© 2016, Wiley Periodicals, Inc. DOI: 10.1111/joic.12331

ORIGINAL INVESTIGATION Effectiveness of Alcohol Septal Ablation Versus Transaortic Extended Myectomy in Hypertrophic Cardiomyopathy with Midventricular Obstruction YIN-JIAN YANG, M.D., 1 CHAO-MEI FAN, M.D., 2 JIN-QING YUAN, M.D., 3 SHUI-YUN WANG, M.D., 4 YUN-HU SONG, M.D., 4 SHU-BIN QIAO, M.D., 3 SHI-JIE YOU, M.D., 3 ZHI-MIN WANG, M.D., 5 FU-JIAN DUAN, M.D., 5 and YI-SHI LI, M.D. 2 From the 1Department of Cardiology, Beijing Luhe Hospital, Capital Medical University, Beijing, China; 2Key Laboratory of Clinical Trial Research in Cardiovascular Drugs, Ministry of Health, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 4Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and 5Department of Echocardiography, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Objectives: Investigate the effectiveness of alcohol septal ablation (ASA) and transaortic extended myectomy (TEM) in hypertrophic cardiomyopathy (HCM) with midventricular obstruction (MVO). Background: MVO is less common than subaortic obstruction. Data on the effectiveness of ASA and TEM in MVO are lacking. Methods: The clinical profiles of 22 patients undergoing ASA and 37 patients undergoing TEM were compared. No patient had apical aneurysm, abnormal chordae, mitral valve replacement or repair. Results: Baseline midventricular pressure gradient and symptoms were comparable between the ASA and TEM groups. During follow-up, both groups demonstrated substantial reduction in pressure gradient (the ASA group: 79.7
21.2 mm Hg to 43.7
28.9 mm Hg, P < 0.001; the TEM group: 69.0
23.9 mm Hg to 15.0
16.9 mm Hg, P < 0.001). The reduction in pressure gradient was greater (78.9
18.6% vs. 46.4
33.4%, P < 0.001) and the residual pressure gradient was lower after TEM versus ASA (P < 0.001). Patients with New York Heart Association class III/IV dyspnea decreased from 59.1 to 18.2% (P ¼ 0.022) in the ASA group and from 56.8 to 5.6% (P < 0.001) in the TEM group. Patients with Canadian Cardiovascular Society class III/IV angina decreased from 40.9 to 9.1% (P ¼ 0.016) in the ASA group and from 32.4 to 0% (P < 0.001) in the TEM group. Conclusions: While ASA and TEM both improve gradients and symptoms, TEM may provide a more reliable reduction in gradients compared to ASA. (J Interven Cardiol 2016;9999:1–9)

Introduction We acknowledge i) that all authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors, and ii) that all authors are in agreement with the manuscript. This work was supported by the National Key Clinical Specialty Project and the National Science and Technology Major Project (no. 2012ZX09303008-001) from the Ministry of Science and Technology of China. Address for reprints: Chao-Mei Fan and Jin-Qing Yuan, 167 Beilishi Rd, Xi Cheng District, Beijing 100037, China. Fax: þ86-010-6835-4535; e-mail: [email protected] (Chao-Mei Fan); [email protected] (Jin-Qing Yuan)

Vol. 9999, No. 9999, 2016

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease.1 Left ventricular intracavity obstruction presents in about 70% of patients with HCM and is associated with adverse outcomes.2–4 This hemodynamic disorder can present in the subaortic or midventricular area of left ventricle. Subaortic obstruction is common, while midventricular obstruction (MVO) is rare.2,3 For the majority of eligible patients with HCM with severe

Journal of Interventional Cardiology

1

YANG, ET AL.

drug-refractory symptoms and subaortic obstruction, surgical septal myectomy is the gold standard in experienced centers. Alcohol septal ablation (ASA) is usually considered as an alternative to myectomy, which is usually performed in patients who are not optimal surgical candidates (e.g., because of comorbidities or advanced age) or have a strong desire to avoid surgery.5,6 However, data on the effectiveness of these two septal reduction therapies in HCM with MVO are lacking. We aimed to investigate the effectiveness of ASA and transaortic extended myectomy (TEM) in HCM with MVO.

Materials and Methods Study Population. This study consecutively screened medical records of 3,140 adult patients (18 years of age) with HCM who were referred to Fuwai Hospital (Beijing, China) between January 2001 and March 2014. Of the 3,140 patients, 205 (6.5%) had MVO (alone or in combination of subaortic obstruction). Seventy-four of the 205 patients underwent ASA (n ¼ 27) and TEM (n ¼ 47), and were consecutively enrolled.7 None of the 74 patients had apical aneurysm. The following conditions excluded patients from this study: abnormal chordae in left ventricle (n ¼ 12), mitral valve replacement or repair concomitant with myectomy (n ¼ 3) (Fig. 1). All enrolled patients aged

Figure 1. Flow chart of patient selection.

2

40 years of more were candidate for invasive or CT coronary angiography.6 This study conformed to the principles laid down in the 1964 Declaration of Helsinki and its later amendments. Local ethical committee approval was obtained. All patients gave their informed consent prior to their inclusion in the study. Definitions. The diagnosis of HCM was based on the presence of left ventricular maximum wall thickness 15 mm in the absence of diseases associated with this degree of hypertrophy.5 MVO was defined as a midcavitary gradient 30 mm Hg originating at the level of the papillary muscles and not related to systolic anterior motion of the mitral leaflets or anomalous insertion of papillary muscles.7 Echocardiography and Cardiovascular Magnetic Resonance Imaging. Echocardiographic data were obtained as previously described.8 Left ventricular intracavity pressure gradient was assessed using continuous wave Doppler echocardiography.8–10 Cardiovascular magnetic resonance imaging was performed on a 1.5-T MAGNETOM Avanto speed clinical scanner (Siemens Healthcare, Erlangen, Germany). The images were acquired using electrocardiogram gating during multiple short breath holds (8–15 seconds). A late gadolinium enhancement (LGE) protocol was used 10 minutes after the intravenous injection of 0.2 mmol/kg gadolinium diethylenetriamine pentaacetic acid (Magnevist; Schering, Berlin, Germany), and the breath-held segmented inversion-recovery sequence was acquired in the same views as the cine images. Septal Reduction Therapy. Septal reduction therapy is considered for patients presenting severe drug-refractory limiting symptoms and a peak pressure gradient 50 mm Hg at rest or with provocation. Severe drug-refractory limiting symptoms were defined as New York Heart Association (NYHA) functional class III/IV dyspnea, Canadian Cardiac Society (CCS) class III/IV angina, or disabling syncope despite optimal medical therapy or being unable to tolerate medical therapy. Optimal medical therapy was defined as beta-blockers titrated to a resting heart rate of approximately 60 beats per minute, verapamil maximum 480 mg/day, and diltiazem maximum 360 mg/day. ASA and TEM were performed as previously reported.11,12 The choice of ASA or TEM was made based on detailed discussion of the risks and benefits of each alternative for every patient in our center. Pressure gradient mentioned below refers

Journal of Interventional Cardiology

Vol. 9999, No. 9999, 2016

ASA VERSUS TEM IN HCM WITH MVO

to midventricular pressure gradient, unless otherwise specified. Alcohol Septal Ablation. ASA was performed using previously described techniques.11 In brief, through a 6F left coronary guiding catheter, a slightly oversized, over-the-wire angioplasty balloon (diameter 1.5 to 2.5  9 mm) was placed in the proximal segment of the selected septal perforator artery. After balloon inflation, angiographic contrast (Sonovue, Bracco-Imaging BV, Geneva, Switzerland) was injected through the balloon catheter together with simultaneous transthoracic 2-dimensional myocardial contrast echocardiography to determine the extent of the myocardium supplied by the selected septal artery. After delineation of the size of targeted myocardium, 1–4 mL of alcohol was slowly (1 mL/min) injected. The balloon was left inflated for 10 min after alcohol injection to prevent retrograde spill of alcohol. A successful procedure was defined as a reduction in the pressure gradient of 50% of the baseline value. For patients with 0.999 0.079 >0.999 0.459 NS NS 0.524

17 (77.3) 6 (27.3)

33 (89.2) 13 (35.1)

0.392 0.532

Values are mean
SD or n (%). ASA, alcohol septal ablation; CCS, Canadian Cardiovascular Society; NS, not significant; NYHA, New York Heart Association; SD, standard deviation; TEM, transaortic extended myectomy.

perforator artery ablated alone, 8 patients (36.4%) had the second septal perforator artery ablated alone or in combination of the first or third septal perforator artery, and 1 patient (4.5%) had the third septal perforator artery ablated alone. No in-hospital mortality occurred. One patient (4.5%) in the ASA group experienced resuscitated ventricular fibrillation 2 days after the ASA procedure. One patient (2.7%) in the

TEM group experienced resuscitated ventricular fibrillation 3 days after myectomy. Complete atrioventricular block occurred in 7 patients (31.8%) of the ASA group. However, atrioventricular conduction restored in all of these patients before discharge and no new permanent pacemaker dependency occurred. No complete atrioventricular block occurred in the TEM group (Table 3).

Table 2. Baseline Echocardiographic and Cardiovascular Magnetic Resonance Features

Echocardiography Maximum septal thickness, mm Left atrium, mm Left ventricle, mm Ejection fraction, % Pressure gradient, mm Hg Cardiovascular magnetic resonance Maximum septal thickness, mm Left atrium, mm Left ventricle, mm Ejection fraction, % Apical late gadolinium enhancement

4

ASA (n ¼ 22)

TEM (n ¼ 37)

P-value

25.1
4.9 41.8
5.5 40.1
5.9 73.0
6.3 79.7
21.2

25.8
4.4 42.0
6.6 39.2
4.3 73.5
6.9 69.0
23.9

0.522 0.880 0.470 0.800 0.089

24.4
3.6 40.7
6.9 45.0
5.2 76.7
7.2 0 (0)

26.4
4.0 43.0
7.5 43.2
4.8 72.5
6.3 2 (9.1)

0.051 0.237 0.183 0.022 0.531

Journal of Interventional Cardiology

Vol. 9999, No. 9999, 2016

ASA VERSUS TEM IN HCM WITH MVO Table 3. Acute Procedural Results and 30-Day Outcomes ASA (n ¼ 22)

Maximum septal thickness, mm† Residual pressure gradient, mm Hg† Reduction in pressure gradient, % Resuscitated VF/sustained VT Complete atrioventricular block

TEM (n ¼ 37)

P-value

20.2
5.1 14.3
10.4 77.1
21.6 1 (2.7) 0 (0)

0.001 0.999 0.001

24.2
2.7 30.3
18.4 61.9
22.8 1 (4.5) 7 (31.8)

Values are mean
SD or n (%). VF, ventricular fibrillation; VT, ventricular tachycardia. echocardiography.

Follow-Up. Follow-up was completed in all of the 59 patients (100%). The follow-up echocardiographic and CMR profiles were obtained median 1.0 year (IQR, 0.8 years; range, 4.0 months to 6.2 years) after ASA and TEM. The measurement of midcavitary pressure gradient is shown in Figure 2. The widening of left ventricular midcavity was evident after both therapies (Fig. 3). The reduction in pressure gradient was greater and the residual pressure gradient was lower in the TEM group versus the ASA group. In the ASA group, the residual pressure gradient at follow-up was higher than that measured immediately after the procedure, while the rebound of pressure gradient did not occur in the TEM group. After a median follow-up of 3.0 years (IQR, 2.0 years; range, 11 months to 13.3 years), 2 patients died (1 patient in the ASA group and 1 patient in the TEM group). The death in the ASA group was due to stroke.



P < 0.001 versus baseline; † measured using

The death in the TEM group was sudden death, which occurred in the patient who experienced resuscitated ventricular fibrillation 3 days after myectomy. There was no significant difference in survival between the ASA and TEM groups (log-rank P ¼ 0.828). The number of patients with severe limiting symptoms was higher in the ASA group than in the TEM group (Table 5). In the ASA group, recurrent severe symptoms occurred in 4 of the 13 patients (30.8%) who had the first septal perforator artery ablated alone. The patient who had the third septal perforator artery ablated alone experienced recurrent severe symptom. None of the 8 patients (0%) who had the second septal perforator artery ablated alone or in combination of the first or third septal perforator artery experienced recurrent severe symptom. One patient undergoing the first septal perforator artery ablated alone presented both NYHA class III/IV dyspnea and CCS class III/IV

Table 4. Clinical Outcomes of Patients Undergoing ASA According to Ablated Septal Branches First (n ¼ 13)

Second (n ¼ 4)

Alcohol dose, mL 2.7
2.3 2.2
0.7 Pressure gradient, mm Hg Baseline 77.4
20.3 79.3
10.9 Immediately post-ASA 30.8
18.5 28.8
13.1 1 year follow-up 46.8
31.6 46.0
9.5 Periprocedural complications Resuscitated VF/sustained VT 1 (7.7) 0 (0) Complete atrioventricular block 4 (30.8) 1 (25.0) Additional septal reduction 1 (7.7) 0 (0) ASA 1 (7.7) 0 (0) TEM 0 (0) 0 (0) Peak CK, U/L 1161.9
508.0 1271.7
471.8 Peak CK-MB, U/L 153.6
62.7 140.3
50.5

Vol. 9999, No. 9999, 2016

Second þ first (n ¼ 3) Second þ third (n ¼ 1) Third (n ¼ 1)

2.9
1.1

4.5

2

80.3
32.5 20.3
25.8 31.7
39.5

67 30 9

122 60 64

0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 944.7
400.9 102.7
21.1

0 (0) 1 (100) 0 (0) 0 (0) 0 (0) 1542.5 191

Journal of Interventional Cardiology

0 (0) 1 (100) 0 (0) 0 (0) 0 (0) 1083 133

5

YANG, ET AL.

Figure 2. Measurement of midcavitary pressure gradient using continuous-wave Doppler. (A) Echocardiographic baseline four-chamber views in systole show HCM and MVO, systolic gradients with acceleration zone and jet formation. Pre-ASA continuous-wave Doppler measurements showed a peak systolic pressure gradient of 108 mm Hg at the mid-left ventricle. (B) PostASA echocardiographic follow-up fourchamber views in systole show the scar with thinning of the interventricular septum without remarkable systolic pressure gradients. LA, left atrium; LV, left ventricle; RA, right atrium.

angina during follow-up. The patient underwent an additional ASA procedure 6 months after the index ASA procedure. The additional ASA procedure, in which the second and third septal perforator arteries were ablated, provided a sustained improvement in symptoms. No patient in the TEM underwent

additional septal reduction therapy. No new permanent pacemaker dependency, resuscitated VF/sustained VT, implantable cardioverter defibrillator implantation occurred. New onset atrial fibrillation occurred in 2 patients, 1 in the ASA group and the other in the TEM group.

Figure 3. Cardiovascular magnetic resonance image after transaortic extended myectomy versus alcohol septal ablation at end-systole. Top panels show long-axis cardiovascular magnetic resonance imaging views before (left) and after (right) myectomy. Bottom panels show long-axis views before (left) and 1 year after (right) alcohol septal ablation. The first septal branch was ablated in this patient. The widening of left ventricular midcavity is evident after both myectomy and alcohol septal ablation. Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

6

Journal of Interventional Cardiology

Vol. 9999, No. 9999, 2016

ASA VERSUS TEM IN HCM WITH MVO Table 5. Clinical and Echocardiographic Profiles at Follow-Up

NYHA class III/IV CCS class III/IV Echocardiography Residual pressure gradient, mm Hg Maximum septal thickness, mm Reduction in pressure gradient, % Ejection fraction, % Left atrium, mm Left ventricle, mm Medications Beta-blocker Calcium-channel blocker

ASA (n ¼ 22)

TEM (n ¼ 37)

4 (18.2) 2 (9.1)

2 (5.6)† 0 (0)†

43.7
28.9†,‡ 22.2
3.9§ 46.4
33.4‡ 69.1
8.0 40.4
7.4 41.3
7.0

15.0
16.9† 20.3
4.7† 78.9
18.6 70.0
7.4§ 39.7
6.6 41.5
5.8

16 (72.7) 1 (4.5)

30 (81.1) 6 (16.2)

P-value

0.277 0.140