Methods

We reviewed the institutional registry data of patients with drug-refractory HOCM who underwent ASA. Of consecutive 156 patients, after excluding cases of severe valvular disease and repeat septal reduction therapy, we investigated the clinical characteristics of patients with labile obstruction (n = 32) and the outcomes after ASA using the IV-NTG test, comparisons were made with those exhibiting basal obstruction (a resting gradient of ≥30 mm Hg, n = 120). In this study, IV-NTG bolus tests were administered during ASA to confirm their acute effects in patients with a resting gradient <30 mm Hg at baseline. At the initial presentation, we had reviewed and optimized the prescribed patient medications. Basically, symptomatic patients with HOCM were given β blocker if titrated. Then, class Ia was added in patients with residual symptoms to improve gradient. Patients were considered as ASA candidates if symptoms were life limiting (New York Heart Association [NYHA] functional class IIm to IV) after optimization of medication and a provoked gradient >50 mm Hg was confirmed by at least 1 method during simultaneous pressure recordings as described in the following. We carefully excluded patients with subaortic stenosis, abnormal insertion of papillary muscle, extreme elongation of anterior mitral leaflet and large apical aneurysm. All patients who underwent ASA had been consecutively assigned to the institutional registry database at the Nippon Medical School Hospital. The institutional review committee approved the study. All patients gave written informed consent.

Diagnosis of hypertrophic cardiomyopathy (HCM) has been established by transthoracic echocardiography (TTE). The definition of HCM in echocardiography was based on the presence of a maximal LV wall thickness ≥15 mm and the absence of other conditions that might explain left ventricular hypertrophy (LVH) during the clinical course. LV cavity size, LV wall thickness, and left atrial diameter were measured in accordance with the American Society of Echocardiography recommendations. LV mass and the number of hypertrophic segments were calculated using cine cardiac magnetic resonance. In accordance with the American Heart Association classification, 17 myocardial segments were defined. In this study, genetic diagnosis was not mandatory for diagnosing clinical HCM.

We diagnosed HOCM in patients with defined HCM and intraventricular velocity ≥2.7 m/s on TTE (or a gradient ≥30 mm Hg on direct simultaneous recording) at rest or on provocation. Hemodynamic state of intraventricular obstruction was determined according to the American College of Cardiology Foundation/American Heart Association Guidelines. In brief, basal obstruction was defined as a consistent presence of significant gradient (≥30 mm Hg) at rest. Labile obstruction was defined as a resting gradient <30 mm Hg but a provoked gradient ≥30 mm Hg confirmed by at least 1 of the following methods: exercise test, Valsalva maneuver, postextrasystolic potentiation, or IV-NTG.

HOCM was stratified into 3 categories of obstruction: LV outflow tract type (LVOT), midventricular type, and combined type in which the patients had extended obstruction at both LVOT and midventricular levels, confirmed by TTE or simultaneous invasive recordings. We excluded patients who exhibited only sigmoid septum but not significant hypertrophy. We treated HCM with midventricular obstruction similar to that with LVOT obstruction, using β blockers and class Ia agents. Furthermore, we carefully chose the indication of ASA for patients with midventricular obstruction, in which muscular obstruction was thought to cause their symptoms.

Symptoms were obtained from medical records of the HCM clinic and during hospitalization. Life-limiting symptoms were categorized according to NYHA functional class. Patients with NYHA functional class II were stratified into 2 groups: those with slight limitation (class IIs) and moderate limitation (class IIm) in physical activity. Other clinical data such as angina, palpitation, fainting, syncopal events, atrial fibrillation, and ventricular arrhythmias were also obtained. Risk factors for sudden cardiac death, coronary risk factors, and history of atrial fibrillation and congestive heart failure were included in baseline characteristics.

Routine coronary angiography, left ventriculography, right-sided catheterization, and pressure studies were performed. All invasive evaluations were performed under medication. Target septal artery candidates were chosen by coronary angiography, and the obstruction level was evaluated by left ventriculography. Gradient was calculated as a peak-to-peak difference of pressures between the ascending aorta and LV apex using a retrograde approach. Pressure recording data were acquired by a fluid-filled catheter system from a pigtail catheter at the LV apex and a catheter placed in the ascending aorta. Simultaneous pressure recordings were made at baseline and after provocation by IV-NTG, Valsalva maneuver, and premature ventricular contraction (PVC) induced by pigtail catheter manipulation. Accordingly, we used specially designed pigtail catheters (Type Mtaka, Medikit, Tokyo, Japan) during LV apical pressure measurements. To obtain an accurate apical LV pressure, a total of 5 holes were made in the distal portion: 1 hole in the distal tip, 1 end hole at the end of the catheter, and 3 side holes close to the pigtail tip. This catheter tip was small and made of soft material to decrease catheter-induced ventricular arrhythmias. Catheter entrapment was carefully excluded by a test bolus injection of contrast medium.

During evaluation by catheterization of those with a resting gradient <30 mm Hg, we acquired provoked gradients during the strain phase of Valsalva maneuver, on postextrasystolic potentiation, and by the IV-NTG test. To obtain the data from IV-NTG, after administration of 0.1-mg NTG into the central venous line, we measured the pressures of the ascending aorta and LV apex simultaneously at the lowest systolic blood pressure. Pressure recording was continuously performed from the administration of NTG until the pressure was restored to baseline level. An IV-NTG–provoked gradient was acquired at the peak of the vasodilator effect. When patient has low systolic blood pressure (100∼120 mm Hg), high gradient provoked by other method with systolic blood pressure (<100 mm Hg), or highly labile gradient, the IV-NTG test was started with smaller doses (0.025∼0.05 mg). Immediately after ASA procedure, IV-NTG was performed with same dosage at before ASA procedure to confirm the acute effect of ASA.

A temporary pacemaker was placed into the right ventricle to prepare for a trifascicular block during the procedure. Using a 6Fr or 7Fr percutaneous transluminal coronary angioplasty (PTCA) guiding catheter and a 4Fr or 5Fr specially designed pigtail catheter, a small over-the-wire PTCA balloon 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. A small amount (1.0 to 2.0 ml for a single branch) of alcohol was slowly injected (0.3 ml/min) through the lumen of the over-the-wire PTCA balloon. Morphine chloride has been used as an analgesic, and general anesthesia was not administered. After the procedure, all patients were admitted to the cardiac care unit fitted with a temporary pacemaker for at least 48 hours as a prophylactic measure for the late-onset heart block.

Continuous variables are expressed as mean ± standard deviation or median with interquartile ranges. Comparisons of continuous variables were analyzed by Mann–Whitney U tests. Changes in categorical variables were compared with Fisher’s exact tests. Correlations of the provoked gradients between IV-NTG and post-PVC were assessed by the Pearson test. For the 8-year survival analysis of this study population, a Kaplan–Meier curve was described, and statistical comparisons with those with basal obstruction were performed by log-rank test. Statistical analyses were performed using the SPSS software program version 20.0.0.0 (IBM Corporation, New York, New York). Statistical significance was indicated when p value <0.05.

Results

From 1998 to 2013, 186 ASA procedures were performed in 156 patients. After exclusion of basal obstruction (resting gradient ≥30 mm Hg, n = 120), repeat procedures (n = 33), and severe valvular disease (n = 6), 32 consecutive patients were classified as labile obstruction. Baseline characteristics of the study population are presented in Table 1 with comparison between labile obstruction and basal obstruction. No patient developed dilated-phase HCM during the observation period. In comparison with basal obstruction, patients with labile obstruction showed less brain natriuretic peptide values, less interventricular septal thickness, and more frequent use of class Ia agents such as cibenzoline, the agent mainly prescribed.

All ASA procedures were successfully performed without 30-day or 1-year mortality. The details are summarized in Table 2 . Details of alterations in IV-NTG tests are provided in Table 3 . The increases in LV systolic pressure and LV end-diastolic pressure were converted to decreases (+12 to −24 and +2 to −2 mm Hg, respectively), and the reduction in SBP by IV-NTG was attenuated (−45 to −23 mm Hg, p = 0.002). No patient experienced hemodynamic collapse during the IV-NTG test. Percentages of the gradient ≥50 mm Hg on each provocation maneuver before and immediately after ASA are shown in Figure 1 . Before ASA, all provocation tests similarly detected gradients ≥50 mm Hg indicated for septal reduction therapy. The gradient provoked by IV-NTG correlated with the post-PVC gradient both before ( r = 0.604, p = 0.003) and after ASA ( r = 0.633, p = 0.002). Of 8 patients in whom Valsalva maneuver or post-PVC provocation provoked gradients ≥50 mm Hg immediately after the first ASA, all patients improved to NYHA functional class I or IIs (class I; 7 patients from IIm [n = 4] or III [n = 3], class IIs; 1 patient from class III) at 1-year follow-up, and then, 2 patients presented recurrent symptoms and required repeat ASA after 2 years.

Table 3

Changes in catheterization parameters before and after alcohol septal ablation (n = 32)

Variable	Baseline			Intravenous nitroglycerin test			p value ∗
	Before	After	p value	Before	After	p value	Before	After
Gradient (mm Hg)	15 ± 7	5 ± 5	<0.0001	74 ± 25	13 ± 9	<0.0001	<0.0001	<0.0001
Left ventricular pressure (mm Hg)
Systolic	160 ± 24	158 ± 26	0.492	172 ± 32	134 ± 26	<0.001	0.003	<0.0001
End-diastolic	19 ± 6	21 ± 7	0.243	21 ± 6	19 ± 6	0.090	0.263	0.153
Systemic blood pressure (mm Hg)
Systolic	145 ± 24	153 ± 27	0.024	100 ± 19	120 ± 27	0.006	<0.0001	<0.0001
Diastolic	69 ± 9	73 ± 12	0.098	57 ± 11	63 ± 14	0.069	<0.0001	<0.0001
Heart rate (/min)	58 ± 6	61 ± 10	0.154	59 ± 6	63 ± 9	0.017	0.016	0.074
Nitroglycerin dosage (mg)				0.07 ± 0.04	0.07 ± 0.04	0.328
Mean pulmonary capillary wedged pressure (mm Hg)	15 ± 5	15 ± 7	0.582
Cardiac output (L/min)	4.4 ± 0.9	4.8 ± 1.1	0.157
Cardiac index (L/min/m 2 )	2.8 ± 0.5	3.0 ± 0.6	0.205

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