PART III - ALTERNATIVE TECHNIQUES TO ALCOHOL SEPTAL ABLATION FOR HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY
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Updated on August 28, 2020
PART III

Alternative techniques to alcohol septal ablation for hypertrophic obstructive cardiomyopathy

Marco G. Mennuni1, Nicole Karam2, Eric Durand3, Bachir Allam4, Antoine Lafont2
1 Azienda Ospedaliero Universitaria Maggiore della Carità, Novara, Italy
2 Hôpital Européen Georges-Pompidou, Paris, France
3 Hôpital Charles Nicolle, Rouen, France
4 Hôpital Hôtel-Dieu Paris, France

Summary

Alcohol septal ablation (ASA), an efficacious treatment to relieve obstruction in patients with hypertrophic obstructive cardiomyopathy, has several drawbacks among which are the occurrence of complete heart block, alcohol diffusion to non-targeted areas and the possible pro-arrhythmogenic nature of the alcohol-induced scar. Alternative techniques have emerged with the aim of lowering complication rates and improving outcomes of catheter-based septal ablation. Non-alcohol septal embolisation techniques (coil embolisation, polyvinyl alcohol foam particle injection and cyanoacrylate septal injection) consist of embolising the septal perforator artery with material less viscous than alcohol. The procedural success rates reported were high (90-100%), with significant and persistent reduction in the left ventricular outflow tract (LVOT) gradient up to 6 months follow-up. No permanent complete heart block (CHB) was reported in the described series. Direct endocavitary ablation of the hypertrophic septum can be achieved by radio frequency or cryotherapy (Endocardial Radiofrequency Ablation of Septal Hypertrophy, ERASH, or Percutaneous Transvalvular Endomyocardial Septal Cryoablation, PTESC). ERASH resulted in a significant and sustained reduction in resting LVOT gradient but a similar rate of CHB as with ASA (21%), despite mapping of the His bundle during the procedure and a small infarct size.

Introduction

After more than 15 years of experience with alcohol septal ablation (ASA) therapy for patients suffering from drug-refractory hypertrophic obstructive cardiomyopathy (HOCM), a plateau of success seems to have been achieved. Comparable results to surgical myectomy in terms of survival, reduction of left ventricular outflow (LVOT) gradient and functional improvement have been obtained [1]. Yet these results, which are mostly described by centres with high experience in the procedure, were insufficient to give ASA an equivalent place to septal myectomy in current recommendations [2]. Several drawbacks of the technique are held to be responsible and constitute the rationale behind the search for alternatives to alcohol ablation. The high rate of complete heart block (CHB) requires pacemaker implantation in almost 10% to 15% of patients, albeit this risk has been lowered with a smaller amount of alcohol injected. The presence of anatomical variability in the size, distribution and collateralisation of the area perfused by the septal perforator artery makes diffusion of ethanol to untargeted myocardial areas possible. In fact, alcohol has been detected in the coronary sinus up to 5 minutes after injection [3]. Furthermore, due to its low viscosity along with its dual stability and direct toxicity, alcohol induces infarcts of unpredictable size with patchy necrosis [4]. A concern has been raised that this inhomogeneous alcohol-induced scar might create a permanent arrhythmogenic substrate for lethal re-entrant arrhythmias, contributing to the risk of sudden cardiac death (SCD) in a predisposed population [5, 7]. Finally, it appears that the low mean annual procedure rate per centre (4 to 5 alcohol ablations/year) in the majority of centres was not reflected by the high volume centre publications in terms of adverse events.

In an effort to prevent these complications and improve outcomes, several alternative catheter-based ablation techniques were suggested ( Table 1 ). The preferred indications for these techniques are listed in Table 2 . These methods can be divided into two categories:

1) Non-alcohol septal embolisation. This item regroups all the techniques that consist of injecting material other than alcohol in the septal perforator artery to induce a controlled infarction in the hypertrophied septum, like coil embolisation, polyvinyl alcohol foam particle injection, glue (cyanoacrylate) septal injection, absorbable gelatin sponge (Spongostan®) or microspheres (Embozene™; CeloNova BioSciences, Inc., San Antonio, TX, USA) injection.

2) Direct endocavitary ablation of the hypertrophic septum, either by radio frequency (Endocardial Radiofrequency Ablation of Septal Hypertrophy, ERASH), percutaneous septal ablation (PIMSRA), or by cryotherapy (Percutaneous Transvalvular Endomyocardial Septal Cryoablation, PTESC).

Patient selection

Similar to patients recommended for alcohol septal ablation [2], candidates for these alternative techniques should have marked interventricular septal thickness (≥18 mm) and elevated outflow gradients due to mitral-septal contact (peak instantaneous gradient usually greater than or equal to 50 mmHg), as measured with continuous wave Doppler echocardiography either under resting/basal conditions and/or with provocation. In addition, they should have severe limiting symptoms, i.e., exertional dyspnoea (NYHA functional classes III and IV) refractory to optimal medical therapy. It is important to exclude in these patients the presence of severe coronary artery disease and congenital mitral apparatus abnormalities (i.e., anomalous papillary muscle insertion) that could explain high subaortic gradients.

FOCUS BOX 1Principles and methods of non-alcohol septal embolisation
  • Coil embolisation avoids direct toxicity of alcohol on the conductive tissue
  • Coils are delivered inside the septal perforator artery through a microcatheter. Usually 2 to 3 coils/artery are needed
  • Small polyvinyl alcohol foam particles adhere to the vessel wall causing thrombosis and inflammation
  • Injection of n-butyl cyanoacrylate (n-BCA) into an epicardial artery results in a well demarcated homogeneous infarct
  • Embolisation of glue material into the left anterior descending artery can happen during microcatheter retrieval

COIL EMBOLISATION

Coils have been widely used to treat intracranial aneurysms, severe bleedings and congenital vascular malformations. Coil embolisation as treatment for refractory HOCM aims to reduce the occurrence of complete heart block by avoiding direct toxicity of alcohol on the conductive tissue [7]. The procedure follows the same steps as with alcohol ablation. It requires placement of a temporary pacing lead in the right ventricular apex and two arterial sheathes – one in the right radial artery for a 4 Fr pigtail catheter used to monitor changes in the LVOT gradient and the second, in the right femoral artery for a 6 Fr coronary angioplasty guiding catheter, preferably an extra backup catheter. A 0.014” guidewire is then positioned deep in the target septal perforator artery. After identification of the target septal artery with myocardial contrast echocardiography (MCE) guidance, coil embolisation can begin. A delivery microcatheter is mounted on the guidewire to reach the septal artery. Embolisation with spiral detachable coils (manufactured by Cook, USA, and later on by ev3, with a modification in the structure of the devices to induce more rapid thrombosis through a feather-like mechanism on the coil surface) delivered through the microcatheter inside the septal branch is then performed ( Figure 1 ). The number of coils delivered depends on the result obtained. After each coil deployment, opacification of the coronary tree should be done to assess permeability of the targeted septal perforator. Usually 2 to 3 coils/artery are needed.

POLYVINYL ALCOHOL FOAM PARTICLES

Polyvinyl alcohol (PVA) foam (Contour® PVA Embolization Particles; Boston Scientific Target Therapeutics, Inc., Fremont, CA, USA) is a particulate embolic agent, mostly used in uterine fibroid embolisation and treatment of hypervascular tumours. The PVA particles were first introduced in 2004 by Gross et al [8] as an alternative treatment to ASA for drug-refractory HOCM. When infused into an artery, the small PVA foam particles (45 to 150 μm) adhere to the vessel wall, reducing blood flow and causing thrombosis and inflammation with focal angionecrosis confined to areas of the vessel wall in direct contact with the particles. [9] This technique consists of a slow injection of a mixed preparation of PVA foam particles and contrast medium (3 to 8 mL) inside the septal artery through a 0.018” angiographic catheter (Vasco 18; Balt Extrusion, Montmorency, France) under fluoroscopic control.

CYANOACRYLATE (GLUE) SEPTAL ABLATION

N-butyl cyanoacrylate (n-BCA) (LiquiBand®; MedLogic Global Ltd., Plymouth, Devon, UK) has been extensively used for embolising arteriovenous malformations of the central nervous system [10]. After an initial feasibility study in a dog model by Matos et al in 2005 [11] showing a well demarcated homogeneous infarct as a result of injecting n-BCA in epicardial arteries, Oto et al [12, 13] introduced this sclerosing agent as an alternative to alcohol ablation in patients with refractory HOCM. The major advantages over ASA are that leakage to non-targeted myocardium through collaterals is prevented and backflow from collaterals to targeted myocardium is not allowed as glue induces thrombosis of small capillaries. In fact, by using a 1/5 dilution of n-BCA, obliteration of capillaries of 14 μm diameter can be detected. The procedure consists of injecting small amounts (0.5 mL) of diluted n-BCA into the septal artery. To do so, n-BCA, a high viscous and radiolucent agent, must be mixed with a radiopaque agent to yield a 1/6 (17%) glue mixture. Glue delivery into the septal artery necessitates special attention and experienced hands. Through a 6-8 Fr guiding catheter, a 4 Fr catheter (Glidecath Vertebral; Terumo Europe N.V., Leuven, Belgium) is advanced inside the septal artery over a 0.014” guidewire. A microcatheter (Excelsior SL-10; Boston Scientific, Fremont, CA, USA) is then introduced deep inside the septal perforator through the 4 Fr catheter. The mixture is then slowly injected inside the artery while watching contrast staining of the septum ( Figure 2 ). The microcatheter is then pulled back inside the 4 Fr catheter to prevent glue adhered to the tip of the microcatheter from escaping into the LAD coronary artery, and the system is withdrawn altogether. It is important to note that n-BCA cannot be injected directly through the lumen of a balloon catheter because the hub of most commercially available angioplasty balloons chemically reacts with the acrylic glue.

ETHYLENE-VINYL ALCOHOL (EVOH)

Ethylene-vinyl alcohol copolymer is a non-adhesive liquid embolic agent composed of EVOH dissolved in dimethyl sulfoxide with suspended micronised tantalum powder (Onyx™ liquid embolic system, Medtronic, Minneapolis, MN, USA). In the field of neuroradiology EVOH copolymer often is preferred because of non-adhesive and less thrombogenic property with lower risk of adverse events in case of left anterior descending artery spilling; precipitation occurs on contact with aqueous solutions and delivers in a cohesive manner, forming a spongy, coherent embolus. Asil et al reported the first series 25 patients with HCOM treated with EVOH, the authors reported a safe and effective results in terms of gradient reduction and symptoms improvement. [14]

The procedure was performed through an 8 Fr guiding catheter in the left main and a 0.014-inch guidewire into the septal branch. Over the wire , the septal branch was selectively cannulated with a 2.4 French (Echelon or Rebar from EV3, Irvine California, Sonic from Balt, Montmercy, France). Then, the use of myocardial contrast echocardiography is used to identify the target septal artery. As EVOH Onyx® 18 was used , because property of penetrating deeper. Once the microcatheter was in place, the injection of EVOH was carried out as: the microcatheter was flushed with 5 ml of normal saline; dimethyl sulfoxide was injected into the microcatheter to fill the dead space; EVOH copolymer (into a 1-ml syringe) was injected from the distal portion of the septal artery until a proximal safe distance of 10 mm to left anterior descending artery. [14]

FOCUS BOX 2Results for non-alcohol septal techniques
  • High procedural success rates (90%-100%) were reported for coil embolisation, PVA foam particle injection and glue septal ablation
  • Coil embolisation results in a significant and sustained improvement in symptoms and reduction in LVOT gradient in 90% and 75% of cases, respectively
  • Cardiac magnetic resonance imaging and creatine kinase (CK) rise suggest a smaller infarct size with coil embolisation than with ASA
  • GSA results in the smallest infarct size among the three alternative techniques as assessed by the CK rise

FOCUS BOX 3Complications
  • Very low number of complete heart block requiring permanent pacemaker implantation was reported with coil embolisation or polyvinyl alcohol foam particle injection or glue septal ablation
  • Transient AV blocks were seen in 17% of patients treated with PVA foam particle injection
  • Embolising glue material into the LAD artery and microcatheter retention are two possible complications during GSA
  • In the dog model, n-BCA injection results in a chronic granulomatous inflammation of the vessel wall, the clinical significance of which remains unknown

Despite the limited number of series reported in the literature, results with the three mentioned techniques are encouraging, especially concerning the occurrence of conduction abnormalities requiring pacemaker implantation ( Table 3 ). Coil embolisation was shown to be a safe procedure in two studies, one using straight coils (Hilal; Cook Medical Inc., Bloomington, IN, USA) and the other using spiral coils (Cook Medical Inc.). In the first, coil embolisation in 7 patients showed a reduction in LVOT pressure gradient of 59% immediately after the procedure, a result that persisted after 3 months of follow-up [15]. There was also a significant improvement in clinical status and no patient needed implantation of a permanent pacemaker for complete heart block after 3 months follow-up. The second study, which consisted of 20 patients with drug-refractory HOCM, showed 90% procedural success [16]. The median number of coils/patient was 4. Significant improvement in symptoms and reduction in LVOT gradient were observed in 90% and 75% of cases at 6 months follow-up, respectively. The reduction in the interventricular septal (IVS) thickness was 19% and persisted over time whilst the LVOT pressure gradient fell by 56% ( Figure 3 ). No ventricular arrhythmia or CHB was noted. However, when compared to ASA, coil embolisation results in a smaller infarct size as shown by cardiac magnetic resonance imaging (CMRI) estimation (4 g vs. 15-20 g) and CK increase. In addition, the reductions in LVOT gradient and IVS thickness are lower, although the improvement in symptoms is comparable. Therefore, coil embolisation seems a reasonable alternative to alcohol ablation, especially in patients with bundle branch blocks or patients with increased risk of CHB. However, a distinction should be made between the two procedures regarding the mechanism of infarct induction. While ASA induces direct toxic effect on myocardial and conductive tissue cells provoking immediate chemical septal necrosis, coil embolisation acts via a pure ischaemic effect on septal myocardium. This difference in pathophysiology can explain the lower rates of CHB seen with coil embolisation, and may also reduce the development of scar tissue and fibrosis, which is seen with ASA and increases the risk of late arrhythmias.

Globally, PVA foam particle embolization, EVOH, and glue septal ablation (GSA) act through the same mechanical effect. By occluding proximal and distal arteries, these agents provoke formation of an organised thrombus producing a sharply demarcated infarct confined to the supply zone of the injected vessel. In opposition to the inhomogeneous scar induced by ASA, which might constitute a substrate for re-entrant arrhythmias as shown in swine models, [4] the homogeneous necrosis of GSA has been shown to be reluctant to programmed stimulation in the dog model [11]. However, the clinical relevance of this concept remains to be proved. Procedural success was noted in 100% of patients with both techniques and no major complications were observed, even when collaterals to the right coronary artery were present [8, 13]. An immediate and significant drop in LVOT gradient was obtained. After a mean follow-up of 44±4 months of patients undergoing PVA foam particle septal embolisation, there was a significant reduction in LVOT gradient as measured by Doppler echocardiography from 82 to 35 mmHg and all patients had symptomatic improvement with reduction in NYHA class from 3.3 to 1.3 and an increase in exercise level, results that are comparable to those with ASA. Transient atrioventricular blocks were noted in 17% of patients and permanent CHB in none of the patients. With GSA, the reduction in LVOT gradient that was present immediately after the procedure persisted after 6 months. However, the infarct size noted with this technique as shown by creatine kinase (CK) rise was the lowest among all alternative methods ( Table 1 ). Moreover, two special technical concerns related to the delivery technique with GSA must be mentioned. Even if it was not reported in humans, embolising glue material during microcatheter withdrawal can easily occur and results in redoubtable complications, in addition to the possibility of catheter retention in the case of adherence of the catheter to the vascular wall due to glue slipping around the microcatheter. Furthermore, in the dog model, n-BCA induced a chronic granulomatous inflammation with giant cell reaction in the vessel wall and adjacent tissues. The natural course and clinical significance of this reaction have to be determined before widespread usage of this technique can be anticipated.

Description of case reports

Other embolisation agents have been reported in the literature. Latsios G et al [17] successfully used spherical embolic materials (Embozene™ colour-advanced microspheres; CeloNova BioSciences, Inc.) in one patient inducing a controlled septal myocardial infarct with no subsequent adverse events. Llamos-Esperon GA et al [18] injected small absorbable gelatin sponge particles (Spongostan®). Other authors reported obstruction of septal perforators by placement of a covered stent in the LAD at the septal take-off; however, this may cause unnecessary damage to the LAD and failure of septal ablation due to collateral formation.

FOCUS BOX 4Direct endocavitary ablation techniques
  • Endocavitary radio-frequency ablation through the LV or RV cavity of a 2 cm2 of IVS is considered enough to produce a defect comparable to that with ASA.
  • Mapping of the His bundle during ERASH is essential to prevent CHB
  • ERASH results in a lower LVOT gradient reduction as compared to ASA
  • High rate of CHB (21%) requiring permanent pacemaker implantation

PERCUTANEOUS INTRAMYOCARDIAL SEPTAL RADIOFREQUANCY ABLATION (PIMSRA)

A percutaneous septal ablation has been described by Liu et al. A radiofrequency electrode needle (17G, Cool-tip RF Ablation System and Switching Controller, Medtronic Minimally Invasive Therapies, Minneapolis, Minnesota) was introduced into the septum the percutaneous intramyocardial approach introduced into the septum through a transthoracic left ventricle apex puncture. The procedure is a transthoracic echo-guided in general anesthesia. A preliminary study of 15 patients has been reported. The ablation power was started at 60 W with mean duration of 5 min and then gradually increase up to 100 W. The total mean ablation time was 58 minutes. PIMSRA was safe and effective treatment in HOCM, and the results were persistent a 6 months of follow-up ( Table 3) [19]

ENDOCARDIAL RADIO-FREQUENCY ABLATION FOR SEPTAL HYPERTROPHY (ERASH)

The aim of this procedure is to induce a localised septal contraction disorder to reduce LVOT pressure gradient rather than to reduce septal myocardial mass. After a first case description in 2004 [20], Lawrenz et al recently reported the first series of 19 patients treated with radio-frequency ablation [21]. Endocardial radio-frequency ablation for hypertrophic obstructive cardiomyopathy (ERASH) is an endocardial, non-transcoronary approach, based on the delivery of a radio-frequency (RF) current to the part of the hypertrophied IVS in relation with LVOT obstruction, either from the left ventricle (LV) side through a retrograde transaortic approach, or from the right ventricular side through an inferior caval approach, in case of catheter instability with the LV ablation. Ablation of a region of 2 cm2 is considered enough to produce a defect comparable to that with ASA. Mapping of the His bundle during the procedure is necessary to prevent induction of complete heart block ( Figure 4 ). RF energy is delivered with a 4 mm irrigated tip ablation catheter (ThermoCool® irrigated tip catheter and integrated ablation system; Biosense Webster, Diamond Bar, CA, USA), 30 ml/min placed at the level of the bundle of His.

Result of direct ablation techniques

ERASH was demonstrated to be safe and effective in lowering LVOT gradient. A significant and sustained 60% reduction of resting LVOT gradient ( Figure 5 ) was noted after the procedure and at 6 months follow-up, despite a minor significant reduction in septal diameter (21.4 ± 3.4 mm vs. 22.6 ± 3.7 mm) and a small infarct size as revealed by CK-MB rise (mean 77.6 ± 52). Significant improvement in NYHA functional class from 3.0 to 1.6, and 6 min walking test (412.9 ± 129 m at baseline to 471.2 ± 139 m after 6 months) was also observed. However, compared to ASA, ERASH results in a lower LVOT gradient reduction with the same rate of complete heart block requiring permanent pacemaker implantation (21%).

A recent metanalysis of 8 studies including 91 patients with HOCM treated by ERASH reported a substantial reduction in LVOT gradient (- 58 mmHg) and a persistent clinical improvement at follow-up. Of note 2 patients died for procedural issues and 8 patients had a complete heart block. [22]

Among the ERASH, a direct percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) has been proposed by Liu et al. A radiofrequency electrode needle (17G, Cool-tip RF Ablation System and Switching Controller, Medtronic Minimally Invasive Therapies, Minneapolis, Minnesota) was introduced into the septum via percutaneous intramyocardial approach. The needle is introduced into the septum through a transthoracic left ventricle apex puncture. The procedure is a transthoracic echo-guided in general anesthesia. A preliminary study of 15 patients has been reported. The ablation power was started at 60 W with mean duration of 5 min and then gradually increase up to 100 W. The total mean ablation time was 58 minutes. PIMSRA was safe and effective treatment in HOCM, and the results were persistent a 6 months of follow-up ( Table 3) [19]

A similar endocavitary technique to ERASH was also tested to relieve obstruction in HOCM patients. Based on the same principle of impairing septal contractile function, percutaneous transvalvular endomyocardial septal cryoablation, which uses cryoenergy (down to -88°C) instead of radio-frequency energy, failed to show a significant reduction in LVOT gradient and symptomatic improvement (in a very small series of 3 patients) [23].

Personal perspective - Antoine Lafont

It is important to mention that eight alternative therapies have been proposed in the last 6 years. This shows that in the real world ASA has failed to convince the physicians on its superior safety and efficacy compared to surgical myectomy. The future will clarify the indications for using these alternative techniques. The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology has recently published new guidelines which deserve to be carefully studied [24]. View chapter

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