Dual Chamber Pacing for Patients With Hypertrophic Obstructive Cardiomyopathy: A Clinical Perspective in 2000

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Dual Chamber Pacing for Patients With Hypertrophic Obstructive Cardiomyopathy: A Clinical Perspective in 2000 JOHN

P. ERWIN III, MD;

RICK

A. NISHIMURA,

MD; MARGARET

AND

A. JAMIL TAJIK, MD

mean ± SD follow-up of 24±14 months, subjective improvement was reported in 47% of patients. However, there was no statistical difference between the maximal oxygen consumption at last follow-up and AAI pacing (atrial sensing and atrial pacing ) (18.6±1.1 mL'kg-I'min-l ) (ie, when the pacemaker was implanted but not pacing continuously). This article discusses the clinical perspective on the utilit y of dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy. Mayo Clin Proc. 2000;75:173-180

In some patients with hypertrophic cardiomyopathy, the dynamic left ventricular outflow tract obstructive gradient results in exercise-limiting symptoms of dyspnea, angina, and syncope. Dual chamber pacing has been proposed as a widely available alternative treatment for a subset of patients with symptomatic hypertrophic obstructive cardiomyopathy. Initial studies showed a reduction in gradient and an improvement in symptoms in almost 90% of patients with severe symptoms. We report the Mayo Clinic experience with dual chamber pacing in 38 patients with hypertrophic obstructive cardiomyopathy who had permanent pacemakers implanted for limiting symptoms intractable to medical therapy. After a

I MYo, =maximal oxygen consumption

H

ypertrophic card iomyopath y is a disease proce ss in which there is unexplained , often severe, and asymmetric hypertroph y of the myocardium ,':' presumabl y due to gene mutation s.' Less than 30% of patients have an associated dynamic left ventricular outflow tract obstru ctive gradient that results in an exercise-limiting symptom triad of dyspnea, angina , and exertional syncope. Relief of the outflow obstruction has been the basis of successful treatment for such patients. !" Medical therapy has consisted of negative inotropi c agents such as ~-blockers, calcium channel blockers, and disopyramide , but a subset of patients continue to have limiting symptoms. Cohort series have shown that septal myotomy-myectom y performed at expe rienced centers reduces the gradient and relieve s symptoms in more than 90% of patients. 1.6·9 Recentl y, dual chamber pacing was proposed as a less invasive and more widely available alternative therapy for the subset of patients with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. " :" Pacing the right ventricular apex causes abnormal septal motion, which may decre ase projection of the basal septum into the left ventricular outflo w tract during systole, thereby interrupti ng the sequence of events that leads to the

dynamic outflow obstruction. In addition, there may be a long-term remod elin g effect of pacing that further decreases the outflo w gradient. 10 Initial studies from cohort trials showed a reduction in the left ventricular outflow tract gradient and improvement in symptoms with dual chamber pacing in almost 90% of patients with hypertrophic obstructive cardiomyopathy, generating a high level of enthusiasm for this therapeutic modality. 10,11 Nevertheless, controversy has arisen concerning the role of dual chamber pacing in this patient population.' >" Evidence from subsequent studie s showed that not all patients achieve the high respon se rate that was described in the initial studies.17·20 Although there is an overall reduction in gradient, this doe s not necessarily correlate with symptomatic response. v-? A subset of patients may experien ce no symptomatic improvement , and the role of a placebo effect has been suggested.P-" The purpose of this article is to present an overview of our experience at Mayo Clinic Rochester with dual chamber pacing in patients with hypertrophic obstructi ve cardiom yopathy , beginning with 2 illustrative case report s. In addition, the Mayo Clinic experi ence with dual chamber pacing to date is described . Finally , an interim clinical perspective on the current role of this therapeutic modalit y is provided. REPORT OF CASES

From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn. Dr Erwin is now with the Scott and White Clinic, Temple, Tex.

Case 1 A 73-year-old woman presented with severe shortness of breath at rest. Four years previously during a work-up for shortness of breath , hypertrophic cardiomyopathy had

Address reprint requests and correspondence to Rick A. Nishimura , MD, Division of Cardiovascular Diseases , Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2000;75: 173-180

A. LLOYD, MD;

173

© 2000 Mayo Foundation f or Medical Education and Research

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been diagnosed. At that time, the cause of her dyspnea was thought to be related to multiple factors, including obesity, severe chronic obstructive pulmonary disease, and hypertrophic cardiomyopathy. She was treated with both bronchodilators and calcium channel blockers but had progressive dyspnea during the next few years. At presentation, the patient was severely short of breath at rest and could not move from her bed to a chair. She underwent surgical excision of endometrial carcinoma I year previously and was being followed up for possible recurrence. An echocardiogram revealed severe hypertrophy of the septum (thickness, 21 mm; normal, ::;11 mm) with severe systolic anterior motion of a structurally normal mitral valve. She had a peak instantaneous left ventricular outflow gradient of 70 mm Hg and severe mitral regurgitation in the resting state. Catheterization confirmed a peak-to-peak gradient of 80 mm Hg and normal coronary arteries. Surgical consultation was sought for consideration of septal myectomy, but the patient was thought to be a high surgical risk because of her serious medical comorbidities. Therefore, the recommendation was that she undergo implantation of a permanent pacemaker. A pacemaker was inserted, and she underwent continuous DDD pacing (ie, sense atrium and pace ventricle) at a sensed atrioventricular delay of 120 milliseconds. This atrioventricular delay resulted in complete preexcitation of the electrocardiogram. At 3-month follow-up, the patient felt better subjectively than she had before the pacemaker was inserted. She was still limited to walking slowly for I block because of shortness of breath, but this did not interfere with her sedentary lifestyle. A repeated echocardiogram revealed a peak resting gradient across the left ventricular outflow tract of 36 mm Hg and moderate mitral regurgitation. She was seen at 1- and 2-year follow-up, with no change in symptoms or hemodynamics. Thus, dual chamber pacing in this patient resulted in an improvement in subjective symptoms accompanied by a decrease in the severity of the left ventricular outflow tract obstruction. Case 2 A 34-year-old man presented to our institution with the diagnosis of hypertrophic cardiomyopathy and severe limiting symptoms of exertional dyspnea, angina, and lightheadedness. Hypertrophic cardiomyopathy had been diagnosed when he was 26 years old, when a loud heart murmur was heard on auscultation and an echocardiogram was obtained. Symptoms had progressed during the past 8 years and now severely limited his daily activity. He was treated appropriately with large doses of 13-blockers and calcium channel blockers with no improvement. He had no other medical problems or family history of sudden death.

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An echocardiogram revealed massive septal hypertrophy (thickness, 31 mm) with hyperdynamic systolic function. There was severe systolic anterior motion of the mitral valve with prolonged septal contact, and Doppler interrogation of the outflow tract demonstrated a peak resting instantaneous gradient of 108 mm Hg. On treadmill testing, the patient was limited to 30% of his age-predicted functional capacity (6 metabolic equivalents). His heart rate increased from 50 to 110 beats/min, and his blood pressure increased from 110/70 to 130/70 mm Hg at peak exercise. Cardiac catheterization revealed normal coronary arteries. A trial of temporary dual chamber pacing was undertaken in the catheterization laboratory, with a modest decrease in peak gradient from 80 to 60 mm Hg during a sensed atrioventricular delay of 100 milliseconds. There was complete preexcitation on the electrocardiogram at this atrioventricular delay. The patient underwent implantation of a dual chamber pacemaker with a sensed atrioventricular interval of 100 milliseconds (complete preexcitation achieved). He was entered into a protocol in which he was randomized to 3 months of no pacing (backup AAI mode, ie, pace atrium only if there is severe sinus brachycardia without pacing ventricle), followed by another 6 months of continuous pacing (DDD mode ).19 The patient returned at the completion of each arm for testing, and both the patient and the investigator were blinded to the pacing mode. The patient felt "somewhat improved" during all his return visits, but he was still severely limited in his daily activity and was unable to climb up a half flight of stairs. His objective exercise and hemodynamic variables are shown in Table 1. At the end of 1 year of continuous DDD pacing, septal myectomy was suggested because of the patient's continued limiting symptoms. This was performed successfully, with a reduction in gradient from 80 to 5 mm Hg. He had an uneventful postoperative course, and after 2 months of recovery, his condition had improved considerably. The pacemaker was set at a backup mode and was not activated. The patient was able to perform his daily activities with no limitations of shortness of breath or chest pressure. He was told not to perform strenuous high-level aerobic activity, but he could now walk up several flights of stairs at a fast pace and up a hill without difficulty. His objective exercise and hemodynamic variables 1 year postoperatively are shown in Table 1. With dual chamber pacing, this patient had initial symptomatic improvement but no objective improvement in exercise duration or maximal oxygen consumption. He still remained severely limited in his daily activities and thus underwent myectomy, which resulted in substantial subjective and objective improvement.

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Table 1. Subjective and Objective Hemodynamic and Exercise Variables for Patient 2 Who Underwent Dual Chamber Pacing and Subsequent Myectomy*

Baseline 3 mo (AAI) 12 mo (DOD) 1 Y postoperatively

NYHA class

Gradient (mm Hg)

METs

(rnl-kgt-mm')

III III III

108 100 64

6 5 6

20.8 18.7 20.8

I

5

11

MVoz

27.0

*AAI = atrial sensing and atrial pacing; DOD = atrial sensing and ventricular pacing; METs = metabolic equivalents; MVoz = maximal oxygenconsumption; NYHA = New York Heart Association. LONG-TERM MAYO CLINIC EXPERIENCE Overall Experience

Between November 1993 and December 1996, we implanted permanent pacemakers in 38 patients with hypertrophic obstructive cardiomyopathy for persistent symptoms (Figure 1), despite a maximal medical program. In all these patients, hypertrophic cardiomyopathy was diagnosed by echocardiography showing a hypertrophied left ventricular myocardium in the absence of a known cause. All patients had a resting left ventricular outflow gradient of greater than 30 mm Hg and a provoked gradient of more than 50 mm Hg. All were in normal sinus rhythm, and none had concomitant severe valvular or coronary artery disease. The short-term results of a subset of 19 of these patients have been reported previously.'? Thirteen patients were entered into a multicenter randomized trial." The remaining 6 patients were unable to perform treadmill testing and underwent pacemaker implantation with no entry into a randomized trial. The mean ± SD age of the total patient population was 56.2±16.4 years (range, 31-85 years), with 19 women and 19 men. The mean ± SD initial left ventricular outflow tract gradient was 94±48 mm Hg (range, 30-250 mm Hg). The 32 patients who were able to exercise underwent an oxygen treadmill exertion test; the mean ± SD maximal oxygen consumption (MVo 2) was l8.0±5.7 mls-kgl-mirr' (range, 8.6-35.0 ml-kgLmin-'), These 32 patients were entered into double-blind randomized studies. They were programmed to either an AAI backup mode or a DDD mode, with crossover at 3 months. Both hemodynamic testing and exercise testing were repeated after 3 months of each mode and then at 1- and 2-year follow-up of continuous DDD pacing. This strategy was used to determine the possible placebo effect of placing the pacemaker and the training effect of repeated exercise testing. Subjective follow-up was done for all 38 patients, with a mean ± SD follow-up of 24±14 months and a maximal follow-up of 50 months. Patients were interviewed and asked whether the pacemaker resulted in improvement or

deterioration of their condition or no change in symptoms. At last follow-up, 18 (47%) of 38 patients reported subjective improvement, and 20 patients (53%) reported no improvement. Four patients experienced a worsening of symptoms during dual chamber pacing and requested that the pacemaker be turned off. Ten of the patients who had no improvement subsequently underwent myectomy, and all experienced pronounced symptomatic improvement. In these 10 patients, myectomy resulted in a decrease in gradient from 96±40 to 8±5 mm Hg. Follow-up of Patients With Objective Exercise Data

For the 20 patients who continued with DDD pacing, hemodynamic and objective exercise data at l-year followup or longer are shown in Figure 1. Similar to the entire group, 55% of patients experienced no subjective symp-

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Figure 1. Analysis of the totalgroupof 38 patients(pt) and select subgroups of patients with hypertrophic obstructive cardiomyopathy (HCM). AAI = atrial sensing and atrial pacing; DOD = atrial sensingand ventricular pacing; PM = pacemaker; TMET = treadmill exertion test.

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Figure 2. Left ventricular outflow tract gradients at baseline (initial) vs gradients at last follow-up (final) for the 9 patients who experienced symptomatic improvement (left) and the 11 who did not experience symptomatic improvement (right).

tomatic improvement. Overall, the left ventricular outflow tract gradient decreased from 95±40 to 62±47 mm Hg. However, there was no significant difference in the percent decrease in gradient of the 11 patients who did not improve symptomatically (79 to 46 mm Hg) compared with the 9 patients who did improve symptomatically (114 to 90 mm Hg) (Figure 2). The long-term follow-up exercise data for these 20 patients are similar to those from other studies. 10,17,20 Data are presented as mean ± SE, and repeated measures of variance are used for analysis, Significance was set a priori at P<.05, There was a significant improvement in exercise duration from 7,7±0.8 minutes at baseline to 10.4±0,7 minutes at last follow-up (P<.05). However, the exercise duration during AAI pacing was 9.5±0.7 minutes, which is longer than that at baseline (P<.Ol). The exercise duration during AAI pacing was not statistically different from that during DDD pacing at 3 months or at last follow-up. There was no significant change in the exercise duration comparing the effect of DDD pacing at last follow-up with the DDD pacing during the first 3 months (Figure 3, left). The trend was toward improvement of the peak MVo 2 achieved between baseline (l8.l±1.5 ml-kgt-min') and last follow-up (l9.0±1.2 mL·kg-l·min- l ) (P=.09), However, there was no statistical difference between the peak MVo 2 achieved during AAI pacing (18.6±1.l ml-kgv-min') and last followup (Figure 4, left), Examination of individual data shows wide variation, with some patients having a substantial improvement and others having no improvement or even a deterioration in exercise capacity at follow-up (Figures 3 and 4, right), Eight patients had severe exercise limitation, with a baseline peak Mvo, ofless than 15 mlvkgt-rnirr'. These 8 patients had a greater improvement in the final peak Mvo, at follow-up compared with the 12 patients who had a

baseline peak MVo z of greater than 15 ml-kgt-min' (increase of 3,2±0.8 mL·kg-l,min- 1 vs O.l±l.l mls-kgt-min"; P=,04). In these 8 patients, the left ventricular outflow tract gradient decreased from 88±42 to 42±27 mm Hg at followup (P=.005). Of the 12 patients with a baseline peak MVo 2 of greater than 15 rnls-kgJ-rnirr', the left ventricular outflow tract gradient decreased from 100±40 to 76±54 mm Hg (P=.04). Three (38%) of 8 patients with a baseline Mvo.Iess than 15 mls-kgl-mirr' had clinical symptomatic improvement. Of 12 patients with a baseline MVo 2 greater than 15 mlc-kgI-mirr", 6 (50%) had clinical symptomatic improvement. There was no overall relationship of the change in MVo 2 vs the change in gradient from baseline to last follow-up.

DISCUSSION The potential beneficial effect of dual chamber pacing for hypertrophic obstructive cardiomyopathy was first recognized several decades ago when studies showed that ventricular pacing could reduce left ventricular outflow tract gradients, presumably because of incoordinate septal contraction.v-" Subsequently, a small series was done in the 1980s,lz,z4 culminating in 2 large cohort series in the early 1990s.IO,11 In these initial series, permanent pacemakers were placed in patients with hypertrophic obstructive cardiomyopathy and limiting symptoms unresponsive to medical therapy. Follow-up over 2 years revealed that symptomatic improvement occurred in almost 90% of patients, with a significant improvement in exercise time and a 50% reduction in gradient. 10,1I There may be a beneficial long-term remodeling effect from continuous pacing because the reduction in gradient persisted even after the pacemaker was temporarily shut off. The issue of whether hypertrophy could regress from longterm pacing was also raised.'? The recommendation was

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Figure 3. Comparison of the peak exercise time (minutes) of patients at baseline (base), after 3 months of a backup nonpaced "control" mode (AAI), after 3 months of continuous dual chamber pacing mode (DDD), and at last follow-up with continuous dual chamber pacing mode (DDD F-U). Left, Group data with mean ± SE at each period. NS = not significant. Right, Plots of the changes in individual patients at baseline (base), during AAI backup, and at last follow-up (DDD F-U).

that dual chamber pacing be performed in all patients with symptomatic obstructive cardiomyopathy unresponsive to medical therapy before consideration of myectomy. II Based on these recommendations, many patients in the United States have undergone implantation of a permanent pacemaker for hypertrophic cardiomyopathy. The initial widespread enthusiasm has been tempered because many of these patients have continued to have limiting symp-

toms. The role of the placebo effect was raised when blinded randomized trials showed more modest changes in objective measures of exercise tolerance. 17,19 Two multicenter randomized trials examined the efficacy of dual chamber pacing, each using an AAI arm as a control state.":" The overall results are similar to our aforementioned results. Analysis of group data shows a reduction in the left ventricular outflow tract gradient with continuous dual chamber pacing. Objective exercise tolerance

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Figure 4. Comparison of the maximal oxygen consumption at peak exercise (rnl-kgt-min') of patients at baseline (base), after 3 months of a backup nonpaced "control" mode (AAI), after 3 months of continuous dual chamber pacing mode (DDD), and at last follow-up with continuous DDD pacing mode (DDD F-D). Left, Group data with mean ± SE at each period. NS = not significant. Right, Plots of the changes in individual patients at baseline (base), during AAI backup, and at last follow-up (DDD F-U).

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increases with dual chamber pacing compared with that at baseline, but there is also an improvement in exercise tolerance comparing AAI pacing with baseline. This improvement in exercise tolerance with AAI pacing may represent a "training effect" in which patients are able to perform better on a treadmill after multiple treadmill tests. In addition, some patients enrolled in a study may actually increase their level of activity and subsequently their cardiovascular fitness. If the objective measurement of exercise tolerance with continuous dual chamber pacing is compared with an AAI "control" mode, the change is small. There is no significant improvement in peak MVo 2 by dual chamber pacing, which is a better measurement of the overall cardiovascular performance than duration on a treadmill. As was shown in a prior study, 17 our patients had an improvement in peak MVo 2 from dual chamber pacing when data from only those with a very low baseline MVo 2 were analyzed. However, this was a post hoc analysis, and these patients did not experience greater symptomatic improvement. There was no relationship between the change in peak MVo 2 and the change in left ventricular outflow tract gradient. Symptomatic improvement is apparent in many patients after pacemaker implantation. However, some patients experience a reduction in symptoms even with the pacemaker turned off, raising the possibility of a placebo effect. The absolute percentage of patients who have subjective improvement varies from 30% to 80%.17,20.21 We have seen no further symptomatic improvement in patients who do not respond during the first 3 months of pacing. The group data from these multicenter studies provide overall information about the effect of dual chamber pacing in patients with hypertrophic obstructive cardiomyopathy. However, there may be wide diversity of response in individual patients. There are clearly patients who experience hemodynamic and symptomatic improvement after implantation of a permanent pacemaker, with a reduction in left ventricular outflow tract gradient and improvement in exercise tolerance, as occurred in case 1. In contrast, some patients claim to have symptomatic relief but have no objective improvement or may even have deterioration in exercise capacity, as shown in case 2. Other patients may have subjective improvement in symptoms and exercise tolerance without a pacemaker turned on, implicating a combination of both the placebo and the training effect. Finally, some patients experience no symptomatic improvement or their condition deteriorates with implantation of a dual chamber pacemaker. We and other investigators have found no correlation between results of a short-term hemodynamic study and the long-term outcome of DDD pacing. However, we still perform the short-term study to identify patients whose condition may deteriorate with pac-

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ing. The mechanism of hemodynamic deterioration is unclear but may be related to a change in mitral regurgitation severity or acute changes in diastolic filling due to altered conduction. If symptomatic improvement occurs, the total benefit for an individual patient depends on the perceived activity level of the patient. In our experience, many older, more sedentary patients might be satisfied with the modest improvement in activity level achieved with dual chamber pacing. However, few of the younger, more active patients have been satisfied with the symptomatic improvement after implantation of a permanent pacemaker. This lack of satisfaction with lifestyle is further realized when patients undergo myectomy and have a significant improvement in activity level. 1.6,7 The mechanism by which dual chamber pacing improves symptoms and exercise tolerance is still unclear. In prior studies and in our own experiences, there does not seem to be a direct correlation of the magnitude of change in left ventricular outflow tract gradient and symptomatic improvement. 17,20,21 This may be a reflection of the lability of the left ventricular outflow tract gradient because changes in the loading conditions and contractility of the left ventricle may affect the outflow obstruction. A complex interplay of multiple pathophysiologic mechanisms is responsible for producing symptoms in patients with hypertrophic cardiomyopathy.I-3,14,25-27 Diastolic dysfunction, mitral regurgitation, and arrhythmias may contribute substantially to symptoms, and the effect of pacing on these mechanisms is still unknown. Dual chamber pacing shifts the end-systolic pressure volume relationship to the right and increases end-systolic volume, and the reduced metabolic demand from this change may have a role in symptomatic relief." Other confounding factors that must be considered in evaluating patients who undergo implantation of a permanent pacemaker are the technical considerations of pacing. There is an optimal atrioventricular interval that must be programmed to achieve the best hemodynamic benefit.P-" If the atrioventricular interval is too brief, cardiac output decreases and diastolic function deteriorates. If the atrioventricular interval is too long and there is incomplete preexcitation of the ventricle, relief of gradient will be inadequate (Figure 5). There is a different mechanical atrioventricular delay depending on whether the atrium is paced or sensed, and a full understanding of the complexities of pacemaker programming is necessary. Rate adaptive pacing may be necessary to obtain full preexcitation during exercise. The position of the lead in the right ventricular apex is also important; the lead must be placed in the far apical region to achieve optimal hemodynamic.benefit.v-" Thus, patients may undergo pacing but not receive full

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Figure 5. High-fidelity pressure curves of left atrium (LA), left ventricle (LV), and ascending aorta (Ao) in a patient with hypertrophic obstructive cardiomyopathy (HOeM), illustrating the hemodynamic effect of different pacing parameters. The baseline state (atrialpacing [A-pace]) is shown in the first portion. In the second portion, the pacing interval is too short, resulting in an elevation of the meanLA pressure and a decrease in Ao pressure. The optimal atrioventricular (A-V) delay is shown in the third portion, with a decrease in gradient but no deterioration of diastolic filling. In the fourth portion, the A-V interval is too long withfusion of the nativeQRS complex, resulting in a suboptimal decrease in gradient (see text for further details) (fromSymanski and Nishimura" withpermission). benefits because of inadequate pacemaker insertion or improper programming. Obviously, dual chamber pacing should not be considered the treatment of choice for all patients with hypertrophic obstructive cardiomyopathy. In a subset of patients, the gradient will decrease and symptoms will diminish with DDD pacing. However, there is also a subset of patients whose condition will not improve or may even deteriorate after implantation of a dual chamber pacemaker. Even if improvement is achieved, the extent of improvement may not result in attainment of a satisfactory lifestyle, particularly in younger patients. The current approach at Mayo Clinic is to offer dual chamber pacing as one of several therapeutic modalities to patients who have severe limiting symptoms unresponsive to medical therapy and a persistent large left ventricular outflow tract gradient. The known short-term outcome of this intervention should be discussed with the patient and compared with the known excellent long-term outcome of myectomy.?? In experienced centers, myectomy can be performed with an operative mortality of less than 5%, and less than 1% to 2% in younger otherwise healthy patients. More than 90% of patients experienced sustained symptomatic relief, with follow-up of greater than 20 years."?

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Both the subjective and the objective outcome of myectomy have been shown to be better than outcomes with pacing." Catheter-based septal ablation is a new investigational technique with promising results, but the extended follow-up is inadequate.P-" We believe that, at the present time, implantation of a dual chamber pacemaker is a reasonable option for patients who do not want to undergo surgery or who have other medical problems that may increase their surgical risk. A decision to proceed with pacemaker implantation should be made only after the patient has been informed of the data on symptomatic outcome that are available from randomized placebo-controlled trials. Several issues need to be addressed about dual chamber pacing in patients with hypertrophic obstructive cardiomyopathy. The exact mechanism by which patients benefit must be determined, and the identification of "responders" must be established. In addition, long-term follow-up results (over decades instead of years) must be documented. In the future, direct comparisons should be made among medical therapy, dual chamber pacing, septal ablation, and septal myectomy. Prior reports of outcomes of myectomy and septal ablation have been from cohort series only and have not been subjected to rigorous randomized placebocontrolled studies. The recent trials of pacing have raised several issues that must be addressed in future trials. Spontaneous improvement in exercise capacity may occur with repeated exercise tests, which has been a limitation of prior studies (as well as the Mayo data). Quantifying subjective symptomatic improvement is difficult. Other markers of hemodynamic improvement, such as neurohumoral markers, in addition to the current indirect measures of valve regurgitation and diastolic function would be ideal. Multicenter randomized trials may be difficult because not all centers are able to achieve the excellent results of myectomy that have been discussed, as the operation requires experience and surgical expertise. Several therapeutic alternatives are now available for symptomatic patients with hypertrophic obstructive cardiomyopathy. Currently, therapy must be individualized for each patient depending on lifestyle, preference, and medical comorbidities. Future comparison studies addressing the aforementioned specific issues are necessary to determine the ultimate role of each therapy in this subset of patients.

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20. 21.

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