Author + information
- Received March 27, 2018
- Revision received July 17, 2018
- Accepted July 23, 2018
- Published online October 8, 2018.
- Liwen Liu, MD, PhDa,∗∗ (, )
- Jing Li, MBBSa,∗,
- Lei Zuo, MBBSa,
- Jinzhou Zhang, MD, PhDb,
- Mengyao Zhou, MBBSa,
- Bo Xu, MBBSb,
- Rebeccca T. Hahn, MDc,
- Martin B. Leon, MDc,
- David H. Hsi, MDd,
- Junbo Ge, MD, PhDe,
- Xiaodong Zhou, MD, PhDa,
- Jun Zhang, MD, PhDa,
- Shuping Ge, MD, PhDf and
- Lize Xiong, MD, PhDg,∗∗ (, )@CRFHeart
- aXijing Hypertrophic Cardiomyopathy Center, Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- bXijing Hypertrophic Cardiomyopathy Center, Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- cColumbia University Medical Center/New York Presbyterian Hospital, New York, New York
- dHeart & Vascular Institute, Stamford Hospital, Stamford, Connecticut
- eShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China
- fDepartment of Cardiology, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania
- gXijing Hypertrophic Cardiomyopathy Center, Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- ↵∗Address for correspondence:
Dr. Liwen Liu, Xijing Hypertrophic Cardiomyopathy Center, Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an, 710032 Shaanxi, China.
- ↵∗∗Dr. Lize Xiong, Xijing Hypertrophic Cardiomyopathy Center, Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an 710032, Shaanxi, China.
Background In patients with disabling symptoms caused by hypertrophic obstructive cardiomyopathy (HOCM), echocardiography-guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) could be a less invasive treatment option.
Objectives This study aimed to investigate the safety and efficacy of the PIMSRA for left ventricular outflow tract (LVOT) gradient reduction in HOCM.
Methods The study enrolled 15 patients with HOCM. These patients underwent electrocardiography, imaging, and blood biochemistry examination over 6 months of follow-up.
Results At 6 months of follow-up, patients showed significant reductions in peak LVOT gradients (resting gradient: from 88.00 [66.00] mm Hg to 11.00 [6.00] mm Hg; p = 0.001; stress-induced gradient: from 117.00 [81.00] mm Hg to 25.00 [20.00] mm Hg; p = 0.005) and interventricular septum (IVS) thickness (anterior IVS: from 25.00 [21.00] mm to 14.00 [12.00] mm; p = 0.001; posterior IVS: from 24.00 [21.00] mm to 14.00 [11.50] mm; p = 0.001). The reductions in IVS thickness and LVOT gradients were associated with improvement in New York Heart Association functional classification (from 3.00 [2.00] to 1.00 [1.00]; p < 0.001), total exercise time (from 6.00 [5.50] min to 9.00 [8.00] min; p = 0.007), and pro B-type natriuretic peptide levels (from 924.00 [370.45] pg/ml to 137.45 [75.73] pg/ml; p = 0.028). No patient had bundle branch block or complete heart block.
Conclusions PIMSRA is a safe and effective treatment approach for severe, symptomatic HOCM and results in sustained improvement in exercise capacity, persistent reduction in LVOT gradient, and sustained improvement in cardiac function.
- echocardiography-guided septal ablation
- hypertrophic obstructive cardiomyopathy
- percutaneous intramyocardial
- radiofrequency septal ablation
Resting or provocative left ventricular outflow tract (LVOT) obstruction has been reported to occur in nearly 70% of patients with hypertrophic cardiomyopathy and can lead to dyspnea, chest pain, atrial fibrillation, heart failure, and even sudden cardiac death (1–4). The removal of LVOT obstruction has been shown to alleviate symptoms and improve prognosis. Two invasive methods, namely, surgical myectomy and alcohol septal ablation (ASA), are used to relieve LVOT obstruction in drug-refractory patients. Although both procedures can clearly improve clinical symptoms and reduce the LVOT gradient, it is important to consider that sternotomy and extracorporeal circulation are required in myectomy, ethanol might be incorrectly injected, and the anatomic variability of the vascularized hypertrophic septum might cause issues in ASA (5–9).
We developed a novel minimally invasive treatment, transthoracic echocardiography (TTE)–guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) of the hypertrophic interventricular septum (IVS). This procedure provides a new approach (percutaneous intramyocardial approach) for treating hypertrophic obstructive cardiomyopathy (HOCM) by using radiofrequency ablation to relieve LVOT obstruction. Our study aimed to evaluate the safety and efficacy of PIMSRA in patients with HOCM.
The study included 15 patients (mean age, 40.73 ± 16.66 years; 2 female patients) who underwent PIMSRA with typical HOCM and severe symptoms (New York Heart Association functional class II or III) despite adequate medications. All patients were part of the study group registered at clinicaltrials.gov (NCT02888132) and provided informed consent to proceed with PIMSRA. All patients underwent clinical examination, standard 12-lead electrocardiography (ECG), TTE at rest and during dynamic bicycle exercise, contrast echocardiographic examination, computed tomography angiography (CTA), cardiac magnetic resonance (CMR) imaging, and blood biochemical examination before the PIMSRA.
All TTE studies were performed with the EPIQ 7C Ultrasound System (Philips Medical Systems, Bothell, Washington) with a 1.0- to 5.0-MHz transducer. Patients were told to lie in the left lateral recumbent position. ECG was performed simultaneously. Patients then underwent a routine echocardiographic study with an S5-1 probe. Subsequently, both left ventricular (LV) end-diastolic mass and LV ejection fraction were calculated using the formula recommended by the American Society of Echocardiography. The LV end-diastolic mass was indexed to the body surface area and was expressed as the LV mass index. Furthermore, LVOT gradients were assessed under resting conditions before the PIMSRA. Stress echocardiography was performed with a bicycle exercise according to a standard protocol (10) for assessment of the provoked LVOT gradient.
CMR studies were then performed with a 1.5-T magnetic resonance scanner (MAGNETOM Aera, Siemens AG, Erlangen, Germany). By using an ECG-gated, breath-holding, steady-state, free-precession pulse sequence, we acquired 3 standard LV cine long-axis slices (4-, 2-, and 3-chamber views) and a stack of contiguous short-axis slices from the atrioventricular ring to the apex (full LV coverage and slice thickness of 8 mm, with no overlap and no gap). The imaging parameters were as follows: 16 temporal phases per slice, 3.0 ms repetition time, 1.5 ms echo time, 50° flip angle, 32 to 36 cm × 32 to 36 cm field of view, 0.75 rectangular field of view, and 192 × 256 matrix. We acquired late gadolinium-enhanced sequences 10 min after intravenous administration of 0.2 mmol/kg gadolinium–diethylenetriamine penta-acetic acid (Magnevist, Schering, Berlin, Germany) using breath-holding, 2-dimensional, phase-sensitive inversion recovery. Furthermore, the Turbo FLASH (fast low-angle shot) sequence was obtained in the same orientation as the cine images. The inversion time ranged from 240 to 300 ms and was chosen to null normal myocardial signals (inversion time optimized by the T1 scout sequence).
The study protocol was approved by the institutional ethics committee of Xijing Hospital (KY20162042-1) and was performed in accordance with the ethical standards of the Declaration of Helsinki. The study was registered at clinicaltrials.gov (NCT02888132).
The patients were placed in the left lateral decubitus position after general anesthesia was introduced. Heart electrical activity, blood pressure, and blood oxygen levels were monitored simultaneously throughout the procedure. A temporary pacing wire was inserted with the tip at the apex of the right ventricle by using a 6F sheath through the right internal jugular vein. The procedure of TTE-guided PIMSRA is shown in the Central Illustration, and the procedure was performed as described previously (11). In brief, under TTE guidance, a radiofrequency electrode needle (17G, Cool-tip RF Ablation System and Switching Controller, Medtronic Minimally Invasive Therapies, Minneapolis, Minnesota) was inserted into the hypertrophied IVS via the percutaneous intramyocardial approach (Figure 1A), with its tip at the region of the IVS basal segment 8 to 10 mm from the subaortic valve. The ablation power was started at 60 W with mean duration of 5 min and a visible hyperechoic region on the echocardiogram (Figure 1B). If the vital signs were stable and the ablation range was not big enough as assessed by TTE, we would gradually increase the ablation power up to 100 W. Each application was up to 12 min, with a mean duration of 11 min for all patients. The ablation needle was then withdrawn 10 mm to prepare for the next application. For hypertrophic anterior and posterior IVS associated with LVOT obstruction, both regions should be ablated to ensure efficiency (Figure 1C). Total ablation time was 28 to 72 min, with a mean duration of 58 min. We verified successful ablation by assessing the contrast perfusion defects in the ablated regions and performing comparisons with the hypertrophic IVS noted before the procedure (Figures 1D vs. 1E). Ablation was considered complete when the peak LVOT gradient decreased to <30 mm Hg or when the area of ablation necrosis reached 30 to 40 mm along the long axis of the IVS (extending distally to 10 mm beyond the point of mitral–septal contact) and was 30 to 40 mm wide along the short axis of the IVS, two-thirds the thickness across the IVS (leaving an 8- to 10-mm unablated section of the IVS). After ablation, we performed a final hemodynamic assessment. The patients were then transferred to the cardiac intensive care unit and were monitored continuously for at least 24 h.
Because of the creation of an ablation-induced myocardial necrotic area, patients were monitored for 24 h in the cardiac intensive care unit and for the following 5 to 7 days in the cardiology ward. The temporary pacemaker was removed on days 2 to 5 in all patients. Continuous telemetric and ECG data were recorded daily until discharge to monitor for ventricular arrhythmia and bundle branch or atrioventricular block. Furthermore, clinical examination, TTE, 12-lead ECG, and blood biochemical examination were performed immediately after the procedure and 1, 3, and 6 months after the procedure. Stress echocardiography was performed at 3 and 6 months after the procedure. CTA was performed 2 weeks after the procedure to assess coronary septal branches. CMR imaging was performed 1, 3, and 6 months after the procedure to verify the effectiveness of ablation.
Data are presented as median (quartiles) when appropriate. Statistical analyses were performed with SPSS statistical software version 11.0 (Cary, North Carolina). All statistical tests were 2 sided, and a p value < 0.05 was considered significant.
Baseline characteristics of patients
Fifteen patients with HOCM and drug-refractory symptoms were enrolled in this study. Their baseline characteristics are summarized in Table 1. The baseline LVOT gradients ranged from 53 to 143 mm Hg at rest and from 65 to 267 mm Hg on provocation. Despite guideline-directed medical therapy, 5 patients had episodes of syncope, and all patients had progressive symptoms. Eleven patients had an intermediate to high risk (sudden cardiac death index ≥4%) on estimation with the sudden cardiac death risk prediction model used by the European Society of Cardiology (1). Furthermore, all patients had systolic anterior motion and mitral regurgitation.
Clinical and hemodynamic benefits after the procedure
All 15 patients survived and showed improvements in symptoms (New York Heart Association functional class improved from III [3.00 (2.00)] to I [1.00 (1.00)]; p < 0.001) and exercise capacities (total exercise time increased from 6.00 [5.50] min to 9.00 [8.00] min; p =0.007) 6 months after the procedure. CMR imaging confirmed the ablation zone, which showed ongoing fibrosis and continuous shrinkage of the ablation-induced septal lesion at the 6-month follow-up (Figure 2). There was a favorable hemodynamic effect, with reduction or elimination of the outflow gradient immediately after the procedure and at the 6-month follow-up (Table 2). Thus, after 6 months, the LVOT significantly widened from 3.60 (2.20) mm to 15.00 (14.00) mm (n = 15; p = 0.001) (Figures 3A to 3D), peak resting LVOT gradient decreased from 88.00 (66.00) mm Hg to 11.00 (6.00) mm Hg (n = 15; p = 0.001) (Figures 3E to 3H and 4A), and provoked LVOT gradient decreased from 117.00 (81.00) mm Hg to 25.00 (20.00) mm Hg (p = 0.005) (Figure 4B). The thickness of the anterior IVS progressively decreased from 25.00 (21.00) mm to 14.00 (12.00) mm (p = 0.001) (Figures 3I to 3L and 5A) and that of the posterior IVS decreased from 24.00 ± 21.00 mm to 14.00 ± 11.50 mm (p = 0.001) (Figures 3I to 3L and 5B). Additionally, mitral regurgitation volume decreased from 4.32 (1.40) ml to 0.50 (0.00) ml (p = 0.001) (Figures 3M to 3P). Moreover, the LV mass index decreased from 147.90 (124.50) g/cm2 to 108.80 (90.60) g/cm2 (p = 0.001) (Figure 5C).
ECG data are presented in Table 2 and Figure 6. There were no significant early or late changes in the Rv5 + Sv1. None of the patients showed a bundle-branch block pattern on surface ECG or had transient or permanent complete heart block during or after the procedure.
The level of the myocardial serum marker troponin I, myohemoglobin, and creatine kinase-MB mass were significantly elevated in all patients immediately after the procedure and then decreased thereafter (Figures 7A to 7C). Pro B-type natriuretic peptide, which is an independent predictor of morbidity and mortality (12), significantly decreased from 924.00 (370.45) pg/ml to 137.45 (75.73) pg/ml (p =0.028) at 6 months after the procedure (Figure 7D).
Complications and procedure modification
PIMSRA requires extensive assessment, careful patient selection, and experienced operators to achieve long-term clinical and hemodynamic benefits and acceptable safety profiles. In this study, ventricular ectopic beats were reported in 9 patients during ablation. All of these patients showed complete recovery 1 to 2 min after the ablation ceased. We recommend maintaining a safe distance of 3 mm between the border of the ablated region and the left side of the LV, with a gradual increase in ablation power from 60 to 100 W to avoid affecting the conduction system. After the appearance of ventricular ectopic beats, ablation was stopped to allow for recovery. There was no complete heart block either during or after ablation in the patients. It is presumed that this procedure was performed within the IVS and that the effects did not reach the conduction system distributed underneath the endocardium.
One patient experienced pericardial tamponade because of an injury to the coronary vein and abnormal blood coagulation requiring operative intervention. In the other patients, we identified the coronary artery near the puncture site by using CTA before the procedure and echocardiography-guided assessment during the procedure. The puncture point of the ablation needle was exactly at the apex, where the risk of injuring the coronary artery is low. The use of CTA and echocardiography substantially enhanced the procedural safety. To reduce heparin-associated bleeding risks, we used continuous TTE instead of catheters to measure the gradients.
This study assessed PIMSRA as a primary interventional therapy for patients with symptomatic HOCM and demonstrated its safety and efficacy. The invasive methods of surgical myectomy and ASA are used to treat HOCM in drug-refractory patients, and both procedures can improve clinical symptoms and relieve LVOT obstruction. Surgical myectomy has been considered as the gold standard for symptomatic patients with significant hemodynamic outflow tract obstruction for more than 50 years (13). The procedure involves the removal of a part of the protruding septal myocardium at the LV via a transaortic approach. ASA has been used as an alternative to surgical myectomy for more than 20 years (14). This catheter-based approach involves the injection of ethanol into a septal perforator branch of the left anterior descending coronary artery (LAD) to induce myocardial infarction within the proximal IVS.
We used a percutaneous intramyocardial, non-transaortic and non-transcoronary approach, which could reduce LVOT obstruction and avoid sternotomy, reliance on alcohol injection, and damage to the conduction system distributed underneath the endocardium. This was accomplished by inserting a radiofrequency needle and ablating the myocardium of the LAD distribution, including the septal perforators. The localized “therapeutic infarction” was induced by ablation energy delivery in the LAD distribution with minimal injury to the surrounding tissues (15). These effects eliminate or reduce the LVOT gradient immediately after the procedure, which might result from hypokinesia of the LV wall and the uncoordinated movement created by thermal myocardial necrosis. The continuous reduction in the gradient and septal thickness, as well as the broadened LVOT, were possibly caused by a local remodeling process of ongoing fibrosis and shrinkage of the ablation-induced septal lesion. Finally, the morphologic result resembled that of a surgical myectomy. Another advantage of PIMSRA was that it did not damage the conduction system either during or after the procedure, which might have contributed to the improved long-term outcomes. If required, the procedure could be repeated.
In this procedure, to protect the conduction system, we chose the percutaneous intramyocardial approach, which could avoid damage to the conduction system because of the proximity of the anatomic distribution of the conduction system to the endocardium. Meanwhile, we recommend maintaining a safe margin of 3 mm between the border of the ablated region and the endocardium of the LV or right ventricle. A distance of 8 to 10 mm from the tip of the needle to the distal end of the membrane segment of the IVS is mandatory. Additionally, an ECG monitor was used during the entire ablation procedure. The ECG recorded was often stable during the ablation; however, if the ECG demonstrated changes in rhythm or configuration, we would stop ablation to check for immediate recovery of the ECG. If the ECG abnormality was transient, then radiofrequency ablation continued. In case of a persistent ECG abnormality, we shifted to the surrounding area ablation to ensure that the ablation was safe and did not damage the conduction system.
Of the 15 patients who underwent the PIMSRA procedure, 1 patient had pericardial tamponade because of needle injury to the coronary vein (7% incidence). The patient was immediately treated via placement of a pericardial drain. If the PIMSRA procedure is to be used more widely in the future, we recommend that a surgeon with experience in pericardial drain or myocardial repair through minimal incision be available to promptly handle the possible complications. In our center, a heart team with advanced skills in managing the rare complications is always immediately available to support the procedures.
PIMSRA was performed in animal studies (healthy sheep models) and 2 patients before we conducted this trial comprising 15 patients. A 12-month follow-up of the animal study showed that the necrosis was fibrotic in nature and that PIMSRA was a safe, effective, and minimally invasive septal reduction therapy. After careful ethical review and approval, we began offering the PIMSRA procedure to patients. The first 2 patients had ablation performed on the anterior IVS, but their LVOT residual gradients were still more than 30 mm Hg at 6-month follow-up. From the early experience on these 2 patients, we recognized that the anterior septal ablation was not extensive enough to adequately treat the LVOT obstruction. We then modified our procedure to ablate anterior and posterior portions of the IVS to reduce LVOT obstruction. Results of the modified PIMSRA indicated the excellent effect of the procedure on reducing resting and provoked LVOT obstruction in the 6-month follow-up.
In this study, patients were primarily selected on the basis of the criteria established for septal myectomy: 1) patients with symptoms that limit daily activities (New York Heart Association functional class >II, exercise-induced syncope) despite adequate medical treatment or when medical treatment is not tolerated; 2) patients with a peak LVOT gradient ≥50 mm Hg; and 3) patients who presented with an LV or coronary morphology unsuitable for surgery or ASA.
Patients with the following criteria were excluded: 1) those with a peak instantaneous Doppler LVOT gradient of <50 mm Hg; 2) those with an indication for septal reduction therapy and other lesions requiring surgical intervention (e.g., mitral valve repair/replacement and papillary muscle intervention); and 3) those with end-stage heart failure.
This was a preliminary study to evaluate the safety and efficacy of PIMSRA (less invasive myocardial reduction) in 15 consecutive patients with HOCM refractory to medical therapy. Therefore, the study population was small, and the follow-up period was short. The further enrollment and follow-up of appropriate patients will continue. Further studies are warranted to compare the effectiveness and safety of septal myocardial reduction using PIMSRA with those of surgery and ASA.
We have shown that PIMSRA is a safe method for reducing LVOT obstruction and improving prognosis in patients with HOCM. The procedure results in significant hemodynamic improvement during 6 months of follow-up and is associated with symptomatic improvement.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: PIMSRA can reduce left ventricular outflow tract obstruction in patients with HOCM refractory to medication therapy, as an alternative to surgical myectomy or alcohol septal ablation.
TRANSLATIONAL OUTLOOK: Additional studies in larger numbers of patients are necessary to compare the effectiveness and safety of PIMSRA with those of surgical myectomy and alcohol septal ablation in patients with drug-refractory HOCM.
↵∗ Drs. Liu and Li contributed equally to this work.
This study was supported by International Cooperation Funding of the China Science and Technology Ministry (grant No. 2014DFA31980); National Natural Science Foundation of China (grant No. 81671693); Shaanxi Provincial Key Project (grant No. 2017ZDXM-SF-058); and a Xijing Funded Project for New Technologies and Services (grant No. 417432A). Dr. Leon is a nonpaid member of the Scientific Advisory Board of Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- alcohol septal ablation
- cardiac magnetic resonance
- computed tomography angiography
- hypertrophic obstructive cardiomyopathy
- interventricular septum
- left anterior descending coronary artery
- left ventricular
- left ventricular outflow tract
- percutaneous intramyocardial septal radiofrequency ablation
- inversion time
- transthoracic echocardiography
- Received March 27, 2018.
- Revision received July 17, 2018.
- Accepted July 23, 2018.
- 2018 American College of Cardiology Foundation
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