Septal myotomy myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy

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1 European Heart Journal (2002) 23, doi: /euhj , available online at on Septal myotomy myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy A comparison of clinical, haemodynamic and exercise outcomes S. Firoozi, P. M. Elliott, S. Sharma, A. Murday, S. J. Brecker, M. S. Hamid, B. Sachdev, R. Thaman and W. J. McKenna Department of Cardiological Sciences, St George s Hospital Medical School, London, U.K. Aims Surgical myectomy has been successfully used to treat patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). More recently, alcohol septal ablation has been advocated as a less invasive, but equally effective alternative therapy. The aim of this nonrandomized cohort study was to compare subjective and objective outcomes in patients undergoing these therapies. Methods Forty-four patients (25 male; age years) with symptomatic drug-refractory obstructive HCM were studied. Twenty-four patients underwent surgical myectomy and 20 alcohol septal ablation. All patients underwent clinical evaluation, echocardiography and upright maximal cardiopulmonary exercise testing using a cycle ergometer before and following their intervention. Results Peak gradient was reduced to a similar extent by both modalities (myectomy: to mmhg (P< ); ablation: to mmhg (P< ); P=0 48 for myectomy vs ablation) and led to similar improvements in NYHA class (myectomy: to (P< ); ablation: to (P<0 0001);P=0 3 for myectomy vs ablation). Myectomy resulted in a greater improvement in peak oxygen consumption (myectomy: to ml. kg 1 min 1 (P< ); ablation: to ml. kg 1 min 1 (P<0 05); P<0 05 for myectomy vs ablation) and work rate achieved (myectomy: to watts (P<0 04); ablation: to watts (P=0 11); P<0 05 for myectomy vs ablation). Conclusion Surgical myectomy and alcohol septal ablation are equally effective at reducing obstruction and subjective exercise limitation in appropriately selected patients. However, the superior effect of surgical myectomy on exercise test parameters suggests that surgery remains the gold standard against which new treatment modalities should be compared. (Eur Heart J, 2002; 23: , doi: /euhj ) 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved. Key Words: Hypertrophic cardiomyopathy, obstruction, myectomy, alcohol septal ablation, peak oxygen consumption. Introduction Approximately 25% of patients with hypertrophic cardiomyopathy (HCM) have left ventricular outflow tract obstruction caused by contact between the anterior mitral valve leaflet and the interventricular septum Revision submitted 29 April 2002, and accepted 1 May Correspondence: Dr P. M. Elliott, Department of Cardiological Sciences, St George s Hospital Medical School, Cranmer Terrace, London SW17 0RE, U.K. during systole [1,2]. When severe, left ventricular outflow tract obstruction can cause dyspnoea, chest pain, and syncope, and predisposes to the development of atrial arrhythmias [3]. For over four decades, surgical septal myotomy myectomy has been successfully used to treat drug-refractory patients with severe outflow tract obstruction [4 10]. More recently, transcoronary alcohol septal ablation has been proposed as a safer, less invasive alternative to surgery [11]. Two recently published studies comparing surgical myectomy and alcohol septal ablation have reported similar improvements in symptoms [12,13]. However, the X/02/$ The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

2 1618 S. Firoozi et al. Table 1 Baseline characteristics of the study subjects Myectomy group (n=24) Septal ablation group (n=20) P-value Age (years) Male sex 54% 60% 0 39 Drugs (%) β-blockers 8 (33) 9 (45) 0 43 CCA 4 (17) 6 (30) 0 29 Disopyramide 6 (25) 6 (30) 0 71 Amiodarone 4 (17) 3 (15) 0 88 Permanent AF Paroxysmal AF NYHA (%) Class II 15 (63) 14 (70) 0 61 Class III 8 (33) 6 (30) 0 81 Class IV 1 (4) Exertional chest pain (%) 12 (50) 9 (45) 0 74 Syncope (%) 5 (21) 2 (10) 0 33 MLVWT (mm) LA (mm) LVEDD (mm) LVESD (mm) FS (%) LVOTG (mmhg) Work (watts) Peak VO 2 (ml.kg 1 min 1 ) % Predicted peak VO AF=atrial fibrillation, CCA=calcium channel antagonist, FS=fractional shortening, LA=left atrium, LVEDD=left ventricular end-diastolic diameter, LVOTG=left ventricular outflow tract gradient, MLVWT=maximal left ventricular wall thickness, NYHA=New York Heart Association, VO 2 =oxygen consumption rate. comparative effects of alcohol ablation and surgery on exercise capacity remain uncertain because of a lack of standardized exercise protocols and the use of estimated rather than directly measured oxygen consumption [12]. The aim of this non-randomized single-centre cohort study was to make a direct comparison of subjective and objective clinical outcomes in patients undergoing these two treatment modalities. Methods Patients The study cohort comprised 44 patients (25 male; age years, range 14 to 74) with obstructive hypertrophic cardiomyopathy referred to the cardiomyopathy clinic at St George s Hospital Medical School, London, U.K., between 1990 and All patients had unexplained myocardial hypertrophy with a maximum left ventricular wall thickness exceeding two standard deviations from the normal range. All patients had drug refractory symptoms and a resting outflow tract gradient of at least 50 mmhg on continuous wave Doppler echocardiography (Table 1) and reported functional limitation (New York Heart Association class II or more) despite optimal medical therapy. The decision to proceed with septal myotomy myectomy or alcohol septal ablation was based on individual patient choice and physician guidance after extensive discussion of the benefits and risks of each therapeutic modality. Younger patients were encouraged to undergo surgery due to the paucity of long-term outcome data with alcohol septal ablation. Twenty-four patients ((13 male, 11 female) mean age years, range 14 to 74) underwent transaortic septal myotomy myectomy between April 1990 and September Twenty patients ((12 male, eight female), mean age years, range 25 to 62) underwent transcoronary alcohol septal ablation between May 1997 and May Echocardiography All patients underwent two-dimensional, M-mode, and Doppler echocardiography prior to their intervention and at regular follow-up clinics at St. George s Hospital using an Acuson 128 XP/10 (Mountain View, CA, U.S.A.), GE Vingmed system V (GE Ultrasound Europe, Horten, Norway) or a Hewlett-Packard Sonos 1000 (Hewlett-Packard, Andover, MA, U.S.A.). Standard views for M-mode and two-dimensional studies were obtained, and conventional techniques were used for sizing of the left atrium and ventricle. End-diastolic left ventricular wall thickness was recorded at the level of the mitral valve and papillary muscle in the anterior and posterior septum, and the lateral and posterior wall

3 Septal myotomy 1619 using short-axis two-dimensional images. Anterior and posterior septal thickness at the apex was assessed from the apical four-chamber and parasternal short-axis views. The maximum left ventricular wall thickness was defined as the maximal measurement recorded in any of the myocardial segments studied. Left ventricular outflow tract velocities were determined using continuous wave Doppler echocardiography, and left ventricular outflow tract gradients were calculated using the modified Bernoulli equation. Metabolic exercise testing Cycle ergometry exercise was performed (Sensormedics ergometrics 800S; Bitz, Germany) using a ramp protocol of 10 to 15 watts per min before and at each clinic visit after surgery or septal alcohol ablation. The ramp protocol was adjusted by assessing the subjective assessment of the patient s functional capacity to ensure appropriate test duration and to avoid premature fatigue. All patients were required to have a respiratory quotient (RQ) 0 85 prior to commencing exercise. Patients cycled at a rate of 60 to 70 revolutions per minute to the point of exhaustion or symptom limitation. Breath-by-breath gas exchange analysis was performed using a Sensormedics metabolic cart (V Max 29 Console, Sensormedics). Respiratory gases were sampled continuously via a mouthpiece and analysed with an 1111D/000 paramagnetic transducer for oxygen and a 2900 MMC non-dispersive infrared sensor for carbon dioxide. Peak oxygen consumption (peak VO 2 ) was defined as the highest VO 2 achieved during exercise. Results were expressed as percentage of the predicted maximal VO 2 to allow for age, gender and body size. A value of <80% of the predicted was considered abnormal. Septal myotomy myectomy Standard cardiopulmonary bypass and myocardial preservation techniques were used. Transoesophageal echocardiography was performed prior to bypass to determine the extent of myectomy required and to evaluate mitral valve morphology. The outflow tract was approached by way of an aortotomy, and the septal resection was initiated by making two parallel longitudinal incisions: the first beneath the nadir of the right coronary cusp and the second beneath the commisure separating the right and left coronary cusps. The incisions were joined superiorly and a mass of muscle was excised to the level of the papillary muscles. The resection was assessed prior to closure of the aortotomy using transoesophageal echocardiography. Transcoronary alcohol septal ablation A transvenous pacemaker lead was introduced via the femoral vein into the right ventricular apex and IU IV heparin was administered. Diagnostic coronary angiography was performed using standard techniques. The major proximal septal perforator was selected as the target vessel and selectively intubated with a inch guide wire introduced through an 8 F percutaneous transluminal coronary angioplasty guiding catheter. A short 2 mm over-the-wire balloon (15 mm length) was introduced and inflated. The distal vessel bed was opacified with angiographic contrast medium (Urograffin; Schering AG, Berlin, Germany) to ensure no dye reflux into the left anterior descending coronary artery (LAD) prior to alcohol injection. After verification of the correct balloon position, 0 5 to 1 ml of the echo contrast agent (Optison; Mallinckrodt Medical GmbH, Sieg, Germany) was injected through the inflated balloon catheter under continuous transthoracic echocardiographic imaging. Alcohol was given only when the area of maximum flow acceleration, that is, gradient formation, and opacified septal myocardium were adjacent to each other. Up to 5 ml of absolute alcohol (median 3 ml) was infused at 1 ml. min 1. The balloon remained inflated for 10 min after the alcohol administration to enhance tissue contact and to avoid alcohol reflux into the LAD. After deflation of the balloon, angiography was repeated to confirm successful blockage of the septal artery. Clinical follow-up All patients returned to the cardiomyopathy clinic at regular intervals following their procedure for a clinical evaluation, echocardiography and metabolic exercise testing. Statistics Data are expressed as mean SD. Paired t-tests were used to evaluate changes in continuous variables following LVOT gradient reduction in each group and unpaired t-tests were used for the comparison between the groups. For non-continuous variables the chi-square test was employed. Significance was set at a P-value <0 05. The software used for analysis was Statistica version 5.0 by Statsoft (Tulsa, Oklahoma, U.S.A.). Results Baseline assessment Patients in the septal ablation group were older than the surgical group, but were matched for other clinical characteristics, cardiac dimensions, baseline left ventricular outflow tract gradient and exercise parameters (Table 1). The baseline symptom status of the patients in the two groups is also summarized in Table 1. Post-therapy follow-up assessment The mean length of follow-up in the myectomy group was months and months in the

4 1620 S. Firoozi et al. Table 2 Cardiac dimensions following LVOTO reduction. (All measurements in mm except FS) Myectomy group Septal ablation group Before After P-value Before After P-value Maximal IVS thickness LVEDD LVESD LA FS (%) LVOTO=left ventricular outflow tract obstruction; IVS=interventricular septum; LVEDD=left ventricular end-diastolic diameter; LVESD=left ventricular end-systolic diameter; LA=left atrium; FS=fractional shortening. Table 3 Wall thickness change after LVOTO reduction. (All measurements in mm) Myectomy group Septal ablation group Before After P-value Before After P-value Mitral valve level Anterior septum < Posterior septum < Posterior wall Lateral wall Papillary muscle level Anterior septum < <0 01 Posterior septum Posterior wall Lateral wall Apical level Anterior wall < Posterior wall septal ablation group (P=0 02). There was one death in each group with one postoperative surgical death due to heart failure and one sudden death 21 days following septal ablation. Permanent dual chamber pacing was required in one patient (4%) in the surgical group and in three (15%) of the patients in the septal ablation group. Gradient By the end of follow-up, peak left ventricular outflow gradient fell from mmhg to mmhg in the myectomy group (P< ) and from mmhg to mmhg (P= ) in the septal ablation group (P=0 48 for the comparison between the groups). Twenty-one (91%) of the myectomy group had post-treatment gradients below 20 mmhg compared with 14 (74%) of the septal ablation group (P=0 09). Cardiac dimensions The changes in cardiac dimensions in the two groups are summarized in Table 2. In both groups, maximum interventricular septal thickness was reduced to the same extent. In the myectomy group, there was no significant change in left ventricular end-diastolic diameter or left ventricular end-systolic diameter and no change in left atrial size. There was a small decrease in systolic left ventricular fractional shortening. In the septal ablation group, there was no change in left ventricular end-diastolic diameter or left atrial size. There was an increase in left ventricular end-systolic diameter with a decrease in fractional shortening. Changes in individual myocardial wall segments are shown in Table 3. The extent of the change was more widespread in the myectomy group with significant reduction of wall thickness in the anterior and posterior septum at the mitral valve level, papillary muscle level and the apex. In contrast, the septal ablation group had more localized reductions in basal myocardial segments (Table 3). Symptoms Following surgical myectomy, NYHA functional class improved from to (P< ). Following septal ablation the NYHA functional class improved from to (P<0 0001). The improvement in functional class after therapy was similar in the two groups (P=0 3). At follow-up, 13 of the 23 patients in the myectomy group were in class I, eight were in class II and two were

5 Septal myotomy 1621 Figure 1 (a) NYHA class change following surgical myectomy. This figure shows the change in NYHA class distribution following myectomy. (b) NYHA class change following alcohol septal ablation. This figure shows the change in NYHA class distribution following alcohol septal ablation. in class III. Five patients reported no improvement in functional class (Fig. 1(a)), however four of the five patients reported an improvement in angina. In the septal ablation group, 10 of the 19 patients were in class I, seven were in class II and two were in class III. Seven patients reported no improvement in functional class (Fig. 1(b)), however four of the seven experienced an improvement in angina. Overall, the number of patients reporting angina decreased from 12 to six in the myectomy group and from nine to four in the septal ablation group (P=0 19 for comparison of the groups). Two patients in the myectomy group and one in the septal ablation group experienced syncope during follow-up. Exercise testing All patients reached a peak exercise RQ >1, with a rise of at least 0 15 and a plateau in the oxygen consumption curve. There was no difference before or after treatment with respect to peak exercise RQ between the two groups. Mean peak VO 2 increased from to ml. kg 1 min 1 following myectomy (P<0 0002) (Fig. 2(a)), and from to ml. kg 1 min 1 (P<0 05) following septal ablation (Fig. 2(b)). The improvement in peak VO 2 was significantly greater following myectomy compared with septal ablation (P=0 02). Similarly, on analysing the percentage predicted peak VO 2 values, a superior benefit was demonstrated with myectomy compared to septal ablation (peak VO 2 increase of 25 12% vs 11 25%, P=0 04). Following myectomy, work rate increased from watts at baseline to watts at follow-up (P=0 04). This compared with a rise in work rate from to watts (P=0 11) following septal ablation. The improvement observed with myectomy was superior to that with septal ablation (P=0 01). Peak oxygen consumption fell in two patients following septal ablation and in one patient following myectomy. The patient in the surgical myectomy group had a drop in systolic fractional shortening from 46% to 31% with a rise in left ventricular end-systolic diameter from 19 mm to 24 mm. The left ventricular end-diastolic diameter was unchanged. Similarly, one of the two patients in the septal ablation group also had a fall in systolic fractional shortening from 50% to 32% with a rise in left ventricular end-systolic diameter from 19 mm to 32 mm and a rise in left ventricular end-diastolic diameter from 38 mm to 47 mm. The remaining patient had no change in echocardiographic dimensions. Twelve month analysis Owing to the different lengths of follow-up between the two groups, a retrospective analysis at 12 months follow-up was carried out. At 12 months follow-up, peak LVOT gradient fell from to mmhg following myectomy (P= ) and from to mmhg (P= ) following septal ablation (P=0 37 for the comparison between the groups). Peak LVOT gradient at 12 months and maximal follow-up were similar with myectomy (17 12 vs mmhg; P=0 32) and with septal ablation (21 12 vs mmhg; P=0 29). The increase in peak VO 2 at 12 months following myectomy was from to ml. kg 1 min 1 (P=0 03) while following septal ablation, the increase was from to ml. kg 1 min 1 (P=0 18). The improvement was significantly greater with myectomy (P=0 04) and similar to the

6 1622 S. Firoozi et al. Figure 2 (a) Change in peak oxygen uptake following myectomy. This graph demonstrates the improvement in peak oxygen consumption following surgical myectomy in each individual patient (solid symbols indicate mean values). (b) Change in peak oxygen uptake following septal ablation. This graph demonstrates the improvement in peak oxygen consumption following alcohol septal ablation in each individual patient (solid symbols indicate mean values). findings at maximal follow-up. The peak VO 2 achieved at 12 months is similar to maximal follow-up in the myectomy ( vs ml. kg 1 min 1 ; P=0 42) and septal ablation groups ( vs ml. kg 1 min 1 ; P=0 81). The increase in work rate at 12 months following myectomy was from to watts (P=0 04) whereas the increase with septal ablation was from to watts (P=0 19). The improvement was significantly greater with myectomy (P=0 03) and similar to the findings at maximal follow-up. The work rate at 12 months was similar to maximal follow-up with myectomy ( vs watts; P=0 38) and septal ablation ( vs watts; P=0 79). Discussion This study demonstrates that, in patients with drug refractory symptomatic obstructive HCM, surgical myectomy and transcoronary alcohol septal ablation are equally effective at reducing left ventricular outflow tract obstruction and lead to similar subjective improvements in functional capacity. Surgical myectomy, however, was

7 Septal myotomy 1623 more effective in improving peak exercise parameters. Although both interventions are acceptable therapies in appropriately selected patients, these data suggest that surgery remains the gold standard against which other therapies should be judged. Recently, two studies have compared the effect of surgical myectomy and alcohol septal ablation on exercise capacity. Nagueh et al. [12] compared subjective and objective outcomes over a 1-year follow-upperiod and showed similar haemodynamic and functional outcomes in both treatment groups. However, different exercise test protocols were used in each cohort and peak oxygen consumption was only indirectly estimated in patients undergoing alcohol septal ablation. In the second study, Qin et al. reported a short term (3 month) follow-up of surgical myectomy and alcohol septal ablation focusing on improvements in NYHA class [13]. Surgery was more effective in reducing outflow tract obstruction and the change in NYHA class in the two cohorts was similar. There was no obvious explanation for the similar improvement in exercise capacity in the face of different degrees of gradient reduction. Effect of gradient reduction on symptoms and exercise capacity The experience with permanent dual chamber pacing in HCM emphasises the importance of peak VO 2 in the assessment of functional capacity. Although studies have reported improvements with active pacing in symptoms and NYHA class, objective assessments of exercise capacity have failed to support these findings [14,15]. Although surgical myotomy myectomy and alcohol ablation resulted in similar improvements in breathlessness and chest pain, subjective reporting of symptoms provides only a semi-quantitative assessment of an individual s exercise capacity and can be substantially influenced by the placebo effect. The measurement of oxygen consumption is a more objective and reliable indicator of true functional capacity and provides specific data on cardiopulmonary performance [16]. In this study, peak VO 2 increased in both treatment groups following outflow tract gradient reduction, but the surgical myectomy group showed greater improvement in peak VO 2 and work rate in comparison to that seen following alcohol septal ablation. Analysis of objective exercise end-points in the two groups in an interim analysis at 1-year following intervention, were consistent with those at the end of the study, indicating that the greater benefit observed in the surgical myectomy group was not due to the longer follow-up period or an associated training effect on exercise testing. Another explanation for the difference in exercise performance may be that myotomy myectomy specifically targets that part of the interventricular septum that makes contact with the anterior mitral valve, whereas septal ablation produces a more diffuse, patchy myocardial scar in the basal septum. However, the precision with which alcohol can be delivered into the septum has been substantially improved with the use of echocardiographic contrast agents prior to injection of alcohol, and in the best hands septal ablation can produce a scar that echocardiographically closely resembles the trough left by surgical myectomy. One obvious functional difference between the techniques is that surgical myectomy typically leads to left bundle branch block (LBBB) [4 10] whereas alcohol septal ablation typically produces a right bundle branch block pattern [17]. The paradoxical septal motion produced by LBBB has been suggested as a mechanism by which dual chamber pacing reduces left ventricular outflow tract obstruction, and it is conceivable that the presence of LBBB following myectomy, but not alcohol septal ablation, conveys some haemodynamic advantage [18,19]. Although the mean reduction in outflow tract gradient was similar in both treatment groups, the proportion of individuals achieving total abolition (gradient <20 mmhg) of the outflow tract gradient was greater following surgical myectomy. It is possible that in some individuals, this resulted in a greater propensity to exercise induced increases in the outflow gradient that in turn resulted in a diminution of peak exercise capacity. Effect on left ventricular function Although left ventricular end-diastolic diameter in both groups remained unaltered, a fall in fractional shortening caused by a small but statistically significant rise in left ventricular end-systolic diameter was observed following surgery and septal ablation. As shortening fraction was derived from M-mode measurements in this study, this probably reflected the reduction in basal septal thickness in most patients [20]. Nevertheless, of the three individuals who experienced deterioration in peak VO 2, two (one surgical and one septal ablation) experienced an 11% decrease in systolic fractional shortening, which may have reflected a deleterious degree of myocardial damage. As expected, left ventricular wall thickness fell in the anterior septal segments in both groups. There was, however, no significant change in the lateral and posterior segments of the left ventricular wall. Mazur et al.[21] have recently reported marked reductions in left ventricular mass and left ventricular wall thickness in all myocardial segments in 26 patients undergoing alcohol septal ablation. Although this more extensive thinning may represent a form of reverse remodelling, the reduction in left ventricular mass correlated strongly with the level of post-procedure creatine kinase and the infarct size on SPECT myocardial scintigraphy. This suggests that the regression of hypertrophy may have been caused by infarction of areas outside the target area of the basal septum. More extensive myocardial infarction may also explain the high incidence of complete heart block (27%) observed in the same study and the long-term consequences of this will only become clearer with longer follow-up.

8 1624 S. Firoozi et al. Study limitations This study was not designed as a prospective investigation, but rather as a retrospective analysis of the two treatment modalities. Patients were assigned to the two treatment modalities based on patient choice and physician guidance and so the two groups may not be comparable. However, with the exception of age the two groups were well matched for baseline clinical, echocardiographic and exercise parameters. As alcohol septal ablations were only performed from 1997 onwards, the follow-up period for myectomy was longer allowing for more cardiac (e.g. remodelling) and peripheral adaptations (e.g. altered endothelial function) to take place. However, an interim analysis at 12 months follow-up revealed similar findings to the long-term follow-up. It has not been our practice to routinely perform provocation of outflow gradients during echocardiographic assessment. We cannot be sure therefore, whether the differences in peak exercise capacity reflect differences in provocable obstruction. Clinical implications and conclusions Myotomy myectomy and alcohol septal ablation appear to be equally effective at improving symptoms in patients with obstructive hypertrophic cardiomyopathy. A prospective registry and large-scale prospective studies are required to determine whether the superior effect of surgery on peak oxygen consumption translates into an important clinical benefit for patients and helps clarify the respective roles of these procedures in the management of obstructive HCM. The authors S.F., M.S.H., B.S. and R.T. were supported by grants from the British Heart Foundation. References [1] Henry WL, Clark CE, Griffith JM, Epstein SE. Mechanism of left ventricular outflow obstruction in patients with obstructive asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis). 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