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Echocardiographic evidence of hemodynamic and clinical improvement in patients paced for heart failure
Echocardiographic Evidence of Hemodynamic and Clinical Improvement in Patients Paced for Heart Failure Ole A. Breithardt, MD, Christoph Stellbrink, MD, Andreas Franke, MD, Angelo Auricchio, MD, PhD, Etienne Huvelle, PhD, Stefan Sack, MD, Patricia Bakker, and Peter Hanrath, MD, on behalf of the Pacing Therapies for Congestive Heart Failure Investigators
MD,
Dilated cardiomyopathy is frequently associated with electrical conduction disturbances. Development of left bundle-branch block with discoordinated ventricular contraction pattern further contributes to impaired hemodynamic performance. Biventricular pacing has evolved as a new treatment option for patients with dilated cardiomyopathy and conduction disturbances. The “electrical” approach aims to normalize the disturbed contraction pattern, thereby improving hemodynamic function by simultaneous stimulation at different ventricular sites. Acute hemodynamic improvement with biventricular pacing has been demonstrated in patients with depressed left ventricular function and delayed
intraventricular conduction. Due to the variations in optimal pacing site and atrioventricular delay, individual optimization to achieve optimal hemodynamic benefit is necessary. Echocardiography has the potential to provide hemodynamic data by Doppler techniques and combine these with geometric information about ventricular volumes, ejection fraction, and contraction patterns. This article focuses on the use of echocardiographic techniques for noninvasive optimization in cardiac pacing and presents preliminary experience from the initial trials on multisite pacing in heart failure. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;86(suppl):133K–137K
ilated cardiomyopathy of ischemic and idiopathic origin is frequently associated with electrical D conduction disturbances. Development of bundle-
mal hemodynamic benefit. Only few patients seem to benefit from conventional right ventricular apical pacing, mostly those with conduction disturbances of the right bundle-branch block type.4 There is substantial need to simplify optimization of pacing site and right ventricular delay noninvasively. Echocardiographic methods may reveal important hemodynamic data by Doppler techniques and combine these with geometric information about ventricular volumes, ejection fraction, and contraction patterns. This article focuses on the use of echocardiographic techniques for noninvasive optimization in cardiac pacing and presents preliminary experience from the first trials on multisite pacing in heart failure.
branch block indicates progression of the disease and is associated with poorer prognosis.1 The discoordinated ventricular contraction pattern further contributes to impaired hemodynamic performance with reduced peak positive left ventricular dP/dt and prolongation of isovolumetric relaxation and contraction time intervals.2,3 Recently, biventricular pacing has evolved as a new treatment option for patients with dilated cardiomyopathy and conduction disturbances. The “electrical” approach aims to normalize the disturbed contraction pattern, thereby improving hemodynamic function by simultaneous stimulation at different ventricular sites. Invasive studies have demonstrated acute hemodynamic improvement in patients with depressed left ventricular function and delayed intraventricular conduction4,5 and concluded that leftventricular– based pacing (left ventricular or biventricular pacing) is the superior pacing modality in most patients with left bundle-branch block. However, it has also become clear that the optimal pacing site and atrioventricular delay show considerable variation that requires individual optimization to achieve optiFrom the Department of Cardiology, RWTH University of Technology, Aachen, Germany; Department of Cardiology, Otto-von-Guericke University, Magdeburg, Germany; Guidant CRM Research, Brussels, Belgium; Department of Cardiology, University Hospital, Essen, Germany; and Department of Cardiac Surgery, University Hospital, Utrecht, the Netherlands. Address for reprints: Ole A. Breithardt, MD, Medizinische Klinik I der RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. ©2000 by Excerpta Medica, Inc. All rights reserved.
NONINVASIVE OPTIMIZATION OF ATRIOVENTRICULAR DELAY Soon after the introduction of programmable dualchamber pacemakers, several studies examined the hemodynamic benefit of sequential atrioventricular pacing by using noninvasive Doppler echocardiography.6 – 8 Beat-to-beat changes in stroke volume were analyzed by measurement of Doppler velocity-time integrals (VTI) across the aortic valve to identify patients who benefited most from synchronized DDD pacing as compared with conventional VVI pacing.9 Doppler-derived cardiac output was shown to be 14 – 30% higher with DDD pacing than in the VVI mode, especially in patients with retrograde ventriculoatrial conduction or clinical signs of pacemaker syndrome. Analysis of transmitral flow patterns by pulsed-wave Doppler echocardiography gave further insights into the role of atrial contribution to left ventricular filling. 0002-9149/00/$ – see front matter PII S0002-9149(00)01193-0
133K
Von Bibra et al10 demonstrated that the mitral valve closes earlier with increasing atrioventricular intervals, whereas the onset of left ventricular systole and the timing of mitral-valve opening remained unchanged. Shorter atrioventricular delays led to a significant prolongation of diastolic filling time and an increase in left ventricular filling volume as an indication for improved cardiac performance.11 Atrial filling fraction, calculated as the ratio between early (E) and late (A) diastolic filling wave, is progressively reduced with shorter atrioventricular delays.12 This is explained by the later occurrence of atrial systole in the cardiac cycle, leaving less volume for the atrial “kick.” At rest, a mean atrioventricular delay around 140 – 150 msec with significant interindividual variation was determined in several independent studies as the optimal interval for the majority of patients with DDD pacing.11,13,14 However, increasing heart rates at exercise and sensed P-waves (VDD) may require shorter atrioventricular delays for optimizing filling time and cardiac output calculated by pulsed-wave Doppler VTI.12,15 M-mode echocardiographic results from a small study on 7 patients with complete heart block and normal left ventricular function suggested that the individual optimum atrioventricular delay is determined by the timing between mitral valve opening and the onset of septal contraction.16 The largest increase in stroke volume was found at the atrioventricular delay in which ventricular contraction takes place between the peaks of the A wave and the end of transmitral flow about 30 msec later. Similar results have been obtained by the application of Doppler tissue imaging for atrioventricular delay optimization in patients with DDD right ventricular pacemakers. Doppler tissue imaging records low-velocity, highintensity signals reflected from the myocardium and measures the regional velocities of myocardial wall motion by pulsed-wave Doppler. Gessner et al17 compared regional Doppler tissue-imaging time intervals at the septum and the posterior wall with conventional parameters of global left ventricular function. They concluded that the atrioventricular delay should be set to obtain a normal interval of 70 – 80 msec between the end of regional A wave measured by Doppler tissue imaging and the onset of the subsequent regional S wave by Doppler tissue imaging. This regional interval roughly corresponds to the isovolumetric contraction time. Ritter et al18 have proposed a simple formula for noninvasive echocardiographic determination of the individual optimal atrioventricular delay in DDD pacing. However, this approach has not yet been validated with invasive hemodynamic measurements. Ishikawa et al19 recently evaluated a similar approach with phonocardiography to measure the interval from cessation of the A wave to complete closure of the mitral valve. Optimal atrioventricular delay was found at the setting at which the end of the atrial contribution to left ventricular filling coincides with complete mitral valve closure. In summary, consistent acute changes in routine 134K THE AMERICAN JOURNAL OF CARDIOLOGY姞
echocardiographic parameters have been found only for diastolic filling time and stroke volume derived from aortic VTI. However, there are no clear guidelines available on how to combine these parameters for atrioventricular delay optimization. Most studies simply identified the optimal atrioventricular delay by the increase in aortic VTI-derived stroke volume; other authors emphasize the importance of an increase in left ventricular diastolic filling time.20,21 No longterm experience about the prognostic value of this approach is yet available. The value of pulsed-wave Doppler tissue imaging still needs to be confirmed.
PACING FOR HEART FAILURE Soon after the introduction of cardiac pacing, several early trials studied the effect of alternate pacing sites on hemodynamics in normal and diseased ventricles,22–24 but results were inconsistent. Combined echocardiographic and hemodynamic studies clarified the pathophysiologic changes that are responsible for the frequently observed abnormal septal motion in patients with right ventricular pacing, intrinsic left bundle-branch block or type B Wolff-ParkinsonWhite syndrome.25 The “paradoxical” septal contraction pattern was normalized by additional stimulation from the left ventricular free wall, which resulted in advanced left ventricular contraction and a normalization of the transseptal pressure gradient. Despite these promising observations, which stress the importance of pacing site, the early clinical trials focused on AV delay optimization in right ventricular DDD pacing to improve hemodynamic function. These trials included only patients with underlying bradyarrhythmias. Most of the included patients were characterized by normal to only moderately depressed left ventricular performance. Hochleitner et al26 were the first to implant DDD pacemakers with the intention of treating patients with advanced heart failure. They used conventional DDD pacing at the right ventricular apex with a short atrioventricular delay of 100 msec in patients with advanced, drug-resistant heart failure of exclusively nonischemic etiology. Shortand long-term results after implantation demonstrated progressive improvement in various clinical and echocardiographic parameters. Echocardiographic dimensions of left ventricular chambers including the left atrium decreased progressively up to 2 years after implant with a concomitant slight, but nonsignificant increase in fractional shortening as assessed by Mmode echocardiography.27 However, at 5-year followup, 10 of 13 patients in this series had died, 4 additional patients received a donor heart, and median survival time was only 22 months. Although they did not report ventricular conduction delays as inclusion criteria, their patients showed a long mean PR interval of 200 msec and about half of the patients presented with intraventricular conduction delay of left bundle-branch block morphology. These important baseline characteristics may help to explain the conflicting negative results in subsequent trials. Linde et al28 included 10 patients with shorter mean intrinsic PR interval and almost exclusively normal
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FIGURE 1. Acute changes in aortic and mitral velocity-time integrals (VTI) with pacing depending on the atrioventricular (AV) delay and plotted against pacing site. Tested AV delays (in milliseconds ⴞ SD) were individually defined in relation to the intrinsic PR interval5—in hemodynamic responders, the optimal AV delay and the 2 adjacent AV delays; in hemodynamic nonresponders, the 3 longest AV delays. BV ⴝ biventricular pacing, IC ⴝ intrinsic conduction; LV ⴝ left ventricular pacing; RV ⴝ right ventricular pacing.
QRS width, only 1 patient had a left bundle-branch block morpholgy. In addition, 70% of patients included had coronary artery disease. Left ventricular volumes assessed by echocardiography did not change significantly, but there was a trend toward longer diastolic filling time and a slight reduction in left atrial size with pacing at an atrioventricular interval optimized by echocardiographic derived stroke volume. It appeared that the presence of interventricular conduction disturbances— defined by QRS prolongation and associated with left ventricular asynergy is an important determinant for improvement with pacing, as was already proposed in 1986 in an editorial by Iskandrian and Mintz.29
VENTRICULAR RESYCHRONIZATION WITH MULTISITE PACING These early studies were limited to modification of atrioventricular timing with alteration of the programmed atrioventricular delay. More recent studies aimed at changing the activation sequence of the left ventricle to reverse the frequently observed asynchronous contraction pattern in patients with bundlebranch block by the addition of left ventricular pacing sites. Inter- and intraventricular conduction delays have been shown earlier to impair ventricular performance2 and are associated with poor prognosis.1 The very first clinical results of biventricular pacing with an epicardial, left ventricular pacing site were reported in 1994.30 Cazeau et al31 demonstrated improved ventricular resynchronization by angioscintigraphy with
4-chamber (biatrial– biventricular) DDD pacing in a case study. Subsequent studies performed extensive acute invasive measurements in heart failure patients with long atrioventricular interval and prolonged QRS complex. Bi- and left ventricular pacing improved parameters of left ventricular contractile function such as stroke work, peak positive left ventricular dP/dt, and pulse pressure.4,5 Left ventricular pacing was achieved either with a temporary pacing electrode advanced into the epicardial veins via the coronary sinus4 or with permanent epicardial electrodes implanted through a small thoracotomy.5 Echocardiographic results for multisite pacing are still sparse and only preliminary data have been reported.32–35 However, the early results indicate favorable effects on echocardiographic parameters of left ventricular function compared with conventional pacing. A positive effect on the interventricular conduction delay has been reported with the use of Doppler echocardiographic measurements. Biventricular pacing reduced the left ventricular pre-ejection delay between the onset of QRS and the onset of left ventricular systolic flow at the outflow tract and thus improved interventricular synchrony.32 Acute improvement in transesophageal left ventricular fractional area change of ⬎30% was reported in 6 open-chest patients before cardiac surgery with biventricular apical pacing.33 Hyperkinesis of anterior segments as assessed by qualitative analysis of 2-dimensional wall motion was obA SYMPOSIUM: ELECTRICAL THERAPIES FOR THE HEART
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FIGURE 2. Pulsed-wave mitral inflow Doppler spectrum in a patient with left bundle-branch block (LBBB) (left) and with biventricular pacing at 70 milliseconds (ms) atrioventricular delay (right). Biventricular (BV) pacing with a short atrioventricular delay results in prolonged mitral filling time (450 vs 298 ms) and E-wave decleration time (190 ms vs 145 ms). Velocity-time integral of E wave and A wave is increased with BV pacing (21.4 vs 17.8 cm), whereas the E:A wave ratio decreased.
served only with biventricular apical pacing and not with conventional right ventricular apical or right ventricular outflow tract pacing alone. Promising results are reported in early experience from the Pacing Therapies for Congestive Heart Failure (PATH-CHF) study, the first controlled and randomized study on multisite pacing for heart failure, which included 42 patients between 1996 and 1998.36 Heart failure patients with New York Heart Association (NYHA) functional class III–IV cardiac failure with significant conduction delays, including long PR intervals ⬎150 msec and bundle-branch block (QRS ⬎120 msec), were selected to undergo implantation of 2 separate DDD pacemakers. An epicardial lead was implanted by limited thoracotomy on the left ventricular free wall to allow right ventricular apical, left ventricular free wall, and biventricular pacing at various atrioventricular delays. For biventricular pacing the second pacemaker was triggered by the pacing spike of the leading device (VVT mode). Individual optimal pacing configuration was selected according to the results of invasive hemodynamic testing during implantation with measurement of peak positive dP/dt and pulse pressure.36 Improvements in conventional echocardiographic parameters such as aortic and mitral VTI (as indices for stroke volume) by continuous and pulsed-wave Doppler in the mitral inflow profile (Figure 1) were measured not only with shorter atrioventricular delays, but also depending on pacing site. Left ventricular– based pacing (left ventricular and biventricular) resulted in a consistent trend toward higher stroke volume compared with no pacing or right ventricular apical pacing.35 The same relation was observed for diastolic filling time (Figure 2). Comparison of end-diastolic volumes assessed by biplane 2-dimensional echocardiography between inclusion and 6 months postimplantation showed only a slight decrease in the total population. However, more than half of the patients decreased by ⬎10% from 136K THE AMERICAN JOURNAL OF CARDIOLOGY姞
baseline and heart size increased by ⬎10% in only a few patients.34 An important finding is that the chronic response to optimized pacing is not predicted by the acute hemodynamic response. In this preliminary experience some of the patients with the largest increase in peak positive dP/dt at optimized pacing did not respond to long-term pacing in terms of volumes, but showed increasing heart size. Mean end-diastolic volume before implantation was significantly higher in these patients compared with the total population and may help to explain the lack of improvement despite impressive acute benefit. Similar lack of improvement in very large hearts has recently been reported for drug treatment of congestive heart failure.37
CONCLUSION Modern pacing techniques can help to resynchronize ventricular activation sequences in patients with disturbed intraventricular conduction. Echocardiography as a noninvasive imaging technique may identify pacemaker patients with impaired hemodynamic performance and help to optimize the atrioventricular delay. Although beneficial effects on noninvasive parameters of hemodynamic performance have been demonstrated in several studies, no consensus exists yet on the optimization algorithm. In recent years, interest has focused on the alteration of ventricular contraction patterns by additional stimulation of left ventricular sites. Whereas pacing in normal hearts without intraventricular conduction disturbances may induce asynchrony, left-ventricular– based pacing may help to normalize abnormal contraction patterns, which are frequently observed in patients with cardiomyopathies and bundle-branch block. At present, this approach requires individual optimization protocols. Invasive studies have demonstrated acute hemodynamic improvement with optimized multisite pacing. However, only short-term experience is available and prognostic data still limited. Whether ventricular re-
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synchronization helps to improve cardiac performance in the long-term is still to be determined, but preliminary echocardiographic results are promising. Doppler echocardiography in combination with 2-dimensional analysis of contraction patterns provides a widely available technique for noninvasive optimization for multisite pacing in heart failure patients. 1. Kelly TL, Cremo R, Nielsen C, Shabetai R. Prediction of outcome in late-stage
cardiomyopathy. Am Heart J 1990;119:1111–1121. 2. Xiao HB, Brecker SD, Gibson DG. Effects of abnormal activation on the time
course of the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403– 407. 3. Xiao HB, Lee CH, Gibson DG. Effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443– 447. 4. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567– 1573. 5. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein H, Kramer A, Ding J, Salo R, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure: The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993–3001. 6. Schuster AH, Nanda NC. Doppler echocardiography and cardiac pacing. PACE Pacing Clin Electrophysiol 1982;5:607– 612. 7. Fagrell B, Lindvall K. Non-invasive beat-to-beat analysis of stroke volume and digital pulse volume in patients with complete heart block and artificial pacing. Acta Med Scand 1979;205:185–190. 8. Reiter MJ, Hindman MC. Hemodynamic effects of acute atrioventricular sequential pacing in patients with left ventricular dysfunction. Am J Cardiol 1982;49:687– 692. 9. Stewart WJ, Dicola VC, Harthorne JW, Gillam LD, Weyman AE. Doppler ultrasound measurement of cardiac output in patients with physiologic pacemakers: effects of left ventricular function and retrograde ventriculo-atrial conduction. Am J Cardiol 1984;54:308 –312. 10. Von Bibra H, Wirtzfeld A, Hall R, Ulm K, Blo¨mer H. Mitral valve closure and left ventricular filling time in patients with VDD pacemakers: assessment of the onset of left ventricular systole and the end of diastole. Br Heart J 1986;55: 355–363. 11. Iwase M, Sotobata I, Yokota M, Takagi S, Jing HX, Kawai N, Hayashi H, Murase M. Evaluation by pulsed Doppler echocardiography of the atrial contribution to left ventricular filling in patients with DDD pacemakers. Am J Cardiol 1986;58:104 –109. 12. Pearson AC, Janosik DL, Redd RR, Buckingham TA, Blum RI, Labovitz AJ. Doppler echocardiographic assessment of the effect of varying atrioventricular delay and pacemaker mode on left ventricular filling. Am Heart J 1988;115:611– 621. 13. Faerestrand S, Ohm OJ. A time-related study of the hemodynamic benefit of atrioventricular synchronous pacing evaluated by Doppler echocardiography. PACE Pacing Clin Electrophysiol 1985;8:838 – 848. 14. Forfang K, Otterstad JE, Ihlen H. Optimal atrioventricular delay in physiological pacing determined by Doppler echocardiography. PACE Pacing Clin Electrophysiol 1986;9:17–20. 15. Mehta D, Gilmour S, Ward DE, Camm AJ. Optimal atrioventricular delay at rest and during exercise in patients with dual chamber pacemakers: a noninvasive assessment by continuous wave Doppler. Br Heart J 1989;61:161–166. 16. Leonelli FM, Wang K, Youssef M, Hall R, Brown D. Systolic and diastolic effects of variable atrioventricular delay in patients with complete heart block and normal ventricular function. Am J Cardiol 1997;80:294 –298. 17. Gessner M, Blazek G, Kainz W, Gruska M, Gaul G. Application of pulsedDoppler tissue imaging in patients with dual chamber pacing: the importance of conduction time and AV delay on regional left ventricular wall dynamics. PACE Pacing Clin Electrophysiol 1998;21:2273–2279.
18. Ritter P, Dib JC, Mahaux V, Lelie`vre T, Soyeur D, Lavergne T, Cazeau S, Guize L, Rabine LM, Daubert JC. New method for determining the optimal atrio-ventricular delay in patients paced in DDD mode for complete atrioventricular block (abstract). PACE Pacing Clin Electrophysiol 1995;18:855. 19. Ishikawa T, Sumita S, Kimura K, Kikuchi M, Kosuge M, Kuji N, Endo T, Sugano T, Sigemasa T, Kobayashi I, Tochikubo O, Usui T. Prediction of optimal atrioventricular delay in patients with implanted DDD pacemakers. PACE Pacing Clin Electrophysiol 1999;22:1365–1371. 20. Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995;25:281–288. 21. Brecker SJ, Xiao HB, Sparrow J, Gibson DG. Effects of dual-chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992;340: 1308 –1312. 22. Benchimol A, Liggett MS. Cardiac hemodynamics during stimulation of the right atrium, right ventricle, and left ventricle in normal and abnormal hearts. Circulation 1966;33:933–944. 23. Chamberlain DA, Leinbach RC, Vassaux CE, Kastor JA, DeSanctis RW, Sanders CA. Sequential atrioventricular pacing in heart block complicating acute myocardial infarction. N Engl J Med 1970;282:577–582. 24. Gibson DG, Chamberlain DA, Coltart DJ, Mercer J. Effect of changes in ventricular activation on cardiac haemodynamics in man: comparison of right ventricular, left ventricular, and simultaneous pacing of both ventricles. Br Heart J 1971;33:397– 400. 25. Little WC, Reeves RC, Arciniegas J, Katholi RE, Rogers EW. Mechanism of abnormal interventricular septal motion during delayed left ventricular activation. Circulation 1982;65:1486 –1491. 26. Hochleitner M, Hortnagl H, Ng CK, Gschnitzer F, Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198 –202. 27. Hochleitner M, Hortnagl H, Fridrich L, Gschnitzer F. Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 1992;70:1320 –1325. 28. Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995;75:919 –923. 29. Iskandrian AS, Mintz GS. Pacemaker therapy in congestive heart failure: a new concept based on excessive utilization of the Frank-Starling mechanism. Am Heart J 1986;112:867– 870. 30. Bakker PF, Meijburg H, de Jonge N, van Mechelen R, Wittkamp F, Mower M, Thomas A. Beneficial effects of biventricular pacing in congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1994;17:820. 31. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, Mundler O, Daubert JC, Mugica J. Four chamber pacing in dilated cardiomyopathy. PACE Pacing Clin Electrophysiol 1994;17:1974 –1979. 32. Cazeau S, Lazarus A, Ritter P, Gras D, Mugica J. Biventricular pacing decreases interventricular but not intraventricular asynchrony in multisite-paced patients for congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1998;21:792. 33. Saxon LA, Cahalan MK, Merrick SH, Kalman JM, Foster E, Shinbane JS. Effects of multi-site ventricular pacing in dilated cardiomyopathy (abstract). PACE Pacing Clin Electrophysiol 1999;19:641. 34. Breithardt OA, Stellbrink C, Diem B, Franke A, Salo R, Auricchio A, Hanrath P. Chronic multisite pacing leads to reduced left ventricular volumes in selected patients with congestive heart failure (abstract). Eur Heart J 1999;20:3. 35. Stellbrink C, Breithardt OA, Diem B, Franke A, Pochet T, Salo R, Auricchio A. Acute effects of multisite pacing with different AV delays on diastolic and systolic function in congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1999;22:829. 36. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Mortensen P, Klein H. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83(suppl 5B):130D–135D. 37. Levine TB, Levine AB, Bolenbaugh J, Stomel RJ. Impact of left ventricular size on pharmacological reverse remodeling in heart failure (abstract). Circulation 1999;100:I-678.
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137K
MD,
Dilated cardiomyopathy is frequently associated with electrical conduction disturbances. Development of left bundle-branch block with discoordinated ventricular contraction pattern further contributes to impaired hemodynamic performance. Biventricular pacing has evolved as a new treatment option for patients with dilated cardiomyopathy and conduction disturbances. The “electrical” approach aims to normalize the disturbed contraction pattern, thereby improving hemodynamic function by simultaneous stimulation at different ventricular sites. Acute hemodynamic improvement with biventricular pacing has been demonstrated in patients with depressed left ventricular function and delayed
intraventricular conduction. Due to the variations in optimal pacing site and atrioventricular delay, individual optimization to achieve optimal hemodynamic benefit is necessary. Echocardiography has the potential to provide hemodynamic data by Doppler techniques and combine these with geometric information about ventricular volumes, ejection fraction, and contraction patterns. This article focuses on the use of echocardiographic techniques for noninvasive optimization in cardiac pacing and presents preliminary experience from the initial trials on multisite pacing in heart failure. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;86(suppl):133K–137K
ilated cardiomyopathy of ischemic and idiopathic origin is frequently associated with electrical D conduction disturbances. Development of bundle-
mal hemodynamic benefit. Only few patients seem to benefit from conventional right ventricular apical pacing, mostly those with conduction disturbances of the right bundle-branch block type.4 There is substantial need to simplify optimization of pacing site and right ventricular delay noninvasively. Echocardiographic methods may reveal important hemodynamic data by Doppler techniques and combine these with geometric information about ventricular volumes, ejection fraction, and contraction patterns. This article focuses on the use of echocardiographic techniques for noninvasive optimization in cardiac pacing and presents preliminary experience from the first trials on multisite pacing in heart failure.
branch block indicates progression of the disease and is associated with poorer prognosis.1 The discoordinated ventricular contraction pattern further contributes to impaired hemodynamic performance with reduced peak positive left ventricular dP/dt and prolongation of isovolumetric relaxation and contraction time intervals.2,3 Recently, biventricular pacing has evolved as a new treatment option for patients with dilated cardiomyopathy and conduction disturbances. The “electrical” approach aims to normalize the disturbed contraction pattern, thereby improving hemodynamic function by simultaneous stimulation at different ventricular sites. Invasive studies have demonstrated acute hemodynamic improvement in patients with depressed left ventricular function and delayed intraventricular conduction4,5 and concluded that leftventricular– based pacing (left ventricular or biventricular pacing) is the superior pacing modality in most patients with left bundle-branch block. However, it has also become clear that the optimal pacing site and atrioventricular delay show considerable variation that requires individual optimization to achieve optiFrom the Department of Cardiology, RWTH University of Technology, Aachen, Germany; Department of Cardiology, Otto-von-Guericke University, Magdeburg, Germany; Guidant CRM Research, Brussels, Belgium; Department of Cardiology, University Hospital, Essen, Germany; and Department of Cardiac Surgery, University Hospital, Utrecht, the Netherlands. Address for reprints: Ole A. Breithardt, MD, Medizinische Klinik I der RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. ©2000 by Excerpta Medica, Inc. All rights reserved.
NONINVASIVE OPTIMIZATION OF ATRIOVENTRICULAR DELAY Soon after the introduction of programmable dualchamber pacemakers, several studies examined the hemodynamic benefit of sequential atrioventricular pacing by using noninvasive Doppler echocardiography.6 – 8 Beat-to-beat changes in stroke volume were analyzed by measurement of Doppler velocity-time integrals (VTI) across the aortic valve to identify patients who benefited most from synchronized DDD pacing as compared with conventional VVI pacing.9 Doppler-derived cardiac output was shown to be 14 – 30% higher with DDD pacing than in the VVI mode, especially in patients with retrograde ventriculoatrial conduction or clinical signs of pacemaker syndrome. Analysis of transmitral flow patterns by pulsed-wave Doppler echocardiography gave further insights into the role of atrial contribution to left ventricular filling. 0002-9149/00/$ – see front matter PII S0002-9149(00)01193-0
133K
Von Bibra et al10 demonstrated that the mitral valve closes earlier with increasing atrioventricular intervals, whereas the onset of left ventricular systole and the timing of mitral-valve opening remained unchanged. Shorter atrioventricular delays led to a significant prolongation of diastolic filling time and an increase in left ventricular filling volume as an indication for improved cardiac performance.11 Atrial filling fraction, calculated as the ratio between early (E) and late (A) diastolic filling wave, is progressively reduced with shorter atrioventricular delays.12 This is explained by the later occurrence of atrial systole in the cardiac cycle, leaving less volume for the atrial “kick.” At rest, a mean atrioventricular delay around 140 – 150 msec with significant interindividual variation was determined in several independent studies as the optimal interval for the majority of patients with DDD pacing.11,13,14 However, increasing heart rates at exercise and sensed P-waves (VDD) may require shorter atrioventricular delays for optimizing filling time and cardiac output calculated by pulsed-wave Doppler VTI.12,15 M-mode echocardiographic results from a small study on 7 patients with complete heart block and normal left ventricular function suggested that the individual optimum atrioventricular delay is determined by the timing between mitral valve opening and the onset of septal contraction.16 The largest increase in stroke volume was found at the atrioventricular delay in which ventricular contraction takes place between the peaks of the A wave and the end of transmitral flow about 30 msec later. Similar results have been obtained by the application of Doppler tissue imaging for atrioventricular delay optimization in patients with DDD right ventricular pacemakers. Doppler tissue imaging records low-velocity, highintensity signals reflected from the myocardium and measures the regional velocities of myocardial wall motion by pulsed-wave Doppler. Gessner et al17 compared regional Doppler tissue-imaging time intervals at the septum and the posterior wall with conventional parameters of global left ventricular function. They concluded that the atrioventricular delay should be set to obtain a normal interval of 70 – 80 msec between the end of regional A wave measured by Doppler tissue imaging and the onset of the subsequent regional S wave by Doppler tissue imaging. This regional interval roughly corresponds to the isovolumetric contraction time. Ritter et al18 have proposed a simple formula for noninvasive echocardiographic determination of the individual optimal atrioventricular delay in DDD pacing. However, this approach has not yet been validated with invasive hemodynamic measurements. Ishikawa et al19 recently evaluated a similar approach with phonocardiography to measure the interval from cessation of the A wave to complete closure of the mitral valve. Optimal atrioventricular delay was found at the setting at which the end of the atrial contribution to left ventricular filling coincides with complete mitral valve closure. In summary, consistent acute changes in routine 134K THE AMERICAN JOURNAL OF CARDIOLOGY姞
echocardiographic parameters have been found only for diastolic filling time and stroke volume derived from aortic VTI. However, there are no clear guidelines available on how to combine these parameters for atrioventricular delay optimization. Most studies simply identified the optimal atrioventricular delay by the increase in aortic VTI-derived stroke volume; other authors emphasize the importance of an increase in left ventricular diastolic filling time.20,21 No longterm experience about the prognostic value of this approach is yet available. The value of pulsed-wave Doppler tissue imaging still needs to be confirmed.
PACING FOR HEART FAILURE Soon after the introduction of cardiac pacing, several early trials studied the effect of alternate pacing sites on hemodynamics in normal and diseased ventricles,22–24 but results were inconsistent. Combined echocardiographic and hemodynamic studies clarified the pathophysiologic changes that are responsible for the frequently observed abnormal septal motion in patients with right ventricular pacing, intrinsic left bundle-branch block or type B Wolff-ParkinsonWhite syndrome.25 The “paradoxical” septal contraction pattern was normalized by additional stimulation from the left ventricular free wall, which resulted in advanced left ventricular contraction and a normalization of the transseptal pressure gradient. Despite these promising observations, which stress the importance of pacing site, the early clinical trials focused on AV delay optimization in right ventricular DDD pacing to improve hemodynamic function. These trials included only patients with underlying bradyarrhythmias. Most of the included patients were characterized by normal to only moderately depressed left ventricular performance. Hochleitner et al26 were the first to implant DDD pacemakers with the intention of treating patients with advanced heart failure. They used conventional DDD pacing at the right ventricular apex with a short atrioventricular delay of 100 msec in patients with advanced, drug-resistant heart failure of exclusively nonischemic etiology. Shortand long-term results after implantation demonstrated progressive improvement in various clinical and echocardiographic parameters. Echocardiographic dimensions of left ventricular chambers including the left atrium decreased progressively up to 2 years after implant with a concomitant slight, but nonsignificant increase in fractional shortening as assessed by Mmode echocardiography.27 However, at 5-year followup, 10 of 13 patients in this series had died, 4 additional patients received a donor heart, and median survival time was only 22 months. Although they did not report ventricular conduction delays as inclusion criteria, their patients showed a long mean PR interval of 200 msec and about half of the patients presented with intraventricular conduction delay of left bundle-branch block morphology. These important baseline characteristics may help to explain the conflicting negative results in subsequent trials. Linde et al28 included 10 patients with shorter mean intrinsic PR interval and almost exclusively normal
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FIGURE 1. Acute changes in aortic and mitral velocity-time integrals (VTI) with pacing depending on the atrioventricular (AV) delay and plotted against pacing site. Tested AV delays (in milliseconds ⴞ SD) were individually defined in relation to the intrinsic PR interval5—in hemodynamic responders, the optimal AV delay and the 2 adjacent AV delays; in hemodynamic nonresponders, the 3 longest AV delays. BV ⴝ biventricular pacing, IC ⴝ intrinsic conduction; LV ⴝ left ventricular pacing; RV ⴝ right ventricular pacing.
QRS width, only 1 patient had a left bundle-branch block morpholgy. In addition, 70% of patients included had coronary artery disease. Left ventricular volumes assessed by echocardiography did not change significantly, but there was a trend toward longer diastolic filling time and a slight reduction in left atrial size with pacing at an atrioventricular interval optimized by echocardiographic derived stroke volume. It appeared that the presence of interventricular conduction disturbances— defined by QRS prolongation and associated with left ventricular asynergy is an important determinant for improvement with pacing, as was already proposed in 1986 in an editorial by Iskandrian and Mintz.29
VENTRICULAR RESYCHRONIZATION WITH MULTISITE PACING These early studies were limited to modification of atrioventricular timing with alteration of the programmed atrioventricular delay. More recent studies aimed at changing the activation sequence of the left ventricle to reverse the frequently observed asynchronous contraction pattern in patients with bundlebranch block by the addition of left ventricular pacing sites. Inter- and intraventricular conduction delays have been shown earlier to impair ventricular performance2 and are associated with poor prognosis.1 The very first clinical results of biventricular pacing with an epicardial, left ventricular pacing site were reported in 1994.30 Cazeau et al31 demonstrated improved ventricular resynchronization by angioscintigraphy with
4-chamber (biatrial– biventricular) DDD pacing in a case study. Subsequent studies performed extensive acute invasive measurements in heart failure patients with long atrioventricular interval and prolonged QRS complex. Bi- and left ventricular pacing improved parameters of left ventricular contractile function such as stroke work, peak positive left ventricular dP/dt, and pulse pressure.4,5 Left ventricular pacing was achieved either with a temporary pacing electrode advanced into the epicardial veins via the coronary sinus4 or with permanent epicardial electrodes implanted through a small thoracotomy.5 Echocardiographic results for multisite pacing are still sparse and only preliminary data have been reported.32–35 However, the early results indicate favorable effects on echocardiographic parameters of left ventricular function compared with conventional pacing. A positive effect on the interventricular conduction delay has been reported with the use of Doppler echocardiographic measurements. Biventricular pacing reduced the left ventricular pre-ejection delay between the onset of QRS and the onset of left ventricular systolic flow at the outflow tract and thus improved interventricular synchrony.32 Acute improvement in transesophageal left ventricular fractional area change of ⬎30% was reported in 6 open-chest patients before cardiac surgery with biventricular apical pacing.33 Hyperkinesis of anterior segments as assessed by qualitative analysis of 2-dimensional wall motion was obA SYMPOSIUM: ELECTRICAL THERAPIES FOR THE HEART
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FIGURE 2. Pulsed-wave mitral inflow Doppler spectrum in a patient with left bundle-branch block (LBBB) (left) and with biventricular pacing at 70 milliseconds (ms) atrioventricular delay (right). Biventricular (BV) pacing with a short atrioventricular delay results in prolonged mitral filling time (450 vs 298 ms) and E-wave decleration time (190 ms vs 145 ms). Velocity-time integral of E wave and A wave is increased with BV pacing (21.4 vs 17.8 cm), whereas the E:A wave ratio decreased.
served only with biventricular apical pacing and not with conventional right ventricular apical or right ventricular outflow tract pacing alone. Promising results are reported in early experience from the Pacing Therapies for Congestive Heart Failure (PATH-CHF) study, the first controlled and randomized study on multisite pacing for heart failure, which included 42 patients between 1996 and 1998.36 Heart failure patients with New York Heart Association (NYHA) functional class III–IV cardiac failure with significant conduction delays, including long PR intervals ⬎150 msec and bundle-branch block (QRS ⬎120 msec), were selected to undergo implantation of 2 separate DDD pacemakers. An epicardial lead was implanted by limited thoracotomy on the left ventricular free wall to allow right ventricular apical, left ventricular free wall, and biventricular pacing at various atrioventricular delays. For biventricular pacing the second pacemaker was triggered by the pacing spike of the leading device (VVT mode). Individual optimal pacing configuration was selected according to the results of invasive hemodynamic testing during implantation with measurement of peak positive dP/dt and pulse pressure.36 Improvements in conventional echocardiographic parameters such as aortic and mitral VTI (as indices for stroke volume) by continuous and pulsed-wave Doppler in the mitral inflow profile (Figure 1) were measured not only with shorter atrioventricular delays, but also depending on pacing site. Left ventricular– based pacing (left ventricular and biventricular) resulted in a consistent trend toward higher stroke volume compared with no pacing or right ventricular apical pacing.35 The same relation was observed for diastolic filling time (Figure 2). Comparison of end-diastolic volumes assessed by biplane 2-dimensional echocardiography between inclusion and 6 months postimplantation showed only a slight decrease in the total population. However, more than half of the patients decreased by ⬎10% from 136K THE AMERICAN JOURNAL OF CARDIOLOGY姞
baseline and heart size increased by ⬎10% in only a few patients.34 An important finding is that the chronic response to optimized pacing is not predicted by the acute hemodynamic response. In this preliminary experience some of the patients with the largest increase in peak positive dP/dt at optimized pacing did not respond to long-term pacing in terms of volumes, but showed increasing heart size. Mean end-diastolic volume before implantation was significantly higher in these patients compared with the total population and may help to explain the lack of improvement despite impressive acute benefit. Similar lack of improvement in very large hearts has recently been reported for drug treatment of congestive heart failure.37
CONCLUSION Modern pacing techniques can help to resynchronize ventricular activation sequences in patients with disturbed intraventricular conduction. Echocardiography as a noninvasive imaging technique may identify pacemaker patients with impaired hemodynamic performance and help to optimize the atrioventricular delay. Although beneficial effects on noninvasive parameters of hemodynamic performance have been demonstrated in several studies, no consensus exists yet on the optimization algorithm. In recent years, interest has focused on the alteration of ventricular contraction patterns by additional stimulation of left ventricular sites. Whereas pacing in normal hearts without intraventricular conduction disturbances may induce asynchrony, left-ventricular– based pacing may help to normalize abnormal contraction patterns, which are frequently observed in patients with cardiomyopathies and bundle-branch block. At present, this approach requires individual optimization protocols. Invasive studies have demonstrated acute hemodynamic improvement with optimized multisite pacing. However, only short-term experience is available and prognostic data still limited. Whether ventricular re-
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synchronization helps to improve cardiac performance in the long-term is still to be determined, but preliminary echocardiographic results are promising. Doppler echocardiography in combination with 2-dimensional analysis of contraction patterns provides a widely available technique for noninvasive optimization for multisite pacing in heart failure patients. 1. Kelly TL, Cremo R, Nielsen C, Shabetai R. Prediction of outcome in late-stage
cardiomyopathy. Am Heart J 1990;119:1111–1121. 2. Xiao HB, Brecker SD, Gibson DG. Effects of abnormal activation on the time
course of the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403– 407. 3. Xiao HB, Lee CH, Gibson DG. Effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443– 447. 4. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567– 1573. 5. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein H, Kramer A, Ding J, Salo R, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure: The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993–3001. 6. Schuster AH, Nanda NC. Doppler echocardiography and cardiac pacing. PACE Pacing Clin Electrophysiol 1982;5:607– 612. 7. Fagrell B, Lindvall K. Non-invasive beat-to-beat analysis of stroke volume and digital pulse volume in patients with complete heart block and artificial pacing. Acta Med Scand 1979;205:185–190. 8. Reiter MJ, Hindman MC. Hemodynamic effects of acute atrioventricular sequential pacing in patients with left ventricular dysfunction. Am J Cardiol 1982;49:687– 692. 9. Stewart WJ, Dicola VC, Harthorne JW, Gillam LD, Weyman AE. Doppler ultrasound measurement of cardiac output in patients with physiologic pacemakers: effects of left ventricular function and retrograde ventriculo-atrial conduction. Am J Cardiol 1984;54:308 –312. 10. Von Bibra H, Wirtzfeld A, Hall R, Ulm K, Blo¨mer H. Mitral valve closure and left ventricular filling time in patients with VDD pacemakers: assessment of the onset of left ventricular systole and the end of diastole. Br Heart J 1986;55: 355–363. 11. Iwase M, Sotobata I, Yokota M, Takagi S, Jing HX, Kawai N, Hayashi H, Murase M. Evaluation by pulsed Doppler echocardiography of the atrial contribution to left ventricular filling in patients with DDD pacemakers. Am J Cardiol 1986;58:104 –109. 12. Pearson AC, Janosik DL, Redd RR, Buckingham TA, Blum RI, Labovitz AJ. Doppler echocardiographic assessment of the effect of varying atrioventricular delay and pacemaker mode on left ventricular filling. Am Heart J 1988;115:611– 621. 13. Faerestrand S, Ohm OJ. A time-related study of the hemodynamic benefit of atrioventricular synchronous pacing evaluated by Doppler echocardiography. PACE Pacing Clin Electrophysiol 1985;8:838 – 848. 14. Forfang K, Otterstad JE, Ihlen H. Optimal atrioventricular delay in physiological pacing determined by Doppler echocardiography. PACE Pacing Clin Electrophysiol 1986;9:17–20. 15. Mehta D, Gilmour S, Ward DE, Camm AJ. Optimal atrioventricular delay at rest and during exercise in patients with dual chamber pacemakers: a noninvasive assessment by continuous wave Doppler. Br Heart J 1989;61:161–166. 16. Leonelli FM, Wang K, Youssef M, Hall R, Brown D. Systolic and diastolic effects of variable atrioventricular delay in patients with complete heart block and normal ventricular function. Am J Cardiol 1997;80:294 –298. 17. Gessner M, Blazek G, Kainz W, Gruska M, Gaul G. Application of pulsedDoppler tissue imaging in patients with dual chamber pacing: the importance of conduction time and AV delay on regional left ventricular wall dynamics. PACE Pacing Clin Electrophysiol 1998;21:2273–2279.
18. Ritter P, Dib JC, Mahaux V, Lelie`vre T, Soyeur D, Lavergne T, Cazeau S, Guize L, Rabine LM, Daubert JC. New method for determining the optimal atrio-ventricular delay in patients paced in DDD mode for complete atrioventricular block (abstract). PACE Pacing Clin Electrophysiol 1995;18:855. 19. Ishikawa T, Sumita S, Kimura K, Kikuchi M, Kosuge M, Kuji N, Endo T, Sugano T, Sigemasa T, Kobayashi I, Tochikubo O, Usui T. Prediction of optimal atrioventricular delay in patients with implanted DDD pacemakers. PACE Pacing Clin Electrophysiol 1999;22:1365–1371. 20. Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995;25:281–288. 21. Brecker SJ, Xiao HB, Sparrow J, Gibson DG. Effects of dual-chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992;340: 1308 –1312. 22. Benchimol A, Liggett MS. Cardiac hemodynamics during stimulation of the right atrium, right ventricle, and left ventricle in normal and abnormal hearts. Circulation 1966;33:933–944. 23. Chamberlain DA, Leinbach RC, Vassaux CE, Kastor JA, DeSanctis RW, Sanders CA. Sequential atrioventricular pacing in heart block complicating acute myocardial infarction. N Engl J Med 1970;282:577–582. 24. Gibson DG, Chamberlain DA, Coltart DJ, Mercer J. Effect of changes in ventricular activation on cardiac haemodynamics in man: comparison of right ventricular, left ventricular, and simultaneous pacing of both ventricles. Br Heart J 1971;33:397– 400. 25. Little WC, Reeves RC, Arciniegas J, Katholi RE, Rogers EW. Mechanism of abnormal interventricular septal motion during delayed left ventricular activation. Circulation 1982;65:1486 –1491. 26. Hochleitner M, Hortnagl H, Ng CK, Gschnitzer F, Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198 –202. 27. Hochleitner M, Hortnagl H, Fridrich L, Gschnitzer F. Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 1992;70:1320 –1325. 28. Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995;75:919 –923. 29. Iskandrian AS, Mintz GS. Pacemaker therapy in congestive heart failure: a new concept based on excessive utilization of the Frank-Starling mechanism. Am Heart J 1986;112:867– 870. 30. Bakker PF, Meijburg H, de Jonge N, van Mechelen R, Wittkamp F, Mower M, Thomas A. Beneficial effects of biventricular pacing in congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1994;17:820. 31. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, Mundler O, Daubert JC, Mugica J. Four chamber pacing in dilated cardiomyopathy. PACE Pacing Clin Electrophysiol 1994;17:1974 –1979. 32. Cazeau S, Lazarus A, Ritter P, Gras D, Mugica J. Biventricular pacing decreases interventricular but not intraventricular asynchrony in multisite-paced patients for congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1998;21:792. 33. Saxon LA, Cahalan MK, Merrick SH, Kalman JM, Foster E, Shinbane JS. Effects of multi-site ventricular pacing in dilated cardiomyopathy (abstract). PACE Pacing Clin Electrophysiol 1999;19:641. 34. Breithardt OA, Stellbrink C, Diem B, Franke A, Salo R, Auricchio A, Hanrath P. Chronic multisite pacing leads to reduced left ventricular volumes in selected patients with congestive heart failure (abstract). Eur Heart J 1999;20:3. 35. Stellbrink C, Breithardt OA, Diem B, Franke A, Pochet T, Salo R, Auricchio A. Acute effects of multisite pacing with different AV delays on diastolic and systolic function in congestive heart failure (abstract). PACE Pacing Clin Electrophysiol 1999;22:829. 36. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Mortensen P, Klein H. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83(suppl 5B):130D–135D. 37. Levine TB, Levine AB, Bolenbaugh J, Stomel RJ. Impact of left ventricular size on pharmacological reverse remodeling in heart failure (abstract). Circulation 1999;100:I-678.
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