Advertisement

Clinical Characteristics and Outcome of Alcohol Septal Ablation With Confirmation by Nitroglycerin Test for Drug-Refractory Hypertrophic Obstructive Cardiomyopathy With Labile Left Ventricular Outflow Obstruction

Open AccessPublished:June 25, 2015DOI:https://doi.org/10.1016/j.amjcard.2015.06.023
      Careful evaluation, including provocation tests, is needed to specify an indication for septal reduction therapy in patients with drug-refractory hypertrophic obstructive cardiomyopathy. This study aimed to evaluate the outcome of alcohol septal ablation (ASA) using an intravenous nitroglycerin test (IV-NTG). 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). The patients with labile obstruction had less left ventricular mass (141 ± 47 vs 182 ± 59 g, p = 0.003) and less brain natriuretic peptide values (414 ± 576 vs 744 ± 625 pg/ml, p <0.001) than those with basal obstruction. Immediately after ASA, the gradients improved from 15 ± 7 to 5 ± 5 mm Hg and the IV-NTG-provoked gradients improved from 74 ± 25 to 13 ± 9 mm Hg, respectively. At 1-year follow-up, the New York Heart Association functional class had improved from 2.7 ± 0.5 to 1.3 ± 0.5. There was no sudden cardiac death during the follow-up period (5.1 ± 3.0 years), and 8-year survival free from cardiovascular death was 94%. In conclusion, patients with labile obstruction had less-severe left ventricular hypertrophy but exhibited symptoms comparable to those with basal obstruction. The IV-NTG test is a useful method for rapidly confirming acute reduction of the latent gradient after the ASA procedure, and the outcome of ASA for labile obstruction was favorable.
      Alcohol septal ablation (ASA) has been performed for hypertrophic obstructive cardiomyopathy (HOCM) when symptoms cannot be treated effectively even after optimization of medical treatment.
      • Sigwart U.
      Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy.
      • Seggewiss H.
      • Gleichmann U.
      • Faber L.
      • Fassbender D.
      • Schmidt H.K.
      • Strick S.
      Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: acute results and 3-month follow-up in 25 patients.
      • Kuhn H.
      • Lawrenz T.
      • Lieder F.
      • Leuner C.
      • Strunk-Mueller C.
      • Obergassel L.
      • Bartelsmeier M.
      • Stellbrink C.
      Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience.
      • Leonardi R.A.
      • Kransdorf E.P.
      • Simel D.L.
      • Wang A.
      Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment.
      • Rigopoulos A.G.
      • Seggewiss H.
      A decade of percutaneous septal ablation in hypertrophic cardiomyopathy.
      • Jensen M.K.
      • Havndrup O.
      • Pecini R.
      • Dalsgaard M.
      • Hassager C.
      • Helqvist S.
      • Kelbaek H.
      • Jorgensen E.
      • Kober L.
      • Bundgaard H.
      Long-term outcome of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: a Scandinavian multicenter study.
      • Gersh B.J.
      • Maron B.J.
      • Bonow R.O.
      • Dearani J.A.
      • Fifer M.A.
      • Link M.S.
      • Naidu S.S.
      • Nishimura R.A.
      • Ommen S.R.
      • Rakowski H.
      • Seidman C.E.
      • Towbin J.A.
      • Udelson J.E.
      • Yancy C.W.
      2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      • Elliott P.M.
      • Anastasakis A.
      • Borger M.A.
      • Borggrefe M.
      • Cecchi F.
      • Charron P.
      • Hagege A.A.
      • Lafont A.
      • Limongelli G.
      • Mahrholdt H.
      • McKenna W.J.
      • Mogensen J.
      • Nihoyannopoulos P.
      • Nistri S.
      • Pieper P.G.
      • Pieske B.
      • Rapezzi C.
      • Rutten F.H.
      • Tillmanns C.
      • Watkins H.
      2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
      To achieve optimal results with ASA in patients with refractory symptoms related to labile obstruction, the nature of the obstruction of the left ventricle (LV) should be accurately described. Previous studies focused on ASA for provocable obstruction have been reported.
      • Lakkis N.
      • Plana J.C.
      • Nagueh S.
      • Killip D.
      • Roberts R.
      • Spencer 3rd, W.H.
      Efficacy of nonsurgical septal reduction therapy in symptomatic patients with obstructive hypertrophic cardiomyopathy and provocable gradients.
      • Gietzen F.H.
      • Leuner C.J.
      • Obergassel L.
      • Strunk-Mueller C.
      • Kuhn H.
      Role of transcoronary ablation of septal hypertrophy in patients with hypertrophic cardiomyopathy, New York Heart Association functional class III or IV, and outflow obstruction only under provocable conditions.
      Both studies demonstrated that provocable obstruction could cause drug-refractory symptoms and ASA was effective for patients without a baseline gradient. In contemporary clinical practice, Valsalva maneuver and postextrasystolic potentiation have been used as nonpharmacologic methods to elucidate immediate improvement of the latent gradient
      • Sorajja P.
      • Valeti U.
      • Nishimura R.A.
      • Ommen S.R.
      • Rihal C.S.
      • Gersh B.J.
      • Hodge D.O.
      • Schaff H.V.
      • Holmes Jr., D.R.
      Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy.
      ; however, it is unclear which provocation method was most appropriate during the ASA procedure. The use of nitrates, which mainly decrease the LV afterload, has been described as a conveniently administered method for immediate detection of the gradient.
      • Sheikh K.H.
      • Pearce F.B.
      • Kisslo J.
      Use of Doppler echocardiography and amyl nitrite inhalation to characterize left ventricular outflow obstruction in hypertrophic cardiomyopathy.
      Nevertheless, there have been no reports that address the usefulness of nitrates during the ASA procedure. Therefore, the purposes of this study were (1) to demonstrate the clinical characteristics of labile obstruction, (2) to determine the usefulness of the intravenous nitroglycerin (IV-NTG) test, and (3) to conduct a follow-up study after ASA for labile obstruction.

      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
      • Gersh B.J.
      • Maron B.J.
      • Bonow R.O.
      • Dearani J.A.
      • Fifer M.A.
      • Link M.S.
      • Naidu S.S.
      • Nishimura R.A.
      • Ommen S.R.
      • Rakowski H.
      • Seidman C.E.
      • Towbin J.A.
      • Udelson J.E.
      • Yancy C.W.
      2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      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.
      • Gersh B.J.
      • Maron B.J.
      • Bonow R.O.
      • Dearani J.A.
      • Fifer M.A.
      • Link M.S.
      • Naidu S.S.
      • Nishimura R.A.
      • Ommen S.R.
      • Rakowski H.
      • Seidman C.E.
      • Towbin J.A.
      • Udelson J.E.
      • Yancy C.W.
      2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      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.
      • Cohn J.
      Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group.
      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.
      Table 1Baseline characteristics of the study population in comparison with basal obstruction
      VariableLabile ObstructionBasal Obstructionp value
      (n = 32)(n = 120)
      Age (years)65 ± 1261 ± 150.282
      Female25 (78%)85 (71%)0.508
      Height (m)1.55 ± 0.121.55 ± 0.100.826
      Body weight (kg)59 ± 1357 ± 120.405
      Body mass index (kg/m2)24.3 ± 3.323.6 ± 3.90.215
      Brain natriuretic peptide (pg/mL, normal <18.4pg/mL)414 ± 576744 ± 625<0.001
      Atrial natriuretic peptide (pg/mL, normal <43.0pg/mL)162 ± 188162 ± 1270.691
      Family history of sudden cardiac death5 (16%)15 (13%)0.769
      Septal thickness ≥ 30 mm1 (3%)6 (5%)1.000
      Ventricular Tachycardia/Fibrillation5 (17%)19 (16%)0.502
      Unexplained syncope9 (28%)30 (25%)0.795
      Abnormal blood pressure response7/15 (47%)9/59 (15%)0.014
      Implantable cardioverter-defibrillator implantation4 (13%)6 (5%)0.219
      Dual chamber pacemaker implantation2 (7%)0 (0%)0.043
      History of congestive heart failure7 (22%)25 (21%)1.000
      Coronary artery disease4 (13%)2 (2%)0.018
      Atrial fibrillation5 (16%)30 (25%)0.054
      Hypertension17 (53%)50 (42%)0.317
      Dyslipidemia18 (56%)54 (45%)0.320
      Diabetes mellitus6 (19%)8 (7%)0.077
      Smoker9 (28%)37 (31%)0.162
      Obstruction Type0.814
       Left ventricular outflow tract type20 (63%)81 (68%)
       Mid-ventricular obstruction3 (9%)14 (12%)
       Combined obstruction9 (28%)25 (21%)
      New York Heart Association functional class2.7 (0.5)2.7 (0.5)0.692
      Anginal symptoms18 (56%)60 (50%)0.691
      Faintness∼Syncope16 (50%)54 (45%)0.694
      Aborted cardiac arrest1 (3%)4 (3%)1.000
      Measurements of the left-sided heart
       Interventricular septum thickness (mm)16.9 ± 3.818.6 ± 4.10.014
       Posterior wall thickness (mm)11.7 ± 2.412.8 ± 3.10.120
       Left ventricular end-diastolic diameter (mm)42.2 ± 5.642.2 ± 6.10.980
       Left ventricular end-systolic diameter (mm)22.9 ± 4.323.9 ± 4.80.320
       Left atrial diameter (mm)42.0 ± 6.544.9 ± 7.80.057
       Mitral regurgitation area (cm2)5.4 ± 5.27.1 ± 5.30.101
       Left ventricular mass (g)141 ± 47182 ± 590.003
       Number of hypertrophic segments2.4 ± 1.64.2 ± 2.90.009
      Medications at alcohol septal ablation procedure
       Beta blockers30 (94%)110 (92)1.000
       Class Ia agents27 (84%)77 (64%)0.033
       Class III agents0 (0%)4 (3%)0.580
       Calcium-channel blockers6 (19%)34 (28%)0.367
       Angiotensin-converting enzyme inhibitors/Angiotensin receptor blockers4 (13%)18 (15%)1.000
       Diuretics6 (19%)30 (25%)0.640
       Nitrates1 (3%)0 (0%)0.211
      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 2Details of the alcohol septal ablation procedure for patients with labile obstruction
      Interval from initial presentation to procedure (days)188 [59–465]
      No of ablated branches
       One branch22 (69%)
       Two branches6 (19%)
       ≥3 branches4 (13%)
      Dosage of ethanol (ml)2.0 [1.5–2.3]
      Peak creatine phosphokinase (IU/L)1252 [915-1542]
      Peak creatine phosphokinase MB-isozyme (IU/L)142 [120–182]
      Periprocedural complications within 30 days
       Transient complete atrioventricular block4 (13%)
      One patient had transient trifascicular block and drug-induced sustained ventricular tachycardia, and received implantable cardioverter-defibrillator implantation.
       Persistent complete atrioventricular block0
       Sustained ventricular tachycardia1 (3%)
      One patient had transient trifascicular block and drug-induced sustained ventricular tachycardia, and received implantable cardioverter-defibrillator implantation.
       Additional pacemaker device1 (3%)
      One patient had transient trifascicular block and drug-induced sustained ventricular tachycardia, and received implantable cardioverter-defibrillator implantation.
       Cerebral infarction1 (3%)
       Ethanol misplacement0
       Coronary vessel dissection0
       Major bleeding0
       Cardiac tamponade0
       Emergency cardiac surgery0
       Death0
      Data are expressed as median [interquartile range] or as number (percentage).
      One patient had transient trifascicular block and drug-induced sustained ventricular tachycardia, and received implantable cardioverter-defibrillator implantation.
      Table 3Changes in catheterization parameters before and after alcohol septal ablation (n = 32)
      VariableBaselineIntravenous nitroglycerin testp value
      In comparison between baseline and intravenous nitroglycerin test.
      BeforeAfterp valueBeforeAfterp valueBeforeAfter
      Gradient (mm Hg)15 ± 75 ± 5<0.000174 ± 2513 ± 9<0.0001<0.0001<0.0001
      Left ventricular pressure (mm Hg)
       Systolic160 ± 24158 ± 260.492172 ± 32134 ± 26<0.0010.003<0.0001
       End-diastolic19 ± 621 ± 70.24321 ± 619 ± 60.0900.2630.153
      Systemic blood pressure (mm Hg)
       Systolic145 ± 24153 ± 270.024100 ± 19120 ± 270.006<0.0001<0.0001
       Diastolic69 ± 973 ± 120.09857 ± 1163 ± 140.069<0.0001<0.0001
      Heart rate (/min)58 ± 661 ± 100.15459 ± 663 ± 90.0170.0160.074
      Nitroglycerin dosage (mg)0.07 ± 0.040.07 ± 0.040.328
      Mean pulmonary capillary wedged pressure (mm Hg)15 ± 515 ± 70.582
      Cardiac output (L/min)4.4 ± 0.94.8 ± 1.10.157
      Cardiac index (L/min/m2)2.8 ± 0.53.0 ± 0.60.205
      In comparison between baseline and intravenous nitroglycerin test.
      Figure thumbnail gr1
      Figure 1Prevalence of significant gradient threshold to septal reduction therapy with provocation method. All provocation methods provoked similarly significant gradients at baseline. Valsalva maneuver and post-PVC provoked significant gradients in some patients immediately after ASA, but not IV-NTG.
      During the 2-year follow-up, changes in HOCM-related symptoms before and after the ASA procedure are shown in Figures 2 and 3. At 6-month follow-up, all patients improved with regard to NYHA functional class (p <0.0001). Any post-ASA gradients at baseline or provocation did not correlate with their symptoms. Two patients received additional ICD implantation. One patient had documented periprocedural complete atrioventricular block and sustained ventricular tachycardia associated with excessive serum concentrations of cibenzoline 11 days later, and another had a documented syncopal attack and inducible ventricular tachycardia 1 year later. However, neither had received ICD therapy for ventricular tachyarrhythmias during the observation periods (5 and 7 years).
      Figure thumbnail gr2
      Figure 2Improvement in NYHA functional class during the 2-year follow-up. *Within 2 years, 2 patients died because of previously diagnosed malignancy.
      Figure thumbnail gr3
      Figure 3Number of patients with HOCM-related symptoms. VT/VF; ventricular tachycardia/ventricular fibrillation.
      The mean follow-up period was 5.1 years (standard deviation 3.0 years). Kaplan–Meier curves are described in Figures 4 and 5. Medical treatments including β blockers and class Ia agents were continued in the all patients during follow-up. During the observation period of patients with labile obstruction, there were 10 clinical events, including 4 deaths and 6 cases of recurrent heart failure. Of the 4 patients who died, 2 showed decreased activities in day-to-day living and died during hospitalization for congestive heart failure (67 and 84 years) with reserved ejection fraction; 2 died because of previously diagnosed malignant diseases (66 and 81 years); there was no case of sudden cardiac death or dilated-phase HCM. Of the 6 patients with recurrent heart failure, 2 developed worsening symptoms associated with atrial fibrillation and 4 others received repeat ASA because of residual protrusion adjacent to the previously ablated septum (n = 3) and recanalization of ablated branches (n = 1). All repeat cases were successfully treated by ASA and their symptoms improved to NYHA class I without further adverse clinical events.
      Figure thumbnail gr4
      Figure 4Kaplan–Meier curve for 8-year survival free from all-cause mortality.
      Figure thumbnail gr5
      Figure 5Kaplan–Meier curve for 8-year survival free from cardiovascular mortality.

      Discussion

      The present study systematically investigated the clinical characteristics and outcome of ASA for those with labile obstruction and also evaluated the detailed data obtained from direct pressure recording before and after ASA incorporating an IV-NTG bolus test.
      Nitrate application has been classically used for provocation, in which the main mechanism is thought to be reduction of LV afterload.
      • Sheikh K.H.
      • Pearce F.B.
      • Kisslo J.
      Use of Doppler echocardiography and amyl nitrite inhalation to characterize left ventricular outflow obstruction in hypertrophic cardiomyopathy.
      • Wigle E.D.
      • Lenkei S.C.
      • Chrysohou A.
      • Wilson D.R.
      Muscular subaortic stenosis: the effect of peripheral vasodilatation.
      • Braunwald E.
      • Oldham Jr., H.N.
      • Ross Jr., J.
      • Linhart J.W.
      • Mason D.T.
      • Fort 3rd, L.
      The circulatory response of patients with idiopathic hypertrophic subaortic stenosis to nitroglycerin and to the Valsalva maneuver.
      • Wigle E.D.
      • Auger P.
      • Marquis Y.
      Muscular subaortic stenosis. The direct relation between the intraventricular pressure difference and the left ventricular ejection time.
      • Powell Jr., W.J.
      • Whiting R.B.
      • Dinsmore R.E.
      • Sanders C.A.
      Symptomatic prognosis in patients with idiopathic hypertrophic subaortic stenosis (IHSS).
      • Hadjimiltiades S.
      • Panidis I.P.
      • McAllister M.
      • Ross J.
      • Mintz G.S.
      Dynamic changes in left ventricular outflow tract flow velocities after amyl nitrite inhalation in hypertrophic cardiomyopathy.
      • Marwick T.H.
      • Nakatani S.
      • Haluska B.
      • Thomas J.D.
      • Lever H.M.
      Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy.
      • Nakatani S.
      • Marwick T.H.
      • Lever H.M.
      • Thomas J.D.
      Resting echocardiographic features of latent left ventricular outflow obstruction in hypertrophic cardiomyopathy.
      • Faber L.
      • Heemann A.
      • Surig M.
      • Michalowski Z.
      • Gleichmann U.
      • Klempt H.W.
      Outflow acceleration assessed by continuous-wave Doppler echocardiography in left ventricular hypertrophy: an analysis of 103 consecutive cases.
      Amyl nitrite had been reported by Wigle in 1963,
      • Wigle E.D.
      • Lenkei S.C.
      • Chrysohou A.
      • Wilson D.R.
      Muscular subaortic stenosis: the effect of peripheral vasodilatation.
      and NTG had been reported by Braunwald in 1964.
      • Braunwald E.
      • Oldham Jr., H.N.
      • Ross Jr., J.
      • Linhart J.W.
      • Mason D.T.
      • Fort 3rd, L.
      The circulatory response of patients with idiopathic hypertrophic subaortic stenosis to nitroglycerin and to the Valsalva maneuver.
      Septal reduction therapies have been performed in patients with provoked gradients related to refractory symptoms.
      • Lakkis N.
      • Plana J.C.
      • Nagueh S.
      • Killip D.
      • Roberts R.
      • Spencer 3rd, W.H.
      Efficacy of nonsurgical septal reduction therapy in symptomatic patients with obstructive hypertrophic cardiomyopathy and provocable gradients.
      • Gietzen F.H.
      • Leuner C.J.
      • Obergassel L.
      • Strunk-Mueller C.
      • Kuhn H.
      Role of transcoronary ablation of septal hypertrophy in patients with hypertrophic cardiomyopathy, New York Heart Association functional class III or IV, and outflow obstruction only under provocable conditions.
      • Schaff H.V.
      • Dearani J.A.
      • Ommen S.R.
      • Sorajja P.
      • Nishimura R.A.
      Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction.
      Indeed, although nitrate provocation has been performed in many institutions, to our knowledge, the present study is the first to address the usefulness of IV-NTG bolus tests during ASA.
      Several studies comparing provocation methods have been reported and comparisons between Valsalva and exercise,
      • Jensen M.K.
      • Havndrup O.
      • Pecini R.
      • Dalsgaard M.
      • Hassager C.
      • Helqvist S.
      • Kelbaek H.
      • Jorgensen E.
      • Kober L.
      • Bundgaard H.
      Comparison of Valsalva manoeuvre and exercise in echocardiographic evaluation of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.
      amyl nitrite and exercise,
      • Marwick T.H.
      • Nakatani S.
      • Haluska B.
      • Thomas J.D.
      • Lever H.M.
      Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy.
      Valsalva and NTG,
      • Braunwald E.
      • Oldham Jr., H.N.
      • Ross Jr., J.
      • Linhart J.W.
      • Mason D.T.
      • Fort 3rd, L.
      The circulatory response of patients with idiopathic hypertrophic subaortic stenosis to nitroglycerin and to the Valsalva maneuver.
      and between sublingual NTG and dobutamine
      • Sohn I.S.
      • Lee J.B.
      • Park J.H.
      • Cho J.M.
      • Kim C.J.
      Valsalva maneuver to predict dynamic intraventricular obstruction during dobutamine stress echocardiography in patients with hypertension.
      have been performed during TTE. There was no sufficient evidence to decide which method was more useful. From the data among the 3 provocation types used in the present study, the post-PVC gradient was fairly excessive and gave values >50 mm Hg even for those who improved at 1-year follow-up after ASA. To standardize the protocol, we have adopted extrasystolic potentiation after 1 beat of PVC accompanied by a compensatory pause. Nevertheless, we could not avoid large variability in post-PVC gradients.
      Vaglio et al reported the clinical characteristics and the long-term follow-up study in large cohort (n = 415) of patients with HCM with latent obstruction.
      • Vaglio Jr., J.C.
      • Ommen S.R.
      • Nishimura R.A.
      • Tajik A.J.
      • Gersh B.J.
      Clinical characteristics and outcomes of patients with hypertrophic cardiomyopathy with latent obstruction.
      In comparisons with the patients, our study population was older and less severe in septal hypertrophy, and the other characteristics were comparable. Meanwhile, the present data identified the differences in clinical characteristics between labile obstruction and basal obstruction. In patients with labile obstruction, the LV wall was less hypertrophied and the serum concentration of brain natriuretic peptide was less than in those with basal obstruction. Interestingly, abnormal response of blood pressure during exercise was observed in more patients with labile obstruction than with basal obstruction (47% vs 15%, p = 0.014). Instability of intraventricular obstruction seemed to cause large variability of the gradient accompanied by the abnormal response as a characteristic feature of labile obstruction. In previous studies of HOCM with basal obstruction,
      • Kuhn H.
      • Lawrenz T.
      • Lieder F.
      • Leuner C.
      • Strunk-Mueller C.
      • Obergassel L.
      • Bartelsmeier M.
      • Stellbrink C.
      Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience.
      • Faber L.
      • Welge D.
      • Fassbender D.
      • Schmidt H.K.
      • Horstkotte D.
      • Seggewiss H.
      Percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: managing the risk of procedure-related AV conduction disturbances.
      • Fernandes V.L.
      • Nielsen C.
      • Nagueh S.F.
      • Herrin A.E.
      • Slifka C.
      • Franklin J.
      • Spencer 3rd., W.H.
      Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy the Baylor and Medical University of South Carolina experience 1996 to 2007.
      • van der Lee C.
      • Scholzel B.
      • ten Berg J.M.
      • Geleijnse M.L.
      • Idzerda H.H.
      • van Domburg R.T.
      • Vletter W.B.
      • Serruys P.W.
      • ten Cate F.J.
      Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation.
      the symptoms, echocardiographic parameters, and effects of ASA were comparable to our study population with labile obstruction, suggesting that severity of symptoms in patients with HOCM is not correlated with gradient regardless of being at rest or after provocation. This study demonstrated that Valsalva maneuver and post-PVC had greater sensitivity to detect the latent gradient immediately after the ASA procedure than IV-NTG test. It should be kept in mind, however, that the post-ASA gradient cannot be regarded as a reliable end point even for basal obstruction.
      • Veselka J.
      • Zemanek D.
      • Tomasov P.
      • Homolova S.
      • Adlova R.
      • Tesar D.
      Complications of low-dose, echo-guided alcohol septal ablation.
      Regardless of the gradient, satisfactory ablation is achieved when sufficient ethanol deposits in septal myocardium attributable to intraventricular obstruction are confirmed by simultaneous TTE.
      • Rigopoulos A.G.
      • Seggewiss H.
      A decade of percutaneous septal ablation in hypertrophic cardiomyopathy.
      At any rate, latent gradients should be evaluated by the combination of multiple provocation tests which provide different types of modification to the hypertrophied LV because it has often been shown that some patients have susceptibility to one specific provocation. In this study, we demonstrated that the IV-NTG test could be available as another method added to the other provocation tests and ASA improved the deterioration of hemodynamics during reduction of LV afterload by IV-NTG.
      Finally, we have investigated survival analysis after the ASA using IV-NTG test in patients with labile obstruction, compared to those with basal obstruction. Although there was no difference between the 2 types, the outcomes presented favorable clinical courses similar to those in populations for which previous reports investigated septal reduction therapy in experienced centers.
      • Kuhn H.
      • Lawrenz T.
      • Lieder F.
      • Leuner C.
      • Strunk-Mueller C.
      • Obergassel L.
      • Bartelsmeier M.
      • Stellbrink C.
      Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience.
      • Sorajja P.
      • Valeti U.
      • Nishimura R.A.
      • Ommen S.R.
      • Rihal C.S.
      • Gersh B.J.
      • Hodge D.O.
      • Schaff H.V.
      • Holmes Jr., D.R.
      Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy.
      • Fernandes V.L.
      • Nielsen C.
      • Nagueh S.F.
      • Herrin A.E.
      • Slifka C.
      • Franklin J.
      • Spencer 3rd., W.H.
      Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy the Baylor and Medical University of South Carolina experience 1996 to 2007.
      • Steggerda R.C.
      • Damman K.
      • Balt J.C.
      • Liebregts M.
      • Ten Berg J.M.
      • van den Berg M.P.
      Periprocedural complications and long-term outcome after alcohol septal ablation versus surgical myectomy in hypertrophic obstructive cardiomyopathy: a single-center experience.
      However, it is unclear what kind of patients with HOCM respond favorably to ASA alternative to surgical myectomy. The present study has indicated that ASA was effective at least for patients with labile obstruction, which accounts for approximately 20% of drug-refractory symptomatic patients with HOCM. Direct comparisons should be performed in further studies to be conducted in a randomized manner.
      Major limitations associated with this study were the small number of patients and the selection bias. Our study population included patients with more severe symptoms and a greater female-to-male ratio, in comparison with other studies for HOCM with labile obstruction. In general, patients with HOCM with labile obstruction have mild symptoms and good prognosis, and most patients with HCM are male.

      Acknowledgment

      The authors thank Eisei Yamamoto, MD, Tadaaki Ohno, MD, and Yoshiyuki Hirayama, MD, for valuable supervision, and all members in their catheterization laboratory for the excellent assistance.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Sigwart U.
        Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy.
        Lancet. 1995; 346: 211-214
        • Seggewiss H.
        • Gleichmann U.
        • Faber L.
        • Fassbender D.
        • Schmidt H.K.
        • Strick S.
        Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: acute results and 3-month follow-up in 25 patients.
        J Am Coll Cardiol. 1998; 31: 252-258
        • Kuhn H.
        • Lawrenz T.
        • Lieder F.
        • Leuner C.
        • Strunk-Mueller C.
        • Obergassel L.
        • Bartelsmeier M.
        • Stellbrink C.
        Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience.
        Clin Res Cardiol. 2008; 97: 234-243
        • Leonardi R.A.
        • Kransdorf E.P.
        • Simel D.L.
        • Wang A.
        Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment.
        Circ Cardiovasc Interv. 2010; 3: 97-104
        • Rigopoulos A.G.
        • Seggewiss H.
        A decade of percutaneous septal ablation in hypertrophic cardiomyopathy.
        Circ J. 2011; 75: 28-37
        • Jensen M.K.
        • Havndrup O.
        • Pecini R.
        • Dalsgaard M.
        • Hassager C.
        • Helqvist S.
        • Kelbaek H.
        • Jorgensen E.
        • Kober L.
        • Bundgaard H.
        Long-term outcome of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: a Scandinavian multicenter study.
        Circ Cardiovasc Interv. 2011; 4: 256-265
        • Gersh B.J.
        • Maron B.J.
        • Bonow R.O.
        • Dearani J.A.
        • Fifer M.A.
        • Link M.S.
        • Naidu S.S.
        • Nishimura R.A.
        • Ommen S.R.
        • Rakowski H.
        • Seidman C.E.
        • Towbin J.A.
        • Udelson J.E.
        • Yancy C.W.
        2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
        J Am Coll Cardiol. 2011; 58: e212-260
        • Elliott P.M.
        • Anastasakis A.
        • Borger M.A.
        • Borggrefe M.
        • Cecchi F.
        • Charron P.
        • Hagege A.A.
        • Lafont A.
        • Limongelli G.
        • Mahrholdt H.
        • McKenna W.J.
        • Mogensen J.
        • Nihoyannopoulos P.
        • Nistri S.
        • Pieper P.G.
        • Pieske B.
        • Rapezzi C.
        • Rutten F.H.
        • Tillmanns C.
        • Watkins H.
        2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
        Eur Heart J. 2014; 35: 2733-2779
        • Lakkis N.
        • Plana J.C.
        • Nagueh S.
        • Killip D.
        • Roberts R.
        • Spencer 3rd, W.H.
        Efficacy of nonsurgical septal reduction therapy in symptomatic patients with obstructive hypertrophic cardiomyopathy and provocable gradients.
        Am J Cardiol. 2001; 88: 583-586
        • Gietzen F.H.
        • Leuner C.J.
        • Obergassel L.
        • Strunk-Mueller C.
        • Kuhn H.
        Role of transcoronary ablation of septal hypertrophy in patients with hypertrophic cardiomyopathy, New York Heart Association functional class III or IV, and outflow obstruction only under provocable conditions.
        Circulation. 2002; 106: 454-459
        • Sorajja P.
        • Valeti U.
        • Nishimura R.A.
        • Ommen S.R.
        • Rihal C.S.
        • Gersh B.J.
        • Hodge D.O.
        • Schaff H.V.
        • Holmes Jr., D.R.
        Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy.
        Circulation. 2008; 118: 131-139
        • Sheikh K.H.
        • Pearce F.B.
        • Kisslo J.
        Use of Doppler echocardiography and amyl nitrite inhalation to characterize left ventricular outflow obstruction in hypertrophic cardiomyopathy.
        Chest. 1990; 97: 389-395
        • Cohn J.
        Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group.
        JAMA. 1988; 259: 539-544
        • Wigle E.D.
        • Lenkei S.C.
        • Chrysohou A.
        • Wilson D.R.
        Muscular subaortic stenosis: the effect of peripheral vasodilatation.
        Can Med Assoc J. 1963; 89: 896-899
        • Braunwald E.
        • Oldham Jr., H.N.
        • Ross Jr., J.
        • Linhart J.W.
        • Mason D.T.
        • Fort 3rd, L.
        The circulatory response of patients with idiopathic hypertrophic subaortic stenosis to nitroglycerin and to the Valsalva maneuver.
        Circulation. 1964; 29: 422-431
        • Wigle E.D.
        • Auger P.
        • Marquis Y.
        Muscular subaortic stenosis. The direct relation between the intraventricular pressure difference and the left ventricular ejection time.
        Circulation. 1967; 36: 36-44
        • Powell Jr., W.J.
        • Whiting R.B.
        • Dinsmore R.E.
        • Sanders C.A.
        Symptomatic prognosis in patients with idiopathic hypertrophic subaortic stenosis (IHSS).
        Am J Med. 1973; 55: 15-24
        • Hadjimiltiades S.
        • Panidis I.P.
        • McAllister M.
        • Ross J.
        • Mintz G.S.
        Dynamic changes in left ventricular outflow tract flow velocities after amyl nitrite inhalation in hypertrophic cardiomyopathy.
        Am Heart J. 1991; 121: 1143-1148
        • Marwick T.H.
        • Nakatani S.
        • Haluska B.
        • Thomas J.D.
        • Lever H.M.
        Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy.
        Am J Cardiol. 1995; 75: 805-809
        • Nakatani S.
        • Marwick T.H.
        • Lever H.M.
        • Thomas J.D.
        Resting echocardiographic features of latent left ventricular outflow obstruction in hypertrophic cardiomyopathy.
        Am J Cardiol. 1996; 78: 662-667
        • Faber L.
        • Heemann A.
        • Surig M.
        • Michalowski Z.
        • Gleichmann U.
        • Klempt H.W.
        Outflow acceleration assessed by continuous-wave Doppler echocardiography in left ventricular hypertrophy: an analysis of 103 consecutive cases.
        Cardiology. 1998; 90: 220-226
        • Schaff H.V.
        • Dearani J.A.
        • Ommen S.R.
        • Sorajja P.
        • Nishimura R.A.
        Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction.
        J Thorac Cardiovasc Surg. 2012; 143: 303-309
        • Jensen M.K.
        • Havndrup O.
        • Pecini R.
        • Dalsgaard M.
        • Hassager C.
        • Helqvist S.
        • Kelbaek H.
        • Jorgensen E.
        • Kober L.
        • Bundgaard H.
        Comparison of Valsalva manoeuvre and exercise in echocardiographic evaluation of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.
        Eur J Echocardiogr. 2010; 11: 763-769
        • Sohn I.S.
        • Lee J.B.
        • Park J.H.
        • Cho J.M.
        • Kim C.J.
        Valsalva maneuver to predict dynamic intraventricular obstruction during dobutamine stress echocardiography in patients with hypertension.
        Int J Cardiol. 2010; 144: 433-435
        • Vaglio Jr., J.C.
        • Ommen S.R.
        • Nishimura R.A.
        • Tajik A.J.
        • Gersh B.J.
        Clinical characteristics and outcomes of patients with hypertrophic cardiomyopathy with latent obstruction.
        Am Heart J. 2008; 156: 342-347
        • Faber L.
        • Welge D.
        • Fassbender D.
        • Schmidt H.K.
        • Horstkotte D.
        • Seggewiss H.
        Percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: managing the risk of procedure-related AV conduction disturbances.
        Int J Cardiol. 2007; 119: 163-167
        • Fernandes V.L.
        • Nielsen C.
        • Nagueh S.F.
        • Herrin A.E.
        • Slifka C.
        • Franklin J.
        • Spencer 3rd., W.H.
        Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy the Baylor and Medical University of South Carolina experience 1996 to 2007.
        JACC Cardiovasc Interv. 2008; 1: 561-570
        • van der Lee C.
        • Scholzel B.
        • ten Berg J.M.
        • Geleijnse M.L.
        • Idzerda H.H.
        • van Domburg R.T.
        • Vletter W.B.
        • Serruys P.W.
        • ten Cate F.J.
        Usefulness of clinical, echocardiographic, and procedural characteristics to predict outcome after percutaneous transluminal septal myocardial ablation.
        Am J Cardiol. 2008; 101: 1315-1320
        • Veselka J.
        • Zemanek D.
        • Tomasov P.
        • Homolova S.
        • Adlova R.
        • Tesar D.
        Complications of low-dose, echo-guided alcohol septal ablation.
        Catheter Cardiovasc Interv. 2010; 75: 546-550
        • Steggerda R.C.
        • Damman K.
        • Balt J.C.
        • Liebregts M.
        • Ten Berg J.M.
        • van den Berg M.P.
        Periprocedural complications and long-term outcome after alcohol septal ablation versus surgical myectomy in hypertrophic obstructive cardiomyopathy: a single-center experience.
        JACC Cardiovasc Interv. 2014; 7: 1227-1234