile range. Categorical variables are presented as numbers and percentages. Continuous variables were analyzed using the Mann-Whitney U-test. Categorical variables were compared using Fisher’s exact test. Serial changes in continuous variables were analyzed using the Friedman test. When differences were detected, the Wilcoxon rank-sum test or Mann-Whitney U-test with Bonferroni correction was used for multiple comparisons. Univariate and multivariate logistic regression analyses were used to identify the predictors of repeat ASA and pacemaker implantation after ASA. Variables with a P<0.1 in the univariate models were selected as candidates for the multivariate models. Statistical analyses were performed using the SPSS version 20.0.0.0 (IBM Corp., Armonk, NY, USA). Two-sided P<0.05 was considered to indicate statistical significance.

Results

Patient Characteristics

The baseline characteristics of the study groups are presented in Table 1. Patients with procedural RBBB were assigned to the RBBB group (n=94), whereas those who did not have procedural RBBB were assigned to the no-RBBB group (n=49). There were significant differences between the 2 groups in sex (P<0.001), the number of ablated branches (P=0.027), peak creatinine phosphokinase (CPK) concentrations (normal laboratory ranges 60–250 IU/L for men, 50–170 IU/L for women; P=0.023), post-ASA gradient (P=0.039), and the reduction in LVPG between baseline and 3 months (P=0.039) or 1 year (P=0.035). Logistic regression analysis revealed no statistically significant differences between the 2 groups in sex (odds ratio [OR] 1.01; 95% confidence interval [CI] 0.976–1.030; P=0.96) using, the number of ablated branches, and peak CPK concentrations as explanatory variables. There were no significant correlations between sex and the number of ablated branches (r=0.13, P=0.143) or peak CPK concentrations (r=0.001, P=0.94).

Table 1. Baseline Characteristics of Patients in the RBBB and No-RBBB Groups

	RBBB (n=95)	No-RBBB (n=49)	P value
Age (years)	64±15	62±14	0.107
Male sex	65 (68)	17 (34)	<0.0001
NYHA class	2.7±0.4	2.7±0.5	0.74
HCM risk factor
Maximal septal thickness >30 mm	2 (2)	2 (4)	0.61
Sustained VT/Vf	1 (1)	1 (2)	1
Family history of SCD	13 (14)	6 (12)	1
Abnormal BP response	7 (7)	8 (16)	0.15
Unexplained syncope	21 (22)	11 (22)	1
Medication at ASA
β-blockers	89 (94)	45 (90)	0.74
Class I agents	73 (77)	38 (76)	1
Class III agents	2 (2)	1 (2)	1
Calcium channel blockers	21 (22)	12 (24)	0.84
ASA procedure
No. branches ablated	2.0±0.9	1.6±0.8	0.027
Volume ethanol injected (mL)	2.88±1.62	2.59±1.34	0.34
Repeat ASA	6 (6)	11 (22)	0.037
Transient CAVB	18 (19)	5 (10)	0.18
Peak CPK (U/L)	1,413±650	1,062±598	0.023
Pacemaker implantation after ASA	6 (6)	5 (10)	0.32
Pressure gradient (mmHg)
At baseline	74±48	75±45	0.82
Post-ASA	27±27	31±33	0.039
Electrocardiographic parameters
HR (ms)	62±10	61±10	0.71
PR (ms)	191±33	184±23	0.97
QRS (ms)	100±13	105±15	0.63
QTc (ms)	457±37	450±41	0.46
Echocardiographic findings
IVST (mm)	18±5	18±4	0.32
PWT (mm)	123	12±3	0.51
LVDd (mm)	42±6	42±6	0.61
LVDs (mm)	23±5	24±5	0.45
LA diameter (mm)	45±5	45±9	0.36
LAA (cm²)	26.5±4.8	26.7±11.6	0.51
LAVI (mL/m²)
Baseline	59.0±15.9	58.2±17.2	0.38
3 months	48.4±12.7	54.1±15.9	0.04
1 year	44.8±11.7	50.6±17.7	0.03
LAVI reduction (%)
Baseline–3 months	18±13	7±15	0.03
Baseline–1 year	24±16	13±15	0.027
3 months–1 year	7±14	9±17	0.58
LVMI (g/m²)
Baseline	163±43	163±52	0.82
3 months	138±45	154±57	0.21
1 year	109±53	135±46	0.04
LVMI reduction (%)
Baseline–3 months	15±35	6±20	0.25
Baseline–1 year	33±29	17±22	0.019
3 months–1 year	8±32	9±26	0.63
E (cm/s)	78±33	72±23	0.24
E/A	1.10±0.50	1.91±0.67	0.049
e′ (cm/s)	4.3±1.2	3.8±1.2	0.04
LVPG (mmHg)
Baseline	104±56	89±50	0.063
3 months	38±31	43±39	0.55
1 year	34±34	40±38	0.18
LVPG reduction (%)
Baseline–3 months	63.4±52.3	51.9±55.7	0.041
Baseline–1 year	67.3±55.8	55.6±41.4	0.039
3 months–1 year	3.8±86.5	3.7±72.9	0.88

Data are expressed as the mean±SD or n (%). ASA, alcohol septal ablation; BP, blood pressure; CAVB, complete atrioventricular block; HCM, hypertrophic cardiomyopathy; HR, heart rate; IVST, intraventricular septal thickness; LA, left atrial; LAA, LA area; LAVI, LA volume index; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVMI, left ventricular mass index; LVPG, left ventricular pressure gradient; NYHA, New York Heart Association; PWT, posterior wall thickness; RBBB, right bundle branch block; SCD, sudden cardiac death; Vf, ventricular fibrillation; VT, ventricular tachycardia.

Results of the ASA Procedure in the RBBB Group

All procedures were successfully performed without 30-day mortality or ventricular tachyarrhythmia. The number of ablated branches was 2.0±0.9, the volume of ethanol injected was 2.9±1.6 mL, and the peak CPK concentration was 1,413±650 IU/L. The resting pressure gradient improved from 74±48 to 27±27 mmHg (P<0.001). As a periprocedural complication within 30 days of ASA, a transient complete AV block was observed in 18 patients (19%; Table 1).

Changes in the echocardiographic parameters are summarized in Table 2. IVST decreased significantly from baseline to 3 months (from 18±5 to 16±4 mm; P<0.001), and from 3 months to 1 year (from 16±4 to 15±3 mm; P=0.001). PWT decreased significantly from 3 months to 1 year (from 12±3 to 11±3 mm; P<0.001), and LVDs increased significantly from baseline to 3 months (from 23±5 to 25±6 mm; P=0.02). Both LA diameter and LAA were decreased significantly between baseline and 3 months (LA diameter: from 45±5 to 41±8 mm [P=0.02]; LAA: from 27±5 to 24±5 cm² [P=0.02]). LAVI decreased significantly from baseline to 3 months (from 59.02 to 48.lmL/m²; P<0.0002). LVMI decreased significantly from baseline to 3 months (from 163±43 to 138±45 g/m²; P<0.001), and from 3 months to 1 year (from 138±85 to 109±53 g/m²; P<0.001). LVPG decreased significantly from baseline to 3 months (from 104±56 to 38±31 mmHg; P<0.001).

Table 2. Echocardiographic and Electrocardiographic Findings in the RBBB Group at Baseline and 3 Months and 1 Year After

	Baseline	3 months	1 year	P value
Echocardiographic parameters
IVST (mm)	18±5	16±4*	15±3^†	<0.0001
PWT (mm)	12±3	12±3	11±2*^,†	<0.0001
LVDd (mm)	42±6	42±7	42±6	0.733
LVDs (mm)	23±5	25±6*	25±5	0.008
LA diameter (mm)	45±5	41±8*	43±6	<0.0001
LAA (cm²)	27±5	24±5*	24±6	<0.0001
LAVI (mL/m²)	59.0±15.9	48.4±12.7*	44.8±11.7*	<0.0001
LVMI (g/m²)	163±43	138±45*	109±53*^,†	<0.0001
E (cm/s)	0.8±0.2	0.7±0.3	0.7±0.3	0.216
E/A	2.5±9.4	1.0±0.5	1.2±0.5	0.198
e′ (cm/s)	4.0±1.4	3.8±1.2	3.9±1.2	0.048
E/e′	23±10	23±11	20±10	0.549
LVPG (mmHg)	104±56	38±31*	34±34*	<0.0001
Electrocardiographic parameters
HR (ms)	62±10	61±8	62±9	0.105
PR (ms)	191±33	195±32	192±24	0.236
QRS (ms)	100±13	128±22*	134±25*	<0.0001
QTc (ms)	457±37	463±36*	478±39*	<0.0001

Data are expressed as the mean±SD. *P<0.05 compared with baseline; ^†P<0.05 compared with 3 months. ASA, alcohol septal ablation. Other abbreviations as in Table 1.

Results of the ASA Procedure in the No-RBBB Group

All procedures were successfully performed without 30-day mortality or ventricular tachyarrhythmia. The number of ablated branches was 1.6±0.8, the volume of ethanol injected was 2.6±1.3 mL, and the peak CPK concentration was 1,062±598 IU/L. The resting pressure gradient improved from 75±45 to 31±33 mmHg (P<0.001). As a periprocedural complication within 30 days of ASA, a transient complete AV block was observed in 5 patents (10%; Table 1).

Changes in the echocardiographic parameters are summarized in Table 3. IVST decreased significantly from baseline to 3 months (from 18±4 to 16±4 mm; P=0.001), PWT decreased significantly from baseline to 1 year (from 12±3 to 11±2 mm; P=0.032), LVMI decreased significantly from baseline to 1 year (from 163±52 to 135±46 g/m²; P<0.001), and LVPG decreased significantly from baseline to 3 months (from 89±50 to 46±42 mmHg; P<0.001).

Table 3. Echocardiographic and Electrocardiographic Findings in the No-RBBB Group at Baseline and 3 Months and 1 Year After ASA

	Baseline	3 months	1 year	P value
Echocardiographic parameters
IVST (mm)	18±4	16±4*	16±4	0.001
PWT (mm)	12±3	12±3	11±2	0.032
LVDd (mm)	42±6	43±42	42±5	0.226
LVDs (mm)	24±6	25±5	24±4	0.101
LA diameter (mm)	45±9	43±10	43±10	0.005
LAA (cm²)	27±10	26±8	26±9	0.653
LAVI (mL/m²)	58.2±17.2	54.1±15.9*	50.6±17.7*	<0.0001
LVMI (g/m²)	163±52	154±57	135±46*^,†	<0.0001
E (cm/s)	0.8±0.3	0.7±0.1	0.7±0.3	0.216
E/A	1.1±0.5	1.1±0.5	1.1±0.5	0.200
e′ (cm)	4.3±1.2	3.7±1.1	4.0±1.4	0.0419
E/e′	19±8	21±7	18±7	0.121
LVPG (mmHg)	89±50	46±42*	40±38*	<0.0001
Electrocardiographic parameters
HR (ms)	61±10	62±11	65±13	0.567
PR (ms)	184±23	182±26	192±26	0.0137
QRS (ms)	105±15	102±15	100±16	0.115
QTc (ms)	450±41	441±38	438±30	0.206

Data are expressed as the mean±SD. *P<0.05 compared with baseline; ^†P<0.05 compared with 3 months. Abbreviations as in Tables 1,2.

NYHA Functional Class After ASA

At the 1-year follow-up, symptoms had improved in all patients. The percentage of patients with an improvement in NYHA functional class ≥2 stages (defined as IV to IIm or less, III to IIs or less, or IIm to I) within 1 year after ASA was significantly greater in the RBBB than no-RBBB group (64.9% vs. 44.9; P=0.021). Conversely, the percentage of patients with NYHA functional class I 1 year after ASA was significantly greater in the RBBB than no-RBBB group (79% vs. 61%; P<0.03; Figure 2).

Figure 2.

New York Heart Association (NYHA) functional classes in the right bundle branch block (RBBB) and no-RBBB groups at baseline and 3 months and 1 year after alcohol septal ablation (ASA), showing the percentage of patients with NYHA improvements of ≥2 classes (defined as IV to IIm or less, III to IIs or less, or IIm to I) within 1 year after ASA.

ECG Changes During the 1-Year Follow-up After ASA

ECG manifestations at each follow-up point are presented in Tables 2 and 3. The QRS duration and QTc interval were significantly increased in the RBBB compared with no-RBBB group during the observation period. In addition, there was a significant difference in the PR interval during the observation period in the no-RBBB group (n=0.014).

Echocardiographic Changes During the 1-Year Follow-up After ASA

Echocardiographic findings at each follow-up point are also presented in Tables 2 and 3. Although there was no significant difference between the 2 groups at each time point, the percentage reduction in LVPG was significantly greater in the RBBB than no-RBBB group (Figure 3). There was no significant difference in LVMI at baseline and 3 months between the 2 groups, but there was a more significant regression in the RBBB than no-RBBB group 1 year after ASA (Figure 3). The percentage reduction in LVMI from baseline to 3 months after ASA was similar in the RBBB and no-RBBB groups (15±35% vs. 6±20%, respectively; P=0.25), but there was a significantly greater reduction in LVMI at 1 year in the RBBB than no-RBBB group (33±29% vs. 17±22%, respectively; P=0.019). There were no significant differences in the percentage reductions in LA diameter between the RBBB and no-RBBB groups from baseline to 3 months (5±15% vs. 4±23%, respectively; P=0.79) or from baseline to 1 year after ASA (5±15% vs. 5±11%, respectively; P=0.85). Similarly, there were no significant differences in the percentage reductions in LAA between the RBBB and no-RBBB groups from baseline to 3 months (8±23% vs. 4±15%, respectively; P=0.26) or from baseline to 1 year after ASA (9±21% vs. 5±15%, respectively; P=0.25). However, the percentage reductions in the LAVI from baseline was significantly greater in the RBBB than no-RBBB group both 3 months (18±13% vs. 7±15%, respectively; P=0.03) and 1 year (24±16% vs. 13±15%, respectively; P=0.03) after ASA.

Figure 3.

Comparison of absolute (Top panel) and percentage (Bottom panel) changes in the left ventricular pressure gradient (LVPG), left ventricular mass index (LVMI), and left atrial volume index (LAVI) from baseline to 3 months and 1 year after alcohol septal ablation in the right bundle branch block (RBBB) and no-RBBB groups.

Adverse Events 1 Year After ASA

There was no occurrence of all-cause death, ventricular arrhythmia, or embolic events after ASA in either the RBBB or no-RBBB group at 1 year after ASA. One patient in the RBBB group had HCM-related heart failure. The percentage of patients requiring a permanent pacemaker after ASA was similar in the RBBB and no-RBBB groups (6% vs. 10%, respectively; P=0.32). The frequency of repeat ASA was significantly lower in the RBBB than no-RBBB group (6% vs. 22%, respectively; P=0.037).

Factors Predictive of Pacemaker Implantation

Univariate analyses showed that age, PR duration, and transient complete AV block were associated with pacemaker implantation. Multivariate analysis showed that age was an independent predictor of pacemaker implantation after ASA (OR 0.96; 95% CI 0.93–1.00; P=0.041). Procedural RBBB was not associated with pacemaker implantation (Table 4).

Table 4. Factors Predictive of Pacemaker Implantation

	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
Age	0.97	0.93–1.00	0.058	0.96	0.93–1.00	0.041
Male sex	0.62	0.17–2.20	0.46
NYHA class	0.56	0.11–2.77	0.48
Maximal septal thickness >30 mm	2.70	0.28–26.4	0.39
Sustained VT/Vf	1.56	0.98–2.48	0.06	1.49	0.90–2.47	0.13
Family history of SCD	0.59	0.07–4.85	0.62
Abnormal BP response	2.05	0.43–9.85	0.37
Unexplained syncope	2.57	0.75–8.73	0.23
β-blockers	0.69	0.08–6.08	0.74
Class I agents	1.60	0.33–7.70	0.56
Class III agents	0.00	0.00	0.99
Calcium channel blockers	2.45	0.72–8.32	0.15
No. branches ablated	1.00	0.52–1.94	1.00
Volume of ethanol injected	0.83	0.50–1.37	0.46
Transient CAVB	2.20	0.67–7.26	0.02	2.05	0.57–7.33	0.27
Peak CPK	1.00	0.99–1.00	0.57
Pressure gradient at baseline	0.99	0.98–1.01	0.48
Pressure gradient after ASA	0.99	0.97–1.02	0.69
HR	0.90	0.80–1.02	0.25
PR duration	1.02	0.99–1.05	0.19
QRS duration	1.02	0.97–1.07	0.42
QTc interval	1.00	0.98–1.03	0.99
Procedural RBBB	0.48	0.14–1.57	0.13

CI, confidence interval; CPK, creatinine phosphokinase; NYHA, New York Heart Association; OR, odds ratio. Other abbreviations as in Tables 1,2.

Factors Predictive of Repeat ASA

Univariate analyses showed that peak CPK concentration, post-ASA gradient >30 mmHg, and procedural RBBB were associated with repeat ASA. Multivariate analysis showed that IVST and procedural RBBB were associated with a reduction in repeat ASA (OR 1.15 [95% CI 1.02–1.31; P=0.027] and OR 0.32 [95% CI 0.11–0.97; P=0.045], respectively; Table 5).

Table 5. Factors Predictive of Repeat ASA

	Univariate			Multivariate
	OR	95% CI	P value	OR	95% CI	P value
Age	0.99	0.96–1.02	0.33
Male sex	0.67	0.23–1.94	0.46
NYHA class	1.22	0.40–3.71	0.73
Maximal septal thickness >30 mm	1.69	0.18–16.0	0.65
Sustained VT/Vf	0.92	0.48–1.75	0.80
Family history of SCD	0.34	0.04–2.72	0.31
Abnormal BP response	0.51	0.10–2.63	0.42
Unexplained syncope	2.73	0.99–7.52	0.051	2.69	0.85–8.50	0.09
β-blockers	7.42	0.00–100.0	0.99
Class I agents	2.53	0.00–100.0	0.99
Class III agents	6.56	0.39–110	0.19
Calcium channel blockers	1.16	0.38–3.51	0.79
No. branches ablated	1.07	0.63–1.820	0.79
Volume of ethanol injected	0.88	0.59–1.30	0.52
Transient CAVB	0.24	0.08–1.82	0.17
Peak CPK	1.00	0.99–1.00	0.09	0.99	0.99–1.00	0.33
Pressure gradient at baseline	1.00	0.99–1.01	0.88
Pressure gradient after ASA	0.98	0.96–1.01	0.18
Reduction ratio of LVPG	1.13	0.41–3.09	0.81
Post-ASA gradient >30 mmHg	0.53	0.15–1.95	0.034	0.55	0.14–2.25	0.41
MR severity	0.88	0.50–1.57	0.67
HR	0.99	0.92–1.07	0.79
PR duration	1.01	0.99–1.04	0.32
QRS duration	1.00	0.96–1.05	0.91
QTc interval	1.00	0.98–1.02	0.92
IVST (mm)	1.12	1.00–1.25	0.043	1.15	1.02–1.31	0.027
PWT (mm)	0.94	0.78–1.12	0.49
LVDd (mm)	1.08	0.99–1.18	0.08
LVDs (mm)	1.04	0.95–1.14	0.42
LA diameter (mm)	1.02	0.96–1.08	0.53
LAA (cm²)	1.04	0.98–1.11	0.22
LAVI (mL/m²)	1.06	0.95–1.17	0.48
LVMI (g/m²)	1.01	1.00–1.01	0.40
E (cm/s)	1.00	0.98–1.02	0.72
E/A	0.86	0.29–2.60	0.79
E′ (cm)	0.40	0.15–1.03	0.058
E/e′	1.03	0.95–1.12	0.47
Procedural RBBB	0.34	0.13–0.92	0.033	0.32	0.11–0.97	0.045

MR, mitral regurgitation. Other abbreviations as in Tables 1,2,4.

Discussion

Although ASA resulted in a significant decrease in LVPG and significantly improved symptoms in both groups, the percentage reductions in LVPG and LVMI between baseline and 3 months or 1 year after ASA were significantly greater and the NYHA functional class at 1 year was significantly better in the RBBB than no-RBBB group. The number of ablated branches and peak CPK concentrations were also significantly greater in the RBBB than no-RBBB group. Although univariate analysis showed a significant difference in sex between the 2 groups, multivariate analysis revealed otherwise. We speculate that ethanol injection into a larger number of branches reached thorough necrosis in the targeted myocardium, including the right bundle branch, resulting in significant reductions in LVPG and LVMI 3 months later and symptomatic improvement 1 year after ASA.

A previous study showed that compared with patients without RBBB at 6 months, those who developed RBBB had similar baseline characteristics and improvements in NYHA functional class and pressure gradients, but received more ethanol and tended to have larger infarct sizes.¹⁷ These data reflect the variation in size or perfusion area of the septal perforator arteries among individuals. Although patients who received a large amount of ethanol tended to develop larger and more extensive infarctions, this does not always lead to a sufficient improvement in the pressure gradient or symptoms. An essential component of the procedure is evaluation of the myocardial distribution of the septal perforator artery, which is assessed using an angiographic contrast medium and myocardial contrast echocardiography.

The proximal bundle branches receive their blood supply from the AV node artery and the first septal branch, or either of these alone. The first septal branch is often used for alcohol injection for ASA.¹⁸ Cui et al¹⁹ found the distance from the first septal artery to the bundle of His to be <5 mm in 12.4% of patients. The proximity of the target branch to the AV conduction system may make it difficult to avoid conduction disturbances. Furthermore, it is important to select the most proximal septal branch as the target for achieving a sufficient reduction in LVPG because most of the thickened myocardium that forms the LVOT obstruction receives its blood supply from the first major septal branch; however, the small septal branch that supplies the AV conduction system is sometimes situated proximally. Although there was no significant difference in the PR interval at baseline and 1 year after ASA between the 2 groups in this study, there was a significant difference in the PR interval during the observation period in the no-RBBB group, despite the post hoc test showing no significant difference during the observation period. The tendency to develop a prolonged PR interval after ASA in the no-RBBB group could be explained by the findings of a previous study, which revealed the presence of a retrograde AV block after ASA as an independent risk factor for delayed AV block;²⁰ this was not investigated in the present study. It is possible that there were more patients with retrograde AV block after ASA in the no-RBBB group. However, this possibility remains purely speculative.

A previous study showed that patients with RBBB had more evidence of reverse remodeling, with significantly greater reductions in LV mass at 6 months than at 1 month after ASA.¹⁷ In the present study, although there was no significant difference in the LV mass between the 2 groups at 3 months after ASA, the LV mass was significantly reduced at 1 year in the RBBB compared with no-RBBB group. Moreover, the percentage reduction in LVMI was similar in the 2 groups, but there was a significantly greater reduction between baseline and 1 year after ASA in the RBBB than no-RBBB group. In the RBBB group, the significantly greater reduction in LVPG contributed to the greater regression of LV hypertrophy 1 year after ASA because of the reverse remodeling effect.

There was no significant difference in percentage reductions in LA diameter and LAA between the 2 groups. However, the percentage reductions in LAVI from baseline to both 3 months and 1 year after ASA were significantly greater in the RBBB than no-RBBB group. The LA volume is a more sensitive indicator of filling pressure and LV diastolic dysfunction than LA diameter and LAA.²¹^,²² These findings also suggest that procedural RBBB patients have more evidence of the reverse remodeling effect of LV diastolic dysfunction.

A prior study showed that it is unlikely that RBBB leads to significant intraventricular dyssynchrony because the interventricular septum in HOCM is normally activated by the left and right bundles of His, and RBBB does not cause late activation of the lateral LV wall.²³ Chen et al²⁴ suggested that dyssynchrony of LV contraction may be present in HOCM, and ASA may reduce the degree of dyssynchrony. Thus, the RBBB-related dyssynchrony after ASA may be counteracted, in part, by the reduction in dyssynchrony related to LVOT obstruction.²⁴

Of the complications of ASA, complete AV block is one of the most concerning, and it has been reported to occurs in approximately 10% of treated patients, who then required a permanent pacemaker.¹⁰ Multivariate analysis in previous studies demonstrated that the most important factors associated with the development of complete AV block were age, a rapid bolus injection of alcohol, left bundle branch block, first-degree AV block, and ablation of ≥2 septal arteries, but not the ablated infarct size.⁷^,¹⁰ In the present study, none of the patients with RBBB developed further conduction system disturbance and required pacemaker implantation 1 year after ASA. Although the infarct size was larger in the RBBB than no-RBBB group, there was no significant difference in the frequency of the need for pacemaker implantation between the 2 groups. This indicates that efforts to prevent procedural RBBB may not be necessary

Furthermore, a previous study showed that an LVPG >25 mmHg after ASA and a peak CPK concentration of <1,300 IU/L were independent predictors of unsatisfactory outcome, such as residual advanced symptoms.²⁵ Another study suggested that a residual obstruction of >30 mmHg at the early post-discharge clinical checkup is associated with a significantly higher occurrence of a post-ASA cardiovascular mortality event.²⁶ In the present study, procedural RBBB was one of the factors predicting a reduction in the need for repeat ASA and symptom improvement. However, neither peak CPK concentration nor post-ASA gradient was associated with a reduction in the need for repeat ASA. Extensive myocardial ablation is not always essential to achieve optimal reductions in the pressure gradient, but it is necessary to ablate the appropriate target regardless of the right bundle branch distribution.

IVST was also a factor predictive of repeat ASA. A previous study reported that patients with mild hypertrophy had lower rates of repeat septal reduction therapy.²⁷ The degree of hypertrophy has been shown to be correlated with the severity of diastolic dysfunction and intramyocardial fibrosis, confirming that IVST is a readily available important structural marker of prognosis and disease severity in patients with HCM. In addition, in patients with an extensive hypertrophic septal myocardium, the target septal myocardium may not be fully ablated during ASA for safety reasons. The use of a large amount of ethanol during ASA resulted in a large infarct size, inducing lethal ventricular arrhythmia.²⁸

With regard to clinical implications, this study provides an important message for ASA operators: the occurrence of RBBB cannot be the endpoint to immediately discontinue septal ablation. The ablation area should be determined by contrast echocardiography in ASA,¹ and this concept should not be altered even if RBBB occurs, because it does not adversely affect the clinical outcome.

Study Limitations

This study has several limitations. First, transient RBBB after ASA was not considered. It is possible that the number of patients with RBBB may have been underestimated. Second, this study was retrospective in nature and therefore has issues associated with such analyses. The present study was subject to selection bias, which should be considered in the interpretation of its results. We also cannot exclude the effect of the operators’ experience, which may play a role in the success of ASA. The ASA procedure is evolving over time. Myocardial contrast echocardiography and a method of gradually injecting a small amount of ethanol have been developed since the early days of the ASA procedure, which led to a decrease in pacemaker implantation associated with complete AV block. Further studies are needed to validate our initial observations.

Conclusions

Although RBBB frequently occurs after ASA, it nevertheless has no association with unfavorable outcomes or adverse events.

Acknowledgments

The authors sincerely thank the members of the Department of Cardiovascular Medicine of Nippon Medical School Hospital.

Sources of Funding

None.

Disclosures

W.S. is a member of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Review Committee of Nippon Medical School (Approval no. 28-07-615).

Data Availability

The deidentified participant data will not be shared.

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