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Clinical and Echocardiographic Variables Fail to Predict Response to Dual-Chamber Pacing for Hypertrophic Cardiomyopathy
Clinical and Echocardiographic Variables Fail to Predict Response to Dual-Chamber Pacing for Hypertrophic Cardiomyopathy Josepha Binder, MD, Steve R. Ommen, MD, Paul Sorajja, MD, Rick A. Nishimura, MD, and A. Jamil Tajik, MD, Graz, Austria; and Rochester, Minnesota
Background: Although dual-chamber pacing therapy for obstructive hypertrophic cardiomyopathy has been relegated to a limited role, there remains a subset of patients who are not good candidates for more definitive therapies. Objective: The goal of this investigation was to determine whether preprocedural variables could help identify patients most likely to respond. Methods: Retrospective review of 84 patients with hypertrophic cardiomyopathy who underwent dualchamber pacing for obstructive physiology at Mayo Clinic, Rochester, MN, included baseline demographics and echocardiographic features known to favor left ventricular outflow tract obstruction. Results of therapy, based on clinical visit, were obtained at two time points: within 2 years after pacemaker placement and at final follow-up (mean 3.7 years). Successful response to therapy was defined by improvement in New York Heart Association of at least 1 class without the need for surgical myectomy. Results: Overall, 66 (79%) patients had a follow-up visit within 2 years after the pacemaker placement, and 78 (93%) had at least one follow-up visit. There were 18 myectomies performed for persistent symptoms. A total of 33 (50%) patients had positive response to pacing therapy at the short-term analysis, whereas 34 (44%) had improvement sustained to the final visit. No preprocedural demographic or echocardiographic variables readily distinguished between responders and nonresponders. Conclusion: Dual-chamber pacing therapy for the relief of symptoms caused by dynamic left ventricular outflow tract obstruction has a limited role because of the availability of more definitive therapies; less than 50% long-term symptom relief; less than 20% long-term relief from a combined end point of death, symptoms, surgery, residual gradient, or a combination of these; and the inability to appropriately identify those patients most likely to derive benefit. Keywords: Hypertrophic cardiomyopathy, Dual-chamber pacing
The treatment of patients with obstructive hypertrophic cardiomyopathy (HCM) has fostered the development of many novel therapies. Although surgical septal myectomy provides unsurpassed safety and efficacy, the search for viable alternatives has engendered some controversy. The current debate regards the relative strengths and weaknesses of percutaneous alcohol septal ablation.1,2 However, before this, there was considerable interest in the potential for dual-chamber pacing as a therapeutic strategy.3-13 Although randomized trials ultimately dimmed the enthusiasm for this technique, there are clearly patients who achieved meaningful relief of symptoms from this therapy. The pathophysiology of obstruction in HCM has evolved to the point that it is now recognized that altered flow around the hypertrophied
From the Department of Cardiology, Karl Franzens Universität, Graz, Austria (J.B.); and Mayo Clinic College of Medicine, Rochester, Minnesota. Reprint requests: Steve R. Ommen, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (E-mail: [email protected]). 0894-7317/$34.00 Copyright 2008 by the American Society of Echocardiography. doi:10.1016/j.echo.2007.11.014
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septum creates significant drag forces on the mitral valve that results in the characteristic systolic anterior motion (SAM) and dynamic left ventricular (LV) outflow tract (LVOT) obstruction.14-17 Physiologic features that promote the obstruction include decreased preload, decreased afterload, and increased contractility. The theoretic mechanisms by which dual-chamber pacing could help diminish the tendency for obstruction include better synchronization of atrial and ventricular contraction (thereby optimizing preload) and changing the contractility or contraction sequence of the ventricular septum by inducing left bundle branch block. The purpose of this investigation was to examine whether there were specific preprocedural anatomic or morphologic features, particularly of the septum and mitral valve structures, that would help identify which patients with HCM are more likely to respond to dualchamber pacing. METHODS Patients Between 1982 and 2002, a total of 207 patients underwent dualchamber pacing after an initial evaluation for HCM at Mayo Clinic, Rochester, MN. Of these, 27 were excluded as the device was placed
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millimeters of mercury) was recorded from the echocardiogram before PPM implantation and from follow-up echocardiograms. Data Collection The time period for the first follow-up includes any measurements taken during the period up to 24 months post-PPM insertion (only 66 of the patients returned to Mayo Clinic, Rochester, MN, within 24 months). Long-term follow-up was obtained at the time of most recent contact with the individual patients.
Figure 1 Echocardiographic measures of relationships of hypertrophy and valvular geometry. A, Length (mm) of the anterior leaflet from the annulus to the coaptation point at mitral valve closure; AMP angle, angle (degrees) between the aortic valve plane and mitral valve plane; C, length (mm) from the coaptation point of the mitral valve leaflets to the most prominent point of the basal septum; D, diameter (mm) of the mitral annulus; LVEDD, left ventricular end-diastolic dimension (mm). Color figure online.
at another institution, 65 were excluded as the primary indication was isolated conduction system disease, and 31 patients did not have adequate preimplant echocardiography to make all of the intended measurements for this study. Thus, 84 patients with obstructive HCM who were referred for placement of a dual-chamber permanent pacemaker (PPM) for the relief of dynamic LVOT obstruction at the authors’ institution comprise the study group. Patients undergoing pacemaker placement at other institutions and those with isolated conduction system disease are not included in this total. Echocardiographic Data Echocardiograms were reviewed and offline measurements of the mitral valve geometry were recorded from the most recent echocardiogram before the PPM implantation date. Mitral valve geometry measurements were recorded from the parasternal long-axis view and included the A, D, and C septum lengths (Figure 1). The A measurement was defined as the length (in millimeters) of the anterior leaflet from the annulus to the coaptation point at mitral valve closure. The D measurement was defined as the diameter (in millimeters) of the mitral annulus. In addition, the A/D ratio was calculated as a measure of the extent of anterior placement of the leaflet with regard to the mitral annulus. C septum was defined as the length (in millimeters) from the coaptation point of the mitral valve leaflets to the most prominent point of the basal septum. Further measurements included the transverse diameter (in millimeters) of the basal ventricular septum in end diastole and end systole, the LV end-diastolic diameter (in millimeters) from parasternal long-axis view, the septum thickness at basal and mid in the apical 4-chamber view, and the aortic-mitral plane angle (angle between mitral plane and ascending aorta). Mitral regurgitation grade, SAM, and chordal SAM were taken from the final interpretation as recorded in the echocardiographic data base. The LVOT gradient (in
Data Analysis Summary statistics were reported using means, SDs, medians, or ranges for continuous and ordinal variables. Nominal variables are summarized with frequencies and percentages. Outcome was assessed at the first visit within 24 months after the PPM insertion. If patients had both short- and long-term follow-up visits, separate data abstraction was performed for each. Success (responders) from PPM was defined by improvement in New York Heart Association (NYHA) functional class by at least one grade and freedom from referral for surgical septal myectomy. A second definition of success included the above criteria plus evidence that the LVOT gradient was less than 20 mm Hg at resting conditions was analyzed separately. Geometric measurements were compared between those who did and did not improve in NYHA class using Wilcoxon rank sum tests. Associations between geometric measurements and the change (baseline minus follow-up) in gradient were assessed using Spearman rank correlation coefficient. Associations of possible confounding variables, such as age, sex, follow-up time, and presence of comorbidities, with the outcomes of interest were also assessed using Wilcoxon rank sum tests or Spearman correlations, as appropriate. Multiple logistic regressions, in the case of NYHA class improvement, and multiple linear regressions, in the case of change in gradient, were used to confirm the relationship with outcome and geometry measurements while adjusting for possible confounders. Statistical analyses were performed using software (JMP, Version 5, SAS Institute Inc, Cary, NC) and tests of statistical significance were performed at an alpha-level of 0.05. RESULTS Overall A total of 84 patients met the study inclusion criteria. Baseline clinical and echocardiographic measures are summarized in Table 1. The average age of patients was 66.7 years, and the mean time from initial diagnosis of HCM to implantation of PPM device was 4.6 ⫾ 5 years. Overall among the entire sample of 84 patients, 6 were lost to follow-up, 5 had cardiac-related deaths, 24 had noncardiac deaths, and 18 required surgical septal myectomy for persistent or recurrent symptoms. (Table 2). Short-Term Outcomes. In all, 66 patients returned for evaluation within the first 2 years after PPM placement. Among these 66 patients, there were 4 deaths (3 noncardiac deaths, and 1 sudden cardiac death), and 10 patients who required surgical myectomy for the relief of persistent symptoms. The mean time from PPM placement to surgical myectomy was 1.1 years (range: 1 month-2 years). At the short-term assessment point, 33 (50%) patients reported improvement of NYHA functional class by one or more grades in the absence of surgical myectomy (Figure 2). None of the baseline echocardiographic or clinical predictors readily distinguished shortterm responders. Notably, the improvement in resting LVOT gradi-
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Table 1 Baseline characteristics Short-term
N Age (y) Male ⱖ1 Comorbidity* Mitral regurgitation grade 0 1 2 3 4 Length of clinical follow-up (mo)† Resting gradient (mm Hg) Provoked gradient (mm Hg) Maximal septal thickness (mm) Midseptal thickness (mm) LVEDD parasternal long axis (mm) Aortic-mitral plane angle (degree) A (mm) D (mm) A/D (mm) C septal distance (mm)
Final follow-up
Symptomatic responders
Nonresponders
Symptomatic responders
Nonresponders
33 63.6 (14) 15 (45) 6 (18)
33 67.8 (17) 12 (36) 12 (36)
34 67.8 (13) 13 (38) 3 (9)
44 65.7 (17) 17 (38) 8 (18)
5 (15) 18 (55) 10 (30) 0 0 8 (6) 61 (38) 102 (49) 22.7 (5) 20.6 (4) 41.9 (7) 143 (6) 14.3 (4) 30.3 (4) 0.48 (0.1) 17.4 (3)
2 17 10 4
(6) (52) (30) (12) 0 9 (5) 66 (43) 81 (37) 23.0 (5) 20.7 (5) 43.2 (7) 143 (6) 14.1 (4) 30.4 (3) 0.46 (0.1) 17.4 (3)
3 20 10 1
(9) (59) (29) (3) 0 49 (41) 59 (35) 90 (54) 22.7 (5) 19.9 (3) 42.9 (7) 142 (5) 14.1 (4) 30.1 (4) 0.47 (0.1) 17.7 (3)
4 21 14 4
(9) (48) (32) (9) 0 38 (31) 69 (41) 101 (39) 22.8 (4) 20.8 (5) 42.4 (7) 143 (6) 14.0 (4) 30.3 (3) 0.46 (0.1) 17.2 (3)
LVEDD, Left ventricular end-diastolic diameter. *Comorbidities included coronary artery disease, stroke, diabetes, hypertension, atrial and fibrillation. †Among patients with at least one follow-up clinical visit. Values are expressed as mean (SD) for continuous data and n (%) for categorical data. There are no significant differences between responders and nonresponders.
Table 2 Outcome
No. of patients Follow-up duration (y) Deaths Myectomy NYHA class NYHA improvement ⱖ 1 class NYHA improvement ⱖ 2 class Rest gradient, mm Hg Improvement in rest gradient (mm Hg )
Baseline
4-24 mo
84
66 0.97 (0.9) 4 10 2.1 (1) 33 (50)
78 3.7 (3) 29 8 2.0 (0.8) 34 (44)
10 (15)
13 (17)
38.7 (32) 29.2 (32)
44.8 (41) 19.4 (50)
2.7 (0.7)
65.6 (36)
Final follow-up
NYHA, New York Heart Association. Values are expressed as mean (SD) for continuous data and n (%) for categorical data.
ent, although impressive, did not correlate to changes in NYHA functional class. Using the combined clinical and hemodynamic end point of at least one class improvement in symptoms, no subsequent myectomy, and resting LVOT gradient less than 20 mm Hg showed that at the short-term assessment, only 20 (30%) patients showed favorable response to pacing. Long-Term Outcomes. A total of 78 patients returned for follow-up beyond 2 years after the PPM placement at a mean interval of 3.7 ⫾ 3 years. There were an additional 8 patients who required
Figure 2 Proportion of hypertrophic cardiomyopathy patients showing successful response to dual-chamber pacing. Success was defined by the absence of death, surgical myectomy, and recurrent New York Heart Association (NYHA) Class III or IV symptoms (white bars); or the absence of death, surgical myectomy, NYHA III-IV symptoms, and recurrent outflow tract gradient ⬎ 20 mm Hg (black bars). LVOT, Left ventricular outflow tract. surgical septal myectomy. Among these 78 patients, 34 (44%) patients improved by at least one full functional class over their baseline assessment and did not undergo surgical myectomy (Figures 2 and 3). No baseline data were predictive of long-term response to PPM therapy. Multivariate logistic regression was performed to adjust
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Figure 3 Cumulative failure rate for hypertrophic cardiomyopathy patients treated with dual-chamber pacing therapy for 2 endpoints. The first endpoint (dashed line) was defined by the occurrence of death, surgical myectomy, or recurrent New York Heart Association (NYHA) Class III or IV symptoms. The second endpoint (solid line) was death, surgical myectomy, NYHA 3-4 symptoms, or recurrent outflow tract gradient ⬎ 20 mm Hg.
for age, sex, and comorbidities, however, none of the echocardiographic variables distinguished responders from nonresponders. Only 14 (18%) patients showed long-term favorable response as defined by improvement in functional class, no surgical intervention, and resting LV outflow gradient less than 20 mm Hg (Figures 2 and 3). Older Patient Subset. Despite the fact that age was not predictive in any of the models, there is a perception that perhaps older patients may be those most likely to respond. Therefore, all analyses were repeated in the subset of patients age 65 years and older (N ⫽ 42). There was no difference in the short- or long-term outcome assessments. DISCUSSION Although once thought to be a promising option for the treatment of obstructive HCM, dual-chamber pacing ultimately did not fair as well in randomized trials.9,10 It had been proposed that pacing from the right ventricular apex alters the pattern of septal contraction and interrupts the pathophysiologic sequence of events causing SAM with mitral regurgitation. However, the therapeutic effect was often incomplete and there was not a uniform response of the LVOT gradient to dual-chamber pacing.7 The mechanism by which pacing benefits SAM is unclear and more complex than simply widening the outflow tract and may include some placebo effect.9,10 Nevertheless, there have been a significant minority of patients who have had lasting improvement in functional capacity as the result of dualchamber pacing as evidenced by the 34 (44%) patients in the current analysis who had achieved an improvement in subjective functional class (13 patients had achieved improvement of at least two functional classes). Only 14 (18%) patients, however, demonstrated both a hemodynamic and symptomatic long-term improvement with pacing therapy. Identification of demographic or anatomic variables that would appropriately identify likely responders would clearly be of benefit for clinical practice.
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The pathophysiology of the dynamic LVOT obstruction has been the subject of intense investigation. Asymmetric hypertrophy, anteriorly displaced mitral valve support structures, elongated leaflets, and abnormal intracavitary flow vectors all coalesce to result in SAM of the mitral valve with further narrowing of the outflow tract and flow obstruction.14-17 Based on these prior investigations, we had postulated that patients with marked abnormalities of the septal and mitral geometry would be less likely to respond to pacing therapy than those with no or only mild abnormalities. However, in our data, no significant associations were found among measures of anterior displacement of the mitral apparatus, severity of hypertrophy, angulation of the outflow tract, or any demographic variables and the response to pacemaker therapy. This lack of association persisted even after adjusting for other, possibly confounding variables such as age, sex, baseline NYHA class, and presence of comorbidities. Although it has been recognized, and reconfirmed in this analysis, that dual-chamber pacing may not provide long-term benefit,10,12 one potential role for pacing may be to achieve temporary improvement to allow other medical or nonmedical issues to be addressed before definitive relief of the outflow tract obstruction. This was the rationale for assessment of results within the first 2 years after placement of the pacemaker device. Still, there were no clinical or imaging features that readily identified the patients who would be most likely to respond. What role remains for dual-chamber pacing in HCM? Clearly patients with coexistent advanced conduction system disease who would benefit from a pacemaker device independent of obstructive physiology may derive secondary benefit. Similarly, patients with significant comorbidity that unduly increases the risk of other more invasive therapies may be considered candidates for pacing. One of the key components to patient treatment in HCM is the assessment of risk for sudden cardiac death. Patients at the highest risk may be advised to pursue implantable defibrillators. If a dual-chamber device is placed, the clinician may consider taking advantage of the pacing function for select patients. Another potential scenario is the patient for whom significant comorbidity (advanced lung disease for instance) favors alcohol septal ablation over surgical myectomy and who has pre-existing left bundle branch block. Such patients are at considerable risk for complete heart block after alcohol ablation18,19 and prophylactic placement of a pacemaker with a trial of observation to the effects of pacing may prove beneficial. Most importantly, patients should always be apprised of the goals, risks, and chances of success for any therapy so that they may make a truly informed decision about their health care. This study has failed to find an association between outcome and mitral valve or ventricular septum geometry of sufficient significance to allow identification of patients with HCM likely to respond to dual-chamber pacing therapy. The lack of preprocedural predictors essentially renders pacemaker therapy for obstructive HCM as a trial-and-error proposition with less than 50% chance of durable relief of symptoms and less than 20% chance of durable relief of symptoms in conjunction with measurable LVOT gradient less than 20 mm Hg. Although there does remain a role for pacing therapy in HCM, this role is limited to a small subset of patients with significant extenuating circumstances that preclude more definitive therapies. REFERENCES 1. Maron BJ, Dearani JA, Ommen SR, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;44: 2044-53.
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2. Hess OM, Sigwart U. New treatment strategies for hypertrophic cardiomyopathy: alcohol ablation of the septum; the new gold standard? J Am Coll Cardiol 2005;44:2054-5. 3. Fananapazir L, Cannon RO III, Tripodi D, Panza JA. Impact of dualchamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation 1992;85:2149-61. 4. Fananapazir L, Epstein N, Curiel R, Panze J, Tripodi D, McAreavey D. Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy: evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 1994;90:2731-42. 5. Kappenberger L. Pacing for obstructive hypertrophic cardiomyopathy. Br Heart J 1995;73:107. 6. Betocchi S, Losi MA, Piscione F, et al. Effects of dual-chamber pacing in hypertrophic cardiomyopathy on left ventricular outflow tract obstruction and on diastolic function. Am J Cardiol 1996;77:498-502. 7. Nishimura RA, Hayes DL, Ilstrup DM, Holmes DR Jr, Tajik AJ. Effect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy: acute Doppler echocardiographic and catheterization hemodynamic study. J Am Coll Cardiol 1996;27:421-30. 8. Slade AK, Sadoul N, Shapiro L, et al. DDD pacing in hypertrophic cardiomyopathy: a multicenter clinical experience. Heart 1996;75:44-9. 9. Nishimura RA, Trusty JM, Hayes DL, et al. Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial. J Am Coll Cardiol 1997;29:435-41. 10. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a randomized, double-blind, crossover study (M-PATHY). Circulation 1999;99:2927-33.
11. Ommen SR, Nishimura RA, Squires RW, Schaff HV, Danielson GK, Tajik AJ. Comparison of dual-chamber pacing versus septal myectomy for the treatment of patients with hypertropic obstructive cardiomyopathy: a comparison of objective hemodynamic and exercise end points. J Am Coll Cardiol 1999;34:191-6. 12. Erwin JP III, Nishimura RA, Lloyd MA, Tajik AJ. Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: a clinical perspective in 2000. Mayo Clin Proc 2000;75:173-80. 13. Meisel E, Rauwolf T, Burghardt M, Kappenberger L. Pacemaker therapy of hypertrophic obstructive cardiomyopathy: PIC (pacing in cardiomyopathy) study group. Herz 2000;25:461-6. 14. Jiang L, Levine RA, King ME, Weyman AE. An integrated mechanism for systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations. Am Heart J 1987;113: 633-44. 15. Cape EG, Simons D, Jimoh A, Weyman AE, Yoganathan AP, Levine RA. Chordal geometry determines the shape and extent of systolic anterior mitral motion: in vitro studies. J Am Coll Cardiol 1989;13:1438-48. 16. Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer EM Jr. An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 1993;22:816-25. 17. Sherrid MV, Gunsburg DZ, Moldenhauer S, Pearle G. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:134454. 18. Talreja DR, Nishimura RA, Edwards WD, et al. Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue. J Am Coll Cardiol 2004;44:2329-32. 19. Qin JX, Shiota T, Lever HM, et al. Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions. Am J Cardiol 2004;93:171-5.
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Background: Although dual-chamber pacing therapy for obstructive hypertrophic cardiomyopathy has been relegated to a limited role, there remains a subset of patients who are not good candidates for more definitive therapies. Objective: The goal of this investigation was to determine whether preprocedural variables could help identify patients most likely to respond. Methods: Retrospective review of 84 patients with hypertrophic cardiomyopathy who underwent dualchamber pacing for obstructive physiology at Mayo Clinic, Rochester, MN, included baseline demographics and echocardiographic features known to favor left ventricular outflow tract obstruction. Results of therapy, based on clinical visit, were obtained at two time points: within 2 years after pacemaker placement and at final follow-up (mean 3.7 years). Successful response to therapy was defined by improvement in New York Heart Association of at least 1 class without the need for surgical myectomy. Results: Overall, 66 (79%) patients had a follow-up visit within 2 years after the pacemaker placement, and 78 (93%) had at least one follow-up visit. There were 18 myectomies performed for persistent symptoms. A total of 33 (50%) patients had positive response to pacing therapy at the short-term analysis, whereas 34 (44%) had improvement sustained to the final visit. No preprocedural demographic or echocardiographic variables readily distinguished between responders and nonresponders. Conclusion: Dual-chamber pacing therapy for the relief of symptoms caused by dynamic left ventricular outflow tract obstruction has a limited role because of the availability of more definitive therapies; less than 50% long-term symptom relief; less than 20% long-term relief from a combined end point of death, symptoms, surgery, residual gradient, or a combination of these; and the inability to appropriately identify those patients most likely to derive benefit. Keywords: Hypertrophic cardiomyopathy, Dual-chamber pacing
The treatment of patients with obstructive hypertrophic cardiomyopathy (HCM) has fostered the development of many novel therapies. Although surgical septal myectomy provides unsurpassed safety and efficacy, the search for viable alternatives has engendered some controversy. The current debate regards the relative strengths and weaknesses of percutaneous alcohol septal ablation.1,2 However, before this, there was considerable interest in the potential for dual-chamber pacing as a therapeutic strategy.3-13 Although randomized trials ultimately dimmed the enthusiasm for this technique, there are clearly patients who achieved meaningful relief of symptoms from this therapy. The pathophysiology of obstruction in HCM has evolved to the point that it is now recognized that altered flow around the hypertrophied
From the Department of Cardiology, Karl Franzens Universität, Graz, Austria (J.B.); and Mayo Clinic College of Medicine, Rochester, Minnesota. Reprint requests: Steve R. Ommen, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (E-mail: [email protected]). 0894-7317/$34.00 Copyright 2008 by the American Society of Echocardiography. doi:10.1016/j.echo.2007.11.014
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septum creates significant drag forces on the mitral valve that results in the characteristic systolic anterior motion (SAM) and dynamic left ventricular (LV) outflow tract (LVOT) obstruction.14-17 Physiologic features that promote the obstruction include decreased preload, decreased afterload, and increased contractility. The theoretic mechanisms by which dual-chamber pacing could help diminish the tendency for obstruction include better synchronization of atrial and ventricular contraction (thereby optimizing preload) and changing the contractility or contraction sequence of the ventricular septum by inducing left bundle branch block. The purpose of this investigation was to examine whether there were specific preprocedural anatomic or morphologic features, particularly of the septum and mitral valve structures, that would help identify which patients with HCM are more likely to respond to dualchamber pacing. METHODS Patients Between 1982 and 2002, a total of 207 patients underwent dualchamber pacing after an initial evaluation for HCM at Mayo Clinic, Rochester, MN. Of these, 27 were excluded as the device was placed
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millimeters of mercury) was recorded from the echocardiogram before PPM implantation and from follow-up echocardiograms. Data Collection The time period for the first follow-up includes any measurements taken during the period up to 24 months post-PPM insertion (only 66 of the patients returned to Mayo Clinic, Rochester, MN, within 24 months). Long-term follow-up was obtained at the time of most recent contact with the individual patients.
Figure 1 Echocardiographic measures of relationships of hypertrophy and valvular geometry. A, Length (mm) of the anterior leaflet from the annulus to the coaptation point at mitral valve closure; AMP angle, angle (degrees) between the aortic valve plane and mitral valve plane; C, length (mm) from the coaptation point of the mitral valve leaflets to the most prominent point of the basal septum; D, diameter (mm) of the mitral annulus; LVEDD, left ventricular end-diastolic dimension (mm). Color figure online.
at another institution, 65 were excluded as the primary indication was isolated conduction system disease, and 31 patients did not have adequate preimplant echocardiography to make all of the intended measurements for this study. Thus, 84 patients with obstructive HCM who were referred for placement of a dual-chamber permanent pacemaker (PPM) for the relief of dynamic LVOT obstruction at the authors’ institution comprise the study group. Patients undergoing pacemaker placement at other institutions and those with isolated conduction system disease are not included in this total. Echocardiographic Data Echocardiograms were reviewed and offline measurements of the mitral valve geometry were recorded from the most recent echocardiogram before the PPM implantation date. Mitral valve geometry measurements were recorded from the parasternal long-axis view and included the A, D, and C septum lengths (Figure 1). The A measurement was defined as the length (in millimeters) of the anterior leaflet from the annulus to the coaptation point at mitral valve closure. The D measurement was defined as the diameter (in millimeters) of the mitral annulus. In addition, the A/D ratio was calculated as a measure of the extent of anterior placement of the leaflet with regard to the mitral annulus. C septum was defined as the length (in millimeters) from the coaptation point of the mitral valve leaflets to the most prominent point of the basal septum. Further measurements included the transverse diameter (in millimeters) of the basal ventricular septum in end diastole and end systole, the LV end-diastolic diameter (in millimeters) from parasternal long-axis view, the septum thickness at basal and mid in the apical 4-chamber view, and the aortic-mitral plane angle (angle between mitral plane and ascending aorta). Mitral regurgitation grade, SAM, and chordal SAM were taken from the final interpretation as recorded in the echocardiographic data base. The LVOT gradient (in
Data Analysis Summary statistics were reported using means, SDs, medians, or ranges for continuous and ordinal variables. Nominal variables are summarized with frequencies and percentages. Outcome was assessed at the first visit within 24 months after the PPM insertion. If patients had both short- and long-term follow-up visits, separate data abstraction was performed for each. Success (responders) from PPM was defined by improvement in New York Heart Association (NYHA) functional class by at least one grade and freedom from referral for surgical septal myectomy. A second definition of success included the above criteria plus evidence that the LVOT gradient was less than 20 mm Hg at resting conditions was analyzed separately. Geometric measurements were compared between those who did and did not improve in NYHA class using Wilcoxon rank sum tests. Associations between geometric measurements and the change (baseline minus follow-up) in gradient were assessed using Spearman rank correlation coefficient. Associations of possible confounding variables, such as age, sex, follow-up time, and presence of comorbidities, with the outcomes of interest were also assessed using Wilcoxon rank sum tests or Spearman correlations, as appropriate. Multiple logistic regressions, in the case of NYHA class improvement, and multiple linear regressions, in the case of change in gradient, were used to confirm the relationship with outcome and geometry measurements while adjusting for possible confounders. Statistical analyses were performed using software (JMP, Version 5, SAS Institute Inc, Cary, NC) and tests of statistical significance were performed at an alpha-level of 0.05. RESULTS Overall A total of 84 patients met the study inclusion criteria. Baseline clinical and echocardiographic measures are summarized in Table 1. The average age of patients was 66.7 years, and the mean time from initial diagnosis of HCM to implantation of PPM device was 4.6 ⫾ 5 years. Overall among the entire sample of 84 patients, 6 were lost to follow-up, 5 had cardiac-related deaths, 24 had noncardiac deaths, and 18 required surgical septal myectomy for persistent or recurrent symptoms. (Table 2). Short-Term Outcomes. In all, 66 patients returned for evaluation within the first 2 years after PPM placement. Among these 66 patients, there were 4 deaths (3 noncardiac deaths, and 1 sudden cardiac death), and 10 patients who required surgical myectomy for the relief of persistent symptoms. The mean time from PPM placement to surgical myectomy was 1.1 years (range: 1 month-2 years). At the short-term assessment point, 33 (50%) patients reported improvement of NYHA functional class by one or more grades in the absence of surgical myectomy (Figure 2). None of the baseline echocardiographic or clinical predictors readily distinguished shortterm responders. Notably, the improvement in resting LVOT gradi-
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Table 1 Baseline characteristics Short-term
N Age (y) Male ⱖ1 Comorbidity* Mitral regurgitation grade 0 1 2 3 4 Length of clinical follow-up (mo)† Resting gradient (mm Hg) Provoked gradient (mm Hg) Maximal septal thickness (mm) Midseptal thickness (mm) LVEDD parasternal long axis (mm) Aortic-mitral plane angle (degree) A (mm) D (mm) A/D (mm) C septal distance (mm)
Final follow-up
Symptomatic responders
Nonresponders
Symptomatic responders
Nonresponders
33 63.6 (14) 15 (45) 6 (18)
33 67.8 (17) 12 (36) 12 (36)
34 67.8 (13) 13 (38) 3 (9)
44 65.7 (17) 17 (38) 8 (18)
5 (15) 18 (55) 10 (30) 0 0 8 (6) 61 (38) 102 (49) 22.7 (5) 20.6 (4) 41.9 (7) 143 (6) 14.3 (4) 30.3 (4) 0.48 (0.1) 17.4 (3)
2 17 10 4
(6) (52) (30) (12) 0 9 (5) 66 (43) 81 (37) 23.0 (5) 20.7 (5) 43.2 (7) 143 (6) 14.1 (4) 30.4 (3) 0.46 (0.1) 17.4 (3)
3 20 10 1
(9) (59) (29) (3) 0 49 (41) 59 (35) 90 (54) 22.7 (5) 19.9 (3) 42.9 (7) 142 (5) 14.1 (4) 30.1 (4) 0.47 (0.1) 17.7 (3)
4 21 14 4
(9) (48) (32) (9) 0 38 (31) 69 (41) 101 (39) 22.8 (4) 20.8 (5) 42.4 (7) 143 (6) 14.0 (4) 30.3 (3) 0.46 (0.1) 17.2 (3)
LVEDD, Left ventricular end-diastolic diameter. *Comorbidities included coronary artery disease, stroke, diabetes, hypertension, atrial and fibrillation. †Among patients with at least one follow-up clinical visit. Values are expressed as mean (SD) for continuous data and n (%) for categorical data. There are no significant differences between responders and nonresponders.
Table 2 Outcome
No. of patients Follow-up duration (y) Deaths Myectomy NYHA class NYHA improvement ⱖ 1 class NYHA improvement ⱖ 2 class Rest gradient, mm Hg Improvement in rest gradient (mm Hg )
Baseline
4-24 mo
84
66 0.97 (0.9) 4 10 2.1 (1) 33 (50)
78 3.7 (3) 29 8 2.0 (0.8) 34 (44)
10 (15)
13 (17)
38.7 (32) 29.2 (32)
44.8 (41) 19.4 (50)
2.7 (0.7)
65.6 (36)
Final follow-up
NYHA, New York Heart Association. Values are expressed as mean (SD) for continuous data and n (%) for categorical data.
ent, although impressive, did not correlate to changes in NYHA functional class. Using the combined clinical and hemodynamic end point of at least one class improvement in symptoms, no subsequent myectomy, and resting LVOT gradient less than 20 mm Hg showed that at the short-term assessment, only 20 (30%) patients showed favorable response to pacing. Long-Term Outcomes. A total of 78 patients returned for follow-up beyond 2 years after the PPM placement at a mean interval of 3.7 ⫾ 3 years. There were an additional 8 patients who required
Figure 2 Proportion of hypertrophic cardiomyopathy patients showing successful response to dual-chamber pacing. Success was defined by the absence of death, surgical myectomy, and recurrent New York Heart Association (NYHA) Class III or IV symptoms (white bars); or the absence of death, surgical myectomy, NYHA III-IV symptoms, and recurrent outflow tract gradient ⬎ 20 mm Hg (black bars). LVOT, Left ventricular outflow tract. surgical septal myectomy. Among these 78 patients, 34 (44%) patients improved by at least one full functional class over their baseline assessment and did not undergo surgical myectomy (Figures 2 and 3). No baseline data were predictive of long-term response to PPM therapy. Multivariate logistic regression was performed to adjust
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Journal of the American Society of Echocardiography Volume 21 Number 7
Figure 3 Cumulative failure rate for hypertrophic cardiomyopathy patients treated with dual-chamber pacing therapy for 2 endpoints. The first endpoint (dashed line) was defined by the occurrence of death, surgical myectomy, or recurrent New York Heart Association (NYHA) Class III or IV symptoms. The second endpoint (solid line) was death, surgical myectomy, NYHA 3-4 symptoms, or recurrent outflow tract gradient ⬎ 20 mm Hg.
for age, sex, and comorbidities, however, none of the echocardiographic variables distinguished responders from nonresponders. Only 14 (18%) patients showed long-term favorable response as defined by improvement in functional class, no surgical intervention, and resting LV outflow gradient less than 20 mm Hg (Figures 2 and 3). Older Patient Subset. Despite the fact that age was not predictive in any of the models, there is a perception that perhaps older patients may be those most likely to respond. Therefore, all analyses were repeated in the subset of patients age 65 years and older (N ⫽ 42). There was no difference in the short- or long-term outcome assessments. DISCUSSION Although once thought to be a promising option for the treatment of obstructive HCM, dual-chamber pacing ultimately did not fair as well in randomized trials.9,10 It had been proposed that pacing from the right ventricular apex alters the pattern of septal contraction and interrupts the pathophysiologic sequence of events causing SAM with mitral regurgitation. However, the therapeutic effect was often incomplete and there was not a uniform response of the LVOT gradient to dual-chamber pacing.7 The mechanism by which pacing benefits SAM is unclear and more complex than simply widening the outflow tract and may include some placebo effect.9,10 Nevertheless, there have been a significant minority of patients who have had lasting improvement in functional capacity as the result of dualchamber pacing as evidenced by the 34 (44%) patients in the current analysis who had achieved an improvement in subjective functional class (13 patients had achieved improvement of at least two functional classes). Only 14 (18%) patients, however, demonstrated both a hemodynamic and symptomatic long-term improvement with pacing therapy. Identification of demographic or anatomic variables that would appropriately identify likely responders would clearly be of benefit for clinical practice.
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The pathophysiology of the dynamic LVOT obstruction has been the subject of intense investigation. Asymmetric hypertrophy, anteriorly displaced mitral valve support structures, elongated leaflets, and abnormal intracavitary flow vectors all coalesce to result in SAM of the mitral valve with further narrowing of the outflow tract and flow obstruction.14-17 Based on these prior investigations, we had postulated that patients with marked abnormalities of the septal and mitral geometry would be less likely to respond to pacing therapy than those with no or only mild abnormalities. However, in our data, no significant associations were found among measures of anterior displacement of the mitral apparatus, severity of hypertrophy, angulation of the outflow tract, or any demographic variables and the response to pacemaker therapy. This lack of association persisted even after adjusting for other, possibly confounding variables such as age, sex, baseline NYHA class, and presence of comorbidities. Although it has been recognized, and reconfirmed in this analysis, that dual-chamber pacing may not provide long-term benefit,10,12 one potential role for pacing may be to achieve temporary improvement to allow other medical or nonmedical issues to be addressed before definitive relief of the outflow tract obstruction. This was the rationale for assessment of results within the first 2 years after placement of the pacemaker device. Still, there were no clinical or imaging features that readily identified the patients who would be most likely to respond. What role remains for dual-chamber pacing in HCM? Clearly patients with coexistent advanced conduction system disease who would benefit from a pacemaker device independent of obstructive physiology may derive secondary benefit. Similarly, patients with significant comorbidity that unduly increases the risk of other more invasive therapies may be considered candidates for pacing. One of the key components to patient treatment in HCM is the assessment of risk for sudden cardiac death. Patients at the highest risk may be advised to pursue implantable defibrillators. If a dual-chamber device is placed, the clinician may consider taking advantage of the pacing function for select patients. Another potential scenario is the patient for whom significant comorbidity (advanced lung disease for instance) favors alcohol septal ablation over surgical myectomy and who has pre-existing left bundle branch block. Such patients are at considerable risk for complete heart block after alcohol ablation18,19 and prophylactic placement of a pacemaker with a trial of observation to the effects of pacing may prove beneficial. Most importantly, patients should always be apprised of the goals, risks, and chances of success for any therapy so that they may make a truly informed decision about their health care. This study has failed to find an association between outcome and mitral valve or ventricular septum geometry of sufficient significance to allow identification of patients with HCM likely to respond to dual-chamber pacing therapy. The lack of preprocedural predictors essentially renders pacemaker therapy for obstructive HCM as a trial-and-error proposition with less than 50% chance of durable relief of symptoms and less than 20% chance of durable relief of symptoms in conjunction with measurable LVOT gradient less than 20 mm Hg. Although there does remain a role for pacing therapy in HCM, this role is limited to a small subset of patients with significant extenuating circumstances that preclude more definitive therapies. REFERENCES 1. Maron BJ, Dearani JA, Ommen SR, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;44: 2044-53.
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2. Hess OM, Sigwart U. New treatment strategies for hypertrophic cardiomyopathy: alcohol ablation of the septum; the new gold standard? J Am Coll Cardiol 2005;44:2054-5. 3. Fananapazir L, Cannon RO III, Tripodi D, Panza JA. Impact of dualchamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation 1992;85:2149-61. 4. Fananapazir L, Epstein N, Curiel R, Panze J, Tripodi D, McAreavey D. Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy: evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 1994;90:2731-42. 5. Kappenberger L. Pacing for obstructive hypertrophic cardiomyopathy. Br Heart J 1995;73:107. 6. Betocchi S, Losi MA, Piscione F, et al. Effects of dual-chamber pacing in hypertrophic cardiomyopathy on left ventricular outflow tract obstruction and on diastolic function. Am J Cardiol 1996;77:498-502. 7. Nishimura RA, Hayes DL, Ilstrup DM, Holmes DR Jr, Tajik AJ. Effect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy: acute Doppler echocardiographic and catheterization hemodynamic study. J Am Coll Cardiol 1996;27:421-30. 8. Slade AK, Sadoul N, Shapiro L, et al. DDD pacing in hypertrophic cardiomyopathy: a multicenter clinical experience. Heart 1996;75:44-9. 9. Nishimura RA, Trusty JM, Hayes DL, et al. Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial. J Am Coll Cardiol 1997;29:435-41. 10. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a randomized, double-blind, crossover study (M-PATHY). Circulation 1999;99:2927-33.
11. Ommen SR, Nishimura RA, Squires RW, Schaff HV, Danielson GK, Tajik AJ. Comparison of dual-chamber pacing versus septal myectomy for the treatment of patients with hypertropic obstructive cardiomyopathy: a comparison of objective hemodynamic and exercise end points. J Am Coll Cardiol 1999;34:191-6. 12. Erwin JP III, Nishimura RA, Lloyd MA, Tajik AJ. Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: a clinical perspective in 2000. Mayo Clin Proc 2000;75:173-80. 13. Meisel E, Rauwolf T, Burghardt M, Kappenberger L. Pacemaker therapy of hypertrophic obstructive cardiomyopathy: PIC (pacing in cardiomyopathy) study group. Herz 2000;25:461-6. 14. Jiang L, Levine RA, King ME, Weyman AE. An integrated mechanism for systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations. Am Heart J 1987;113: 633-44. 15. Cape EG, Simons D, Jimoh A, Weyman AE, Yoganathan AP, Levine RA. Chordal geometry determines the shape and extent of systolic anterior mitral motion: in vitro studies. J Am Coll Cardiol 1989;13:1438-48. 16. Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer EM Jr. An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 1993;22:816-25. 17. Sherrid MV, Gunsburg DZ, Moldenhauer S, Pearle G. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:134454. 18. Talreja DR, Nishimura RA, Edwards WD, et al. Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue. J Am Coll Cardiol 2004;44:2329-32. 19. Qin JX, Shiota T, Lever HM, et al. Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions. Am J Cardiol 2004;93:171-5.
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