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Extent of myocardial viability predicts response to biventricular pacing in ischemic cardiomyopathy
Extent of myocardial viability predicts response to biventricular pacing in ischemic cardiomyopathy James P. Hummel, MD,a Jonathan R. Lindner, MD,a J. Todd Belcik, BS, RDCS,a John D. Ferguson, BM, BCh,a J. Michael Mangrum, MD,a James D. Bergin, MD,a David E. Haines, MD,b Douglas E. Lake, PhD,a John P. DiMarco, MD, PhD,a J. Paul Mounsey, BM, BCh, PhDa a
From the Cardiovascular Division, University of Virginia School of Medicine, Charlottesville, Virginia, and The Heart Rhythm Center, Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan.
b
BACKGROUND The clinical response to biventricular pacing is unpredictable, especially in patients with ischemic cardiomyopathy. OBJECTIVES The purpose of this study was to prospectively examine the relationship between the extent of myocardial viability and the response to cardiac resynchronization therapy. METHODS Twenty-one patients with ischemic left ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF] 21 ⫾ 5%), New York Heart Association (NYHA) functional class III–IV, and QRS ⬎120 ms received biventricular devices. Myocardial viability was assessed by myocardial contrast echocardiography, and a perfusion score index (PSI) was calculated from summed segmental perfusion scores. LV performance was assessed by echocardiography on the day after implantation and at 6 months. RESULTS PSI was closely correlated with acute improvement in LVEF (P ⫽ .003, r ⫽ 0.65), stroke volume (P ⫽ .02, r ⫽ 0.54), and end-systolic volume (P ⫽ .05, r ⫽ ⫺0.49). PSI also correlated with early diastolic LV relaxation (E=, P ⬍ .05, r ⫽ 0.50) and global myocardial performance or Tei index (P ⫽ .003, r ⫽ 0.63). By multiple linear regression analysis, PSI provided incremental predictive value to the degree of dyssynchrony, measured by tissue Doppler imaging, for predicting improvement in LVEF. At 6 months, PSI remained positively correlated with improvement in ventricular performance and with reduction in LV end-diastolic dimension (P ⫽ .003, r ⫽ ⫺0.68). PSI also influenced the clinical variables of NYHA class, 6-minute walk distance, quality-of-life score, and number of hospitalizations for heart failure. CONCLUSION In patients with ischemic cardiomyopathy, the extent of myocardial viability predicts acute and long-term improvement in LV performance, exercise tolerance, and reduction in LV end-diastolic dimension with biventricular pacing. KEYWORDS Conduction; Echocardiography; Heart failure; Pacemakers (Heart Rhythm 2005;2:1211–1217) © 2005 Heart Rhythm Society. All rights reserved.
Introduction Intraventricular conduction delay is common in patients with dilated cardiomyopathies and can result in inefficient contraction and reduced ventricular performance. Biventricular cardiac pacing improves mechanical synchrony and can improve systolic function, hemodynamic parameters,
Address reprint requests and correspondence: Dr. James P. Hummel, Box 800158, Cardiovascular Division, University of Virginia Medical Center, Charlottesville, Virginia 22908. E-mail address: [email protected]. (Received January 5, 2005; accepted July 27, 2005.)
heart failure symptoms, and mortality.1–3 Up to one third of patients with congestive heart failure and QRS duration ⬎120 ms, however, do not clinically improve after cardiac resynchronization therapy (CRT).1 The factors that influence whether patients will respond to therapy are not completely understood. It has been shown that improvement in systolic performance and symptoms with CRT is less likely in patients with a history of previous myocardial infarction.4 Because electrical conduction and regional wall thickening are influenced by the extent of myocardial fibrosis, we hypothesized that the response to CRT would correlate with myocardial viability in patients with ischemic left ventricular (LV) dysfunction.
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doi:10.1016/j.hrthm.2005.07.027
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Methods
Heart Rhythm, Vol 2, No 11, November 2005 derived by dividing the summed scores by the number of interpretable segments.
Subjects The study protocol was approved by the Human Investigation Committee at the University of Virginia. All patients gave informed consent. Patients with ischemic cardiomyopathy (left ventricular ejection fraction [LVEF] ⬍35%), New York Heart Association (NYHA) class III–IV heart failure symptoms on optimal medical therapy, and QRS duration ⬎120 ms on surface ECG were enrolled. Patients with both left and right bundle branch block patterns, and those who were chronically pacemaker dependent, were included in the study. Ischemic cardiomyopathy was defined as documented coronary artery disease with segmental LV dysfunction and no other reasons for cardiomyopathy. Patients with hemodynamic instability, atrial fibrillation, and rapid ventricular response requiring AV junction ablation, severe aortic or mitral valvular disease, poor acoustic windows, or intracardiac shunts were excluded. Patients with recent (⬍3 months) unstable angina, acute coronary syndrome, or coronary revascularization also were excluded.
Device placement All patients underwent implantation of a biventricular pacemaker or defibrillator (Medtronic models 8040, 7272 and 8042, Medtronic, Inc., Minneapolis, MN, USA; Guidant models 1823 and H135, Guidant Corp., St. Paul, MN) using standard techniques. Only patients with a lateral or posterolateral LV transvenous lead placement were accepted for inclusion in the study. Patients in sinus rhythm received a right atrial pacing lead.
Myocardial contrast echocardiography Myocardial contrast echocardiography was performed to determine the extent of myocardial viability. Intermittent ultraharmonic imaging (Sonos 5500, Philips Ultrasound, Andover, MA) was performed at a transmission frequency of 1.3 MHz at the maximal mechanical index. Images were acquired in the apical two-, three-, and four-chamber views. Gain settings were optimized and kept constant. For contrast enhancement, 1 mL of Definity microbubbles (Bristol-Myers Squibb Imaging, Billerica, MA) were diluted in 29 mL saline and infused intravenously at 1.0 –1.4 mL · min⫺1 to produce optimal opacification without far-field attenuation. End-systolic images were acquired at pulsing intervals of every 1 to 10 cardiac cycles. Blinded analysis of echocardiographic data was performed by an experienced reader. Each interpretable segment was assigned a perfusion score based on the change in myocardial signal intensity with prolongation of the pulsing interval and the degree of opacification at the longest pulsing interval, as previously described.5 Scores were graded as follows: 2 ⫽ normal, 1 ⫽ reduced, 0 ⫽ absent.5 A perfusion score index (PSI) was
Two-dimensional and Doppler echocardiography protocols Echocardiographic indices of LV performance were assessed on the day after device placement, during and without biventricular pacing. For patients who were pacemaker dependent, comparisons were made between right ventricular and biventricular pacing. All echocardiographic parameters were reassessed 6 months after pacemaker implantation. Transmitral Doppler was used to select the shortest AV delay that did not truncate the A wave. End-diastolic volume, end-systolic volume, and ejection fraction (averaged from the apical two- and four-chamber views) were determined using automated border tracking software during LV cavity opacification or by biplane Simpson rule. In this study, the mean relative interobserver variation for volumes and ejection fraction by these methods was 12% and 10%, respectively. The intraobserver variation was 8% for both ejection fraction and volumes. The Tei index, which reflects combined systolic and diastolic performance, was calculated from pulsed-wave Doppler recordings of transmitral flow velocity by the sum of the isovolumic contraction and relaxation times divided by LV ejection time.6 Peak early diastolic mitral annular velocity (E=) was measured at the septum using spectral tissue Doppler. Tissue Doppler imaging also was used to determine the degree of dyssynchrony, quantified by the difference in the time from QRS onset to peak systolic velocities for septal vs lateral basal segments.7
Clinical evaluation of patients At baseline and at 6 months, patients were evaluated according to the distance walked in 6 minutes, quality of life as assessed using the Minnesota Living with Heart Failure questionnaire, NYHA classification, and the number of hospitalizations for congestive heart failure in the preceding 6-month period. Six-minute hall walk was conducted in a 25-m corridor using guidelines previously described.8 The Minnesota Heart Failure questionnaire consists of 21 questions assessing the severity (on a scale from 0 –5) of heart failure symptoms over the preceding month.9
Statistical analysis Data are expressed as mean ⫾ SD. Responses to biventricular pacing were made using the paired Student’s t-test. Comparisons between groups were assessed using unpaired analysis. Correlations were analyzed with regression analysis, and data were curve fitted using a least-squares fit. Multiple linear regression analysis was performed to deter-
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mine incremental predictive value using adjusted r values. P ⬍ .05 was considered significant.
Results Echocardiographic data were collected prospectively in 21 patients the day after biventricular pacemaker placement. Two patients were excluded from analysis. One had inadequate acoustic windows to evaluate perfusion, and the other had potentially severe aortic stenosis. The baseline characteristics of the remaining 19 patients are given in Table 1. There was no significant correlation between any baseline characteristic and either improvement in echocardiographic parameters or PSI. The PSI was averaged from the summed scores of 13.0 ⫾ 1.5 (mean ⫾ SD) of 15 possible segments that could be analyzed by myocardial contrast echocardiography in the apical views. Examples of background-subtracted color-coded myocardial contrast echocardiography images in two patients are shown in Figure 1. Five patients in this study were chronically pacemaker dependent and were upgraded from right ventricular to biventricular pacing. There were no significant differences in any clinical characteristics between this group and those with bundle branch block. The two groups had similar PSI and acute improvement in ventricular performance after CRT.
Acute changes in measures of systolic and diastolic function Acute improvements in LVEF and stroke volume were significantly correlated with the degree of viability, determined by PSI (Figure 2). The PSI also correlated well with improvement in early diastolic mitral annular velocity (E=), Table 1
Figure 1 Background-subtracted color-coded myocardial contrast echocardiographic apical four-chamber view of the left ventricle showing examples from a patient with preserved viability (A) and with poor viability (B). Images are shown at the longest pulsing interval.
a measure of early diastolic relaxation, and the Tei index, a measure of combined systolic and diastolic performance (Figure 2). Correlations of borderline significance also were found between the PSI and changes in end-systolic volume (r ⫽ ⫺0.37, P ⫽ .12) and dP/dT (r ⫽ 0.50, P ⫽ .08) with CRT. There was no relation between PSI and acute reduction in end-diastolic volume (r ⫽ ⫺0.09, P ⫽ NS).
Improvement in LV performance, remodeling, and clinical status at 6 months Two patients died suddenly during the 6-month study period, one of apparent sudden cardiac death and the other of a ruptured abdominal aortic aneurysm. Among the remaining 17 patients who completed follow-up at 6 months, there was improvement in cardiac performance as assessed by
Baseline characteristics
Age (years) Male gender New York Heart Association functional class III IV Left ventricular ejection fraction QRS duration (ms) ECG pattern Left bundle branch block Right bundle branch block Right ventricular paced Rhythm Sinus rhythm Atrial fibrillation Previous coronary artery bypass graft Medical therapy Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Beta-blocker Digoxin Spironolactone Perfusion score index
67.8 ⫾ 10.4 16 (84%) 15 (79%) 4 (21%) 22.0 ⫾ 5.1 152 ⫾ 26 12 (63%) 2 (11%) 5 (26%) 17 (89%) 2 (11%) 11 (63%)
19 (100%) 12 (63%) 12 (63%) 11 (58%) 1.24 ⫾ 0.37
Figure 2 Relationships between perfusion score index and the acute change in (A) left ventricular ejection fraction (EF), (B) stroke volume (SV), (C) peak early diastolic mitral annular velocity (E=), and (D) Tei index.
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Heart Rhythm, Vol 2, No 11, November 2005 The 17 patients who completed 6-month follow-up were divided into tertiles based on global PSI (Table 2). Patients with higher PSI tended to have greater improvement in NYHA class, 6-minute hall walk distance, Minnesota Living with Heart Failure quality-of-life score, and number of hospitalizations for heart failure. End-diastolic left ventricular internal dimension measured in the parasternal long axis was used as a marker of positive remodeling after biventricular pacing. The 6-month reduction in LV internal dimension was closely correlated with the degree of viability (P ⫽ .003, r ⫽ 0.68; Figure 4). No significant decrease in LV internal dimension was observed in patients with poor global viability (PSI ⬍1.0).
Effect of regional viability
Figure 3 Relationships between perfusion score index (PSI) and the change at 6 months in (A) left ventricular ejection fraction (EF), (B) stroke volume (SV), (C) peak early diastolic mitral annular velocity (E=), and (D) Tei index.
ejection fraction (mean 4.1 ⫾ 5.9%, range ⫺7.3 to 12.7), E= (0.94 ⫾ 1.50 cm/s, range ⫺2.3 to 3.5), and the Tei index (⫺0.13 ⫾ 0.11, range ⫺0.28 to 0.01). The ratio of transmitral E-wave velocity to E=, an index of the status of LV preload, was not significantly different between the acute and 6-month follow-up study on paired analysis (P ⫽ .93). These improvements were associated with improvements in 6-minute hall walk distance (202 ⫾ 176 ft, range ⫺40 to 560), Minnesota Living with Heart Failure quality-of-life score (16.9 ⫾ 12.2 points, range ⫺4 to 38), and NYHA class (0.7 ⫾ 0.6, range 0 to 2). LVEF and stroke volume from one patient were excluded from analysis because of a significant change in heart rate (⬎40 bpm) from baseline to follow-up echocardiogram. After 6 months of biventricular pacing, the relationship between myocardial viability as assessed by PSI and the degree of improvement in measures of systolic and diastolic performance and of global myocardial performance were preserved (Figure 3).
Table 2
The effect of regional viability on LV performance was analyzed. Segments typically supplied by the left anterior descending artery were grouped as anterior segments, whereas those supplied by the right or circumflex coronary artery were considered posterior segments. The posterolateral wall segments underlying the LV lead were considered separately. The correlation coefficients for the regional viability scores for each of the echocardiographic parameters are given in Table 3. In this patient cohort, there were significant correlations between all regional viability scores and the global PSI. Therefore, it is difficult to separate the influence of regional from global viability. Nonetheless, the global viability score (PSI) predicted improvement as well as or better than the regional scores for most parameters.
Other predictors of response There was no significant correlation between any baseline characteristic from Table 1 and either improvement in echocardiographic parameters or PSI. Baseline LVEF was not significantly correlated to PSI (r ⫽ 0.19, P ⫽ NS) and was a poor predictor of acute improvement in EF (r ⫽ 0.31, P ⫽ NS) and other echocardiographic and clinical parameters. Several measures of baseline dyssynchrony and the amount of resynchronization and their relation to improvement in ventricular performance were examined. Neither baseline
Six-month improvement in clinical parameters according to tertile of myocardial viability PSI tertile Low (n ⫽ 5)
PSI ⌬ New York Heart Association class ⌬ 6-minute hall walk (ft) ⌬ QOL score ⌬ Hospitalizations for congestive heart failure
0.73 0.2 5 11.2 0.2
⫾ ⫾ ⫾ ⫾ ⫾
0.14 0.4 54 14.8 0.4
Medium (n ⫽ 6) 1.23 0.8 211 11.8 ⫺0.2
⫾ ⫾ ⫾ ⫾ ⫾
0.11 0.4 145 4.3 1.1
High (n ⫽ 6) 1.61 1.0 358 24.7 ⌬0.7
⫾ ⫾ ⫾ ⫾ ⫾
0.12 0.6 123 12.0 1.0
P value — .05 .01 .10 NS
P values from analysis of variance for continuous variables and Chi-square test for nominal variables. PSI ⫽ perfusion score index; QOL ⫽ quality of life (Minnesota Living with Heart Failure Questionnaire); ⌬ ⫽ change with cardiac resynchronization therapy.
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Figure 4 Relationship between perfusion score index and change in end-diastolic left ventricular internal dimension (LVID) at 6 months.
QRS duration (r ⫽ 0.01) nor reduction in QRS duration (r ⫽ 0.00) correlated with acute improvement in LVEF. Baseline intraventricular dyssynchrony, measured by tissue Doppler imaging as the basal wall-motion delay, and the degree of resynchronization, or amount of shortening of the basal wall-motion delay, only weakly predicted acute LVEF improvement (r ⫽ 0.12 and r ⫽ 0.34). Figure 5 shows the relation between acute change in systolic performance (LVEF) and the improvement in basal wall-motion delay. Improved mechanical synchrony resulted in improvement in LVEF only when PSI was ⬎1 (r ⫽ 0.58, P ⫽ 0.05). On multiple linear regression analysis, PSI added significant incremental value to the amount of mechanical resynchronization for predicting acute change in LVEF (r ⫽ 0.34 for resynchronization alone; r ⫽ 0.75 for PSI and resynchronization). Viability appeared to have little effect on the degree of resynchronization. There was no significant correlation between shortening of the QRS complex or basal wall-motion delay and global PSI (r ⫽ ⫺0.12, r ⫽ ⫺0.11).
Discussion CRT often improves symptoms in patients with severely reduced LVEF and intraventricular conduction delay. Symptomatic improvement is thought to be related, in part, Table 3 Correlation coefficients between regional viability and improvement in left ventricular performance
Acute ⌬ EF ⌬ SV ⌬ E= ⌬ Tei index Six Months ⌬ EF ⌬ SV ⌬ E= ⌬ Tei index
Global
Lateral
Anterior
Posterior
0.63* 0.53* 0.47 ⫺0.72*
0.54* 0.31 0.48 ⫺0.79*
0.49* 0.47* 0.36 ⫺0.54*
0.41 0.24 0.40 ⫺0.66*
0.48 0.45 0.71* ⫺0.78*
0.52* 0.24 0.33 ⫺0.84*
0.32 0.40 0.79* ⫺0.67*
0.54* 0.25 0.04 ⫺0.64*
EF ⫽ ejection fraction; SV ⫽ stroke volume; E= ⫽ early diastolic mitral annular velocity; ⌬ ⫽ change with cardiac resynchronization therapy. *P ⬍ .05.
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Figure 5 Relationships between improvement in mechanical synchrony and improvement in left ventricular ejection fraction (EF) for patients with perfusion score index (PSI) ⬍1.0 or ⱖ1.0
to improved systolic and diastolic performance. In this study, we demonstrated that, in patients with ischemic heart disease, the degree of improvement in systolic and diastolic performance is influenced by the extent of myocardial viability. Selection of patients for CRT currently is based on symptoms, LVEF, and QRS complex duration on ECG. Large clinical trials evaluating the efficacy of CRT, however, have indicated that between 25% and 30% of patients with standard indications do not show clinical improvement.1 Better selection criteria for CRT would avoid exposure to risk in patients unlikely to receive benefit and would improve resource utilization. There are several potential mechanisms by which myocardial viability may influence acute responses to biventricular pacing. Slower conduction velocities through fibrotic regions could preclude electrical resynchronization despite multisite pacing. In this study, however, we found no relation between viability and the amount of resynchronization. In fact, several patients with poor viability still were able to significantly decrease the septal to lateral wall-motion delay as assessed by tissue Doppler imaging. A second more plausible explanation is that resynchronization reverses wasted work toward cardiac output only in viable segments where some potential for wall thickening exists. Akinetic or dyskinetic regions that are largely nonviable contribute little to systolic performance, whether or not their relatively passive motion is synchronized. Accordingly, improvement in LV systolic performance did not occur when a large number of segments had a perfusion score of 0. Baseline LVEF did not predict improvement because, for patients with severely reduced systolic function, LVEF does not necessarily correlate with viability. For example, several patients in this study had preserved viability but profound LV systolic dysfunction from diffuse severe hypokinesis. Echocardiographic parameters of diastolic performance were related to viability in this study. These changes occurred acutely, eliminating the possibility of positive LV remodeling, which has been observed in selected patients. Because PSI did not necessarily correlate with improvement in synchronization, synchronization of diastole probably played a minor role. The fact that early diastolic relaxation
1216 is largely dependent upon systolic performance10 suggests that improvement in E= and Tei index was secondary to improvement in systolic performance. An alternative possibility for the findings of this study is that biventricular pacing improves systolic and diastolic performance by diminishing energy cost, which has been shown in patients with dilated cardiomyopathy.11 These effects would be expected only in tissue where myocyte viability is maintained, although this was not directly tested in this study. The amount of reverse remodeling at 6 months was highly correlated to the degree of viability. Penicka et al12 reported that positive remodeling is predicted by the degree of baseline dyssynchrony. In this study, patients with poor viability (PSI ⬍1.0) did not have significant remodeling regardless of baseline dyssynchrony. This may imply that, in patients with ischemic cardiomyopathy, resynchronization alone may not result in reverse remodeling if adequate viability is not present. We demonstrated that improvement in myocardial performance after biventricular pacing is dependent on global myocardial viability. It is possible that this result is driven by viability of the paced myocardial segment, because if this segment contains mainly scar (i.e., is not viable), conduction may be too slow to resynchronize surrounding areas. Among patients in this study, global PSI was highly correlated with viability of the lateral paced segment, so separate evaluation of the influence of lateral viability is difficult. However, global viability was a better predictor of improvement of many parameters than was lateral viability. Additionally, neither global nor lateral viability correlated well with the degree of QRS shortening or improvement in basal wall-motion delay. Therefore, it appears unlikely that the viability of the paced segment is the sole critical factor mediating the influence of viability. Future studies are needed in larger groups of patients to further assess the effects of regional viability defects. Often nonresponse is believed to occur due to lack of intraventricular resynchronization. It is clear that QRS duration is a poor indicator of intraventricular dyssynchrony of the LV. Thus, tissue Doppler measurements of baseline intraventricular synchrony are better predictors of response than QRS duration alone. In addition, patients whose latest segments to be activated are not located in the posterolateral wall may not restore intraventricular synchrony with a standard coronary sinus lead position. Thus, it has been suggested that tissue Doppler imaging should be used routinely both to screen for baseline dyssynchrony and to individualize the LV lead position to the latest activated segment.13 Various methods have been described to define the degree of LV dyssynchrony using tissue Doppler imaging in multisegmental models.14 –17 Some have not gained widespread clinical use because of their complexity and technical considerations. In this study population at our institution, for instance, there was a high interobserver variability using multisegmental models partly due to difficulty differ-
Heart Rhythm, Vol 2, No 11, November 2005 entiating actual thickening from passive motion in the failing heart. A simpler index of dyssynchrony using tissue Doppler imaging to measure the delay from peak systolic velocity in the basal septal and lateral segments has been shown to correlate with response to CRT.7,14 In our study group, there was a positive correlation between both baseline septal to lateral wall motion delay and improvement in the delay after CRT with acute improvement in function. It is important to note, however, that in this study shortening of the septal to lateral wall motion delay resulted in improved ventricular performance only in patients with good viability (PSI ⱖ1).
Study limitations The patient cohort was relatively small. However, we believe these results bring to bear a new issue that may influence clinical response to a therapy that is not without risk or cost. There was no control group that did not undergo biventricular pacemaker placement. However, this limitation does not necessarily affect our ability to test the hypothesis that the degree of myocardial viability influences clinical response to resynchronization therapy. There are several potential methodologic limitations regarding the precision of echocardiographic measurements. Echocardiographic assessment of LV volume and EF may be associated with relative intraobserver and interobserver variation of up to 10%. To address this limitation, we used automatic border tracking software during LV opacification in the majority of patients, except where limited by poor acoustic windows (in four patients). Moreover, the relative increases in ejection fraction of up to 40% observed in this study likely were not caused solely by errors in measurement, and any trends caused by these errors would be expected to be similar among all patients irrespective of myocardial viability. The Tei index, a measure of global performance, relies on measurement of the isovolumic contraction period and ejection times and probably was influenced by the change in AV delay during pacing. Again, any influence of pacing on the Tei index would be expected to affect all patients similarly because there was no relation between change in AV delay and degree of myocardial viability. Finally, the correlation between baseline dyssynchrony and the response to CRT was less than expected. It is important to note that this relation was much closer when patients with poor myocardial viability were excluded. Hence, it is reasonable to expect that patients with ischemic cardiomyopathy who have the most viability and the most dyssynchrony receive the greatest benefit from CRT.
Conclusion In this study, we demonstrated that myocardial viability is an important factor influencing improvement in ventricular performance after CRT in patients with ischemic cardiomy-
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opathy. Our data indicate that significant improvement in myocardial performance, symptoms, and ventricular remodeling can be expected only if there is both viability and improvement in mechanical synchronization.
References 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: 1845–1853. 2. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Effects of multisite pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 880. 3. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289:730 –740. 4. Reuter S, Garrigue S, Barold SS, Jais P, Hocini M, Haissaguerre M, Clementy J. Comparison of characteristics in responders versus nonresponders with biventricular pacing for drug-resistant congestive heart failure. Am J Cardiol 2002;89:346 –350. 5. Balcells E, Powers ER, Lepper W, Belcik T, Wei K, Ragosta M, Samady H, Lindner JR. Detection of myocardial viability by contrast echocardiography in acute myocardial infarction predicts recovery of resting function and contractile reserve. J Am Coll Cardiol 2003;41: 827– 833. 6. Tei C, Dujardin KS, Hodge DO, Kyle RA, Tajik AJ, Seward JB. Doppler index combining systolic and diastolic myocardial performance: clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658 – 664. 7. Bax JJ, Molhoek SG, Marwick TH, van Erven L, Voogd PJ, Somer S, Boersma E, Steendijk P, Schalij MJ, Van der Wall EE. Usefulness of myocardial tissue Doppler echocardiography to evaluate left ventricular dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 2003;91:94 –97.
1217 8. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley, SO, Taylor DW, Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. CMAJ 1985; 132:919 –923. 9. Rector RS, Kubo SH, Cohn JN. Patients’ self-assessment of their congestive heart failure: content, reliability, and validity of a new measure—the Minnesota Living with Heart Failure Questionnaire. Heart Fail 1987;3:198 –209. 10. Udelson JE, Bacharach SL, Cannon RO, Bonow RO. Minimum left ventricular pressure during -adrenergic stimulation in human subjects. Evidence for elastic recoil and diastolic “suction” in the normal heart. Circulation 1990;82:1174 –1182. 11. Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, Kass DA. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102: 3053–3059. 12. Penicka M, Bartunek J, De Bruyne B, Vanderheyden M, Goethals M, De Zutter M, Brugada P, Geelen P. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004;109:978 –983. 13. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Biventricular pacing in heart failure: back to basics in the pathophysiology of left bundle branch block to reduce the number of nonresponders. Am J Cardiol 2003;91S:55– 61. 14. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, Guida P, Andriani A, Mastropasqua F, Rizzon P. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Card 2002;40:1615–1622. 15. Sogaard P, Egeblad H, Kim WY, Jensen HK, Pedersen AK, Kristensen BO, Mortensen PT. Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J Am Coll Card 2002; 40:723–730. 16. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, Kong SL, Lam YM, Hill MR, Lau CP. Tissue Doppler echocardiography evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438 – 445. 17. Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39:194 –201.
From the Cardiovascular Division, University of Virginia School of Medicine, Charlottesville, Virginia, and The Heart Rhythm Center, Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan.
b
BACKGROUND The clinical response to biventricular pacing is unpredictable, especially in patients with ischemic cardiomyopathy. OBJECTIVES The purpose of this study was to prospectively examine the relationship between the extent of myocardial viability and the response to cardiac resynchronization therapy. METHODS Twenty-one patients with ischemic left ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF] 21 ⫾ 5%), New York Heart Association (NYHA) functional class III–IV, and QRS ⬎120 ms received biventricular devices. Myocardial viability was assessed by myocardial contrast echocardiography, and a perfusion score index (PSI) was calculated from summed segmental perfusion scores. LV performance was assessed by echocardiography on the day after implantation and at 6 months. RESULTS PSI was closely correlated with acute improvement in LVEF (P ⫽ .003, r ⫽ 0.65), stroke volume (P ⫽ .02, r ⫽ 0.54), and end-systolic volume (P ⫽ .05, r ⫽ ⫺0.49). PSI also correlated with early diastolic LV relaxation (E=, P ⬍ .05, r ⫽ 0.50) and global myocardial performance or Tei index (P ⫽ .003, r ⫽ 0.63). By multiple linear regression analysis, PSI provided incremental predictive value to the degree of dyssynchrony, measured by tissue Doppler imaging, for predicting improvement in LVEF. At 6 months, PSI remained positively correlated with improvement in ventricular performance and with reduction in LV end-diastolic dimension (P ⫽ .003, r ⫽ ⫺0.68). PSI also influenced the clinical variables of NYHA class, 6-minute walk distance, quality-of-life score, and number of hospitalizations for heart failure. CONCLUSION In patients with ischemic cardiomyopathy, the extent of myocardial viability predicts acute and long-term improvement in LV performance, exercise tolerance, and reduction in LV end-diastolic dimension with biventricular pacing. KEYWORDS Conduction; Echocardiography; Heart failure; Pacemakers (Heart Rhythm 2005;2:1211–1217) © 2005 Heart Rhythm Society. All rights reserved.
Introduction Intraventricular conduction delay is common in patients with dilated cardiomyopathies and can result in inefficient contraction and reduced ventricular performance. Biventricular cardiac pacing improves mechanical synchrony and can improve systolic function, hemodynamic parameters,
Address reprint requests and correspondence: Dr. James P. Hummel, Box 800158, Cardiovascular Division, University of Virginia Medical Center, Charlottesville, Virginia 22908. E-mail address: [email protected]. (Received January 5, 2005; accepted July 27, 2005.)
heart failure symptoms, and mortality.1–3 Up to one third of patients with congestive heart failure and QRS duration ⬎120 ms, however, do not clinically improve after cardiac resynchronization therapy (CRT).1 The factors that influence whether patients will respond to therapy are not completely understood. It has been shown that improvement in systolic performance and symptoms with CRT is less likely in patients with a history of previous myocardial infarction.4 Because electrical conduction and regional wall thickening are influenced by the extent of myocardial fibrosis, we hypothesized that the response to CRT would correlate with myocardial viability in patients with ischemic left ventricular (LV) dysfunction.
1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2005.07.027
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Methods
Heart Rhythm, Vol 2, No 11, November 2005 derived by dividing the summed scores by the number of interpretable segments.
Subjects The study protocol was approved by the Human Investigation Committee at the University of Virginia. All patients gave informed consent. Patients with ischemic cardiomyopathy (left ventricular ejection fraction [LVEF] ⬍35%), New York Heart Association (NYHA) class III–IV heart failure symptoms on optimal medical therapy, and QRS duration ⬎120 ms on surface ECG were enrolled. Patients with both left and right bundle branch block patterns, and those who were chronically pacemaker dependent, were included in the study. Ischemic cardiomyopathy was defined as documented coronary artery disease with segmental LV dysfunction and no other reasons for cardiomyopathy. Patients with hemodynamic instability, atrial fibrillation, and rapid ventricular response requiring AV junction ablation, severe aortic or mitral valvular disease, poor acoustic windows, or intracardiac shunts were excluded. Patients with recent (⬍3 months) unstable angina, acute coronary syndrome, or coronary revascularization also were excluded.
Device placement All patients underwent implantation of a biventricular pacemaker or defibrillator (Medtronic models 8040, 7272 and 8042, Medtronic, Inc., Minneapolis, MN, USA; Guidant models 1823 and H135, Guidant Corp., St. Paul, MN) using standard techniques. Only patients with a lateral or posterolateral LV transvenous lead placement were accepted for inclusion in the study. Patients in sinus rhythm received a right atrial pacing lead.
Myocardial contrast echocardiography Myocardial contrast echocardiography was performed to determine the extent of myocardial viability. Intermittent ultraharmonic imaging (Sonos 5500, Philips Ultrasound, Andover, MA) was performed at a transmission frequency of 1.3 MHz at the maximal mechanical index. Images were acquired in the apical two-, three-, and four-chamber views. Gain settings were optimized and kept constant. For contrast enhancement, 1 mL of Definity microbubbles (Bristol-Myers Squibb Imaging, Billerica, MA) were diluted in 29 mL saline and infused intravenously at 1.0 –1.4 mL · min⫺1 to produce optimal opacification without far-field attenuation. End-systolic images were acquired at pulsing intervals of every 1 to 10 cardiac cycles. Blinded analysis of echocardiographic data was performed by an experienced reader. Each interpretable segment was assigned a perfusion score based on the change in myocardial signal intensity with prolongation of the pulsing interval and the degree of opacification at the longest pulsing interval, as previously described.5 Scores were graded as follows: 2 ⫽ normal, 1 ⫽ reduced, 0 ⫽ absent.5 A perfusion score index (PSI) was
Two-dimensional and Doppler echocardiography protocols Echocardiographic indices of LV performance were assessed on the day after device placement, during and without biventricular pacing. For patients who were pacemaker dependent, comparisons were made between right ventricular and biventricular pacing. All echocardiographic parameters were reassessed 6 months after pacemaker implantation. Transmitral Doppler was used to select the shortest AV delay that did not truncate the A wave. End-diastolic volume, end-systolic volume, and ejection fraction (averaged from the apical two- and four-chamber views) were determined using automated border tracking software during LV cavity opacification or by biplane Simpson rule. In this study, the mean relative interobserver variation for volumes and ejection fraction by these methods was 12% and 10%, respectively. The intraobserver variation was 8% for both ejection fraction and volumes. The Tei index, which reflects combined systolic and diastolic performance, was calculated from pulsed-wave Doppler recordings of transmitral flow velocity by the sum of the isovolumic contraction and relaxation times divided by LV ejection time.6 Peak early diastolic mitral annular velocity (E=) was measured at the septum using spectral tissue Doppler. Tissue Doppler imaging also was used to determine the degree of dyssynchrony, quantified by the difference in the time from QRS onset to peak systolic velocities for septal vs lateral basal segments.7
Clinical evaluation of patients At baseline and at 6 months, patients were evaluated according to the distance walked in 6 minutes, quality of life as assessed using the Minnesota Living with Heart Failure questionnaire, NYHA classification, and the number of hospitalizations for congestive heart failure in the preceding 6-month period. Six-minute hall walk was conducted in a 25-m corridor using guidelines previously described.8 The Minnesota Heart Failure questionnaire consists of 21 questions assessing the severity (on a scale from 0 –5) of heart failure symptoms over the preceding month.9
Statistical analysis Data are expressed as mean ⫾ SD. Responses to biventricular pacing were made using the paired Student’s t-test. Comparisons between groups were assessed using unpaired analysis. Correlations were analyzed with regression analysis, and data were curve fitted using a least-squares fit. Multiple linear regression analysis was performed to deter-
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mine incremental predictive value using adjusted r values. P ⬍ .05 was considered significant.
Results Echocardiographic data were collected prospectively in 21 patients the day after biventricular pacemaker placement. Two patients were excluded from analysis. One had inadequate acoustic windows to evaluate perfusion, and the other had potentially severe aortic stenosis. The baseline characteristics of the remaining 19 patients are given in Table 1. There was no significant correlation between any baseline characteristic and either improvement in echocardiographic parameters or PSI. The PSI was averaged from the summed scores of 13.0 ⫾ 1.5 (mean ⫾ SD) of 15 possible segments that could be analyzed by myocardial contrast echocardiography in the apical views. Examples of background-subtracted color-coded myocardial contrast echocardiography images in two patients are shown in Figure 1. Five patients in this study were chronically pacemaker dependent and were upgraded from right ventricular to biventricular pacing. There were no significant differences in any clinical characteristics between this group and those with bundle branch block. The two groups had similar PSI and acute improvement in ventricular performance after CRT.
Acute changes in measures of systolic and diastolic function Acute improvements in LVEF and stroke volume were significantly correlated with the degree of viability, determined by PSI (Figure 2). The PSI also correlated well with improvement in early diastolic mitral annular velocity (E=), Table 1
Figure 1 Background-subtracted color-coded myocardial contrast echocardiographic apical four-chamber view of the left ventricle showing examples from a patient with preserved viability (A) and with poor viability (B). Images are shown at the longest pulsing interval.
a measure of early diastolic relaxation, and the Tei index, a measure of combined systolic and diastolic performance (Figure 2). Correlations of borderline significance also were found between the PSI and changes in end-systolic volume (r ⫽ ⫺0.37, P ⫽ .12) and dP/dT (r ⫽ 0.50, P ⫽ .08) with CRT. There was no relation between PSI and acute reduction in end-diastolic volume (r ⫽ ⫺0.09, P ⫽ NS).
Improvement in LV performance, remodeling, and clinical status at 6 months Two patients died suddenly during the 6-month study period, one of apparent sudden cardiac death and the other of a ruptured abdominal aortic aneurysm. Among the remaining 17 patients who completed follow-up at 6 months, there was improvement in cardiac performance as assessed by
Baseline characteristics
Age (years) Male gender New York Heart Association functional class III IV Left ventricular ejection fraction QRS duration (ms) ECG pattern Left bundle branch block Right bundle branch block Right ventricular paced Rhythm Sinus rhythm Atrial fibrillation Previous coronary artery bypass graft Medical therapy Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Beta-blocker Digoxin Spironolactone Perfusion score index
67.8 ⫾ 10.4 16 (84%) 15 (79%) 4 (21%) 22.0 ⫾ 5.1 152 ⫾ 26 12 (63%) 2 (11%) 5 (26%) 17 (89%) 2 (11%) 11 (63%)
19 (100%) 12 (63%) 12 (63%) 11 (58%) 1.24 ⫾ 0.37
Figure 2 Relationships between perfusion score index and the acute change in (A) left ventricular ejection fraction (EF), (B) stroke volume (SV), (C) peak early diastolic mitral annular velocity (E=), and (D) Tei index.
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Heart Rhythm, Vol 2, No 11, November 2005 The 17 patients who completed 6-month follow-up were divided into tertiles based on global PSI (Table 2). Patients with higher PSI tended to have greater improvement in NYHA class, 6-minute hall walk distance, Minnesota Living with Heart Failure quality-of-life score, and number of hospitalizations for heart failure. End-diastolic left ventricular internal dimension measured in the parasternal long axis was used as a marker of positive remodeling after biventricular pacing. The 6-month reduction in LV internal dimension was closely correlated with the degree of viability (P ⫽ .003, r ⫽ 0.68; Figure 4). No significant decrease in LV internal dimension was observed in patients with poor global viability (PSI ⬍1.0).
Effect of regional viability
Figure 3 Relationships between perfusion score index (PSI) and the change at 6 months in (A) left ventricular ejection fraction (EF), (B) stroke volume (SV), (C) peak early diastolic mitral annular velocity (E=), and (D) Tei index.
ejection fraction (mean 4.1 ⫾ 5.9%, range ⫺7.3 to 12.7), E= (0.94 ⫾ 1.50 cm/s, range ⫺2.3 to 3.5), and the Tei index (⫺0.13 ⫾ 0.11, range ⫺0.28 to 0.01). The ratio of transmitral E-wave velocity to E=, an index of the status of LV preload, was not significantly different between the acute and 6-month follow-up study on paired analysis (P ⫽ .93). These improvements were associated with improvements in 6-minute hall walk distance (202 ⫾ 176 ft, range ⫺40 to 560), Minnesota Living with Heart Failure quality-of-life score (16.9 ⫾ 12.2 points, range ⫺4 to 38), and NYHA class (0.7 ⫾ 0.6, range 0 to 2). LVEF and stroke volume from one patient were excluded from analysis because of a significant change in heart rate (⬎40 bpm) from baseline to follow-up echocardiogram. After 6 months of biventricular pacing, the relationship between myocardial viability as assessed by PSI and the degree of improvement in measures of systolic and diastolic performance and of global myocardial performance were preserved (Figure 3).
Table 2
The effect of regional viability on LV performance was analyzed. Segments typically supplied by the left anterior descending artery were grouped as anterior segments, whereas those supplied by the right or circumflex coronary artery were considered posterior segments. The posterolateral wall segments underlying the LV lead were considered separately. The correlation coefficients for the regional viability scores for each of the echocardiographic parameters are given in Table 3. In this patient cohort, there were significant correlations between all regional viability scores and the global PSI. Therefore, it is difficult to separate the influence of regional from global viability. Nonetheless, the global viability score (PSI) predicted improvement as well as or better than the regional scores for most parameters.
Other predictors of response There was no significant correlation between any baseline characteristic from Table 1 and either improvement in echocardiographic parameters or PSI. Baseline LVEF was not significantly correlated to PSI (r ⫽ 0.19, P ⫽ NS) and was a poor predictor of acute improvement in EF (r ⫽ 0.31, P ⫽ NS) and other echocardiographic and clinical parameters. Several measures of baseline dyssynchrony and the amount of resynchronization and their relation to improvement in ventricular performance were examined. Neither baseline
Six-month improvement in clinical parameters according to tertile of myocardial viability PSI tertile Low (n ⫽ 5)
PSI ⌬ New York Heart Association class ⌬ 6-minute hall walk (ft) ⌬ QOL score ⌬ Hospitalizations for congestive heart failure
0.73 0.2 5 11.2 0.2
⫾ ⫾ ⫾ ⫾ ⫾
0.14 0.4 54 14.8 0.4
Medium (n ⫽ 6) 1.23 0.8 211 11.8 ⫺0.2
⫾ ⫾ ⫾ ⫾ ⫾
0.11 0.4 145 4.3 1.1
High (n ⫽ 6) 1.61 1.0 358 24.7 ⌬0.7
⫾ ⫾ ⫾ ⫾ ⫾
0.12 0.6 123 12.0 1.0
P value — .05 .01 .10 NS
P values from analysis of variance for continuous variables and Chi-square test for nominal variables. PSI ⫽ perfusion score index; QOL ⫽ quality of life (Minnesota Living with Heart Failure Questionnaire); ⌬ ⫽ change with cardiac resynchronization therapy.
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Figure 4 Relationship between perfusion score index and change in end-diastolic left ventricular internal dimension (LVID) at 6 months.
QRS duration (r ⫽ 0.01) nor reduction in QRS duration (r ⫽ 0.00) correlated with acute improvement in LVEF. Baseline intraventricular dyssynchrony, measured by tissue Doppler imaging as the basal wall-motion delay, and the degree of resynchronization, or amount of shortening of the basal wall-motion delay, only weakly predicted acute LVEF improvement (r ⫽ 0.12 and r ⫽ 0.34). Figure 5 shows the relation between acute change in systolic performance (LVEF) and the improvement in basal wall-motion delay. Improved mechanical synchrony resulted in improvement in LVEF only when PSI was ⬎1 (r ⫽ 0.58, P ⫽ 0.05). On multiple linear regression analysis, PSI added significant incremental value to the amount of mechanical resynchronization for predicting acute change in LVEF (r ⫽ 0.34 for resynchronization alone; r ⫽ 0.75 for PSI and resynchronization). Viability appeared to have little effect on the degree of resynchronization. There was no significant correlation between shortening of the QRS complex or basal wall-motion delay and global PSI (r ⫽ ⫺0.12, r ⫽ ⫺0.11).
Discussion CRT often improves symptoms in patients with severely reduced LVEF and intraventricular conduction delay. Symptomatic improvement is thought to be related, in part, Table 3 Correlation coefficients between regional viability and improvement in left ventricular performance
Acute ⌬ EF ⌬ SV ⌬ E= ⌬ Tei index Six Months ⌬ EF ⌬ SV ⌬ E= ⌬ Tei index
Global
Lateral
Anterior
Posterior
0.63* 0.53* 0.47 ⫺0.72*
0.54* 0.31 0.48 ⫺0.79*
0.49* 0.47* 0.36 ⫺0.54*
0.41 0.24 0.40 ⫺0.66*
0.48 0.45 0.71* ⫺0.78*
0.52* 0.24 0.33 ⫺0.84*
0.32 0.40 0.79* ⫺0.67*
0.54* 0.25 0.04 ⫺0.64*
EF ⫽ ejection fraction; SV ⫽ stroke volume; E= ⫽ early diastolic mitral annular velocity; ⌬ ⫽ change with cardiac resynchronization therapy. *P ⬍ .05.
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Figure 5 Relationships between improvement in mechanical synchrony and improvement in left ventricular ejection fraction (EF) for patients with perfusion score index (PSI) ⬍1.0 or ⱖ1.0
to improved systolic and diastolic performance. In this study, we demonstrated that, in patients with ischemic heart disease, the degree of improvement in systolic and diastolic performance is influenced by the extent of myocardial viability. Selection of patients for CRT currently is based on symptoms, LVEF, and QRS complex duration on ECG. Large clinical trials evaluating the efficacy of CRT, however, have indicated that between 25% and 30% of patients with standard indications do not show clinical improvement.1 Better selection criteria for CRT would avoid exposure to risk in patients unlikely to receive benefit and would improve resource utilization. There are several potential mechanisms by which myocardial viability may influence acute responses to biventricular pacing. Slower conduction velocities through fibrotic regions could preclude electrical resynchronization despite multisite pacing. In this study, however, we found no relation between viability and the amount of resynchronization. In fact, several patients with poor viability still were able to significantly decrease the septal to lateral wall-motion delay as assessed by tissue Doppler imaging. A second more plausible explanation is that resynchronization reverses wasted work toward cardiac output only in viable segments where some potential for wall thickening exists. Akinetic or dyskinetic regions that are largely nonviable contribute little to systolic performance, whether or not their relatively passive motion is synchronized. Accordingly, improvement in LV systolic performance did not occur when a large number of segments had a perfusion score of 0. Baseline LVEF did not predict improvement because, for patients with severely reduced systolic function, LVEF does not necessarily correlate with viability. For example, several patients in this study had preserved viability but profound LV systolic dysfunction from diffuse severe hypokinesis. Echocardiographic parameters of diastolic performance were related to viability in this study. These changes occurred acutely, eliminating the possibility of positive LV remodeling, which has been observed in selected patients. Because PSI did not necessarily correlate with improvement in synchronization, synchronization of diastole probably played a minor role. The fact that early diastolic relaxation
1216 is largely dependent upon systolic performance10 suggests that improvement in E= and Tei index was secondary to improvement in systolic performance. An alternative possibility for the findings of this study is that biventricular pacing improves systolic and diastolic performance by diminishing energy cost, which has been shown in patients with dilated cardiomyopathy.11 These effects would be expected only in tissue where myocyte viability is maintained, although this was not directly tested in this study. The amount of reverse remodeling at 6 months was highly correlated to the degree of viability. Penicka et al12 reported that positive remodeling is predicted by the degree of baseline dyssynchrony. In this study, patients with poor viability (PSI ⬍1.0) did not have significant remodeling regardless of baseline dyssynchrony. This may imply that, in patients with ischemic cardiomyopathy, resynchronization alone may not result in reverse remodeling if adequate viability is not present. We demonstrated that improvement in myocardial performance after biventricular pacing is dependent on global myocardial viability. It is possible that this result is driven by viability of the paced myocardial segment, because if this segment contains mainly scar (i.e., is not viable), conduction may be too slow to resynchronize surrounding areas. Among patients in this study, global PSI was highly correlated with viability of the lateral paced segment, so separate evaluation of the influence of lateral viability is difficult. However, global viability was a better predictor of improvement of many parameters than was lateral viability. Additionally, neither global nor lateral viability correlated well with the degree of QRS shortening or improvement in basal wall-motion delay. Therefore, it appears unlikely that the viability of the paced segment is the sole critical factor mediating the influence of viability. Future studies are needed in larger groups of patients to further assess the effects of regional viability defects. Often nonresponse is believed to occur due to lack of intraventricular resynchronization. It is clear that QRS duration is a poor indicator of intraventricular dyssynchrony of the LV. Thus, tissue Doppler measurements of baseline intraventricular synchrony are better predictors of response than QRS duration alone. In addition, patients whose latest segments to be activated are not located in the posterolateral wall may not restore intraventricular synchrony with a standard coronary sinus lead position. Thus, it has been suggested that tissue Doppler imaging should be used routinely both to screen for baseline dyssynchrony and to individualize the LV lead position to the latest activated segment.13 Various methods have been described to define the degree of LV dyssynchrony using tissue Doppler imaging in multisegmental models.14 –17 Some have not gained widespread clinical use because of their complexity and technical considerations. In this study population at our institution, for instance, there was a high interobserver variability using multisegmental models partly due to difficulty differ-
Heart Rhythm, Vol 2, No 11, November 2005 entiating actual thickening from passive motion in the failing heart. A simpler index of dyssynchrony using tissue Doppler imaging to measure the delay from peak systolic velocity in the basal septal and lateral segments has been shown to correlate with response to CRT.7,14 In our study group, there was a positive correlation between both baseline septal to lateral wall motion delay and improvement in the delay after CRT with acute improvement in function. It is important to note, however, that in this study shortening of the septal to lateral wall motion delay resulted in improved ventricular performance only in patients with good viability (PSI ⱖ1).
Study limitations The patient cohort was relatively small. However, we believe these results bring to bear a new issue that may influence clinical response to a therapy that is not without risk or cost. There was no control group that did not undergo biventricular pacemaker placement. However, this limitation does not necessarily affect our ability to test the hypothesis that the degree of myocardial viability influences clinical response to resynchronization therapy. There are several potential methodologic limitations regarding the precision of echocardiographic measurements. Echocardiographic assessment of LV volume and EF may be associated with relative intraobserver and interobserver variation of up to 10%. To address this limitation, we used automatic border tracking software during LV opacification in the majority of patients, except where limited by poor acoustic windows (in four patients). Moreover, the relative increases in ejection fraction of up to 40% observed in this study likely were not caused solely by errors in measurement, and any trends caused by these errors would be expected to be similar among all patients irrespective of myocardial viability. The Tei index, a measure of global performance, relies on measurement of the isovolumic contraction period and ejection times and probably was influenced by the change in AV delay during pacing. Again, any influence of pacing on the Tei index would be expected to affect all patients similarly because there was no relation between change in AV delay and degree of myocardial viability. Finally, the correlation between baseline dyssynchrony and the response to CRT was less than expected. It is important to note that this relation was much closer when patients with poor myocardial viability were excluded. Hence, it is reasonable to expect that patients with ischemic cardiomyopathy who have the most viability and the most dyssynchrony receive the greatest benefit from CRT.
Conclusion In this study, we demonstrated that myocardial viability is an important factor influencing improvement in ventricular performance after CRT in patients with ischemic cardiomy-
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opathy. Our data indicate that significant improvement in myocardial performance, symptoms, and ventricular remodeling can be expected only if there is both viability and improvement in mechanical synchronization.
References 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: 1845–1853. 2. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Effects of multisite pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 880. 3. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289:730 –740. 4. Reuter S, Garrigue S, Barold SS, Jais P, Hocini M, Haissaguerre M, Clementy J. Comparison of characteristics in responders versus nonresponders with biventricular pacing for drug-resistant congestive heart failure. Am J Cardiol 2002;89:346 –350. 5. Balcells E, Powers ER, Lepper W, Belcik T, Wei K, Ragosta M, Samady H, Lindner JR. Detection of myocardial viability by contrast echocardiography in acute myocardial infarction predicts recovery of resting function and contractile reserve. J Am Coll Cardiol 2003;41: 827– 833. 6. Tei C, Dujardin KS, Hodge DO, Kyle RA, Tajik AJ, Seward JB. Doppler index combining systolic and diastolic myocardial performance: clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658 – 664. 7. Bax JJ, Molhoek SG, Marwick TH, van Erven L, Voogd PJ, Somer S, Boersma E, Steendijk P, Schalij MJ, Van der Wall EE. Usefulness of myocardial tissue Doppler echocardiography to evaluate left ventricular dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 2003;91:94 –97.
1217 8. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley, SO, Taylor DW, Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. CMAJ 1985; 132:919 –923. 9. Rector RS, Kubo SH, Cohn JN. Patients’ self-assessment of their congestive heart failure: content, reliability, and validity of a new measure—the Minnesota Living with Heart Failure Questionnaire. Heart Fail 1987;3:198 –209. 10. Udelson JE, Bacharach SL, Cannon RO, Bonow RO. Minimum left ventricular pressure during -adrenergic stimulation in human subjects. Evidence for elastic recoil and diastolic “suction” in the normal heart. Circulation 1990;82:1174 –1182. 11. Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, Kass DA. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102: 3053–3059. 12. Penicka M, Bartunek J, De Bruyne B, Vanderheyden M, Goethals M, De Zutter M, Brugada P, Geelen P. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004;109:978 –983. 13. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Biventricular pacing in heart failure: back to basics in the pathophysiology of left bundle branch block to reduce the number of nonresponders. Am J Cardiol 2003;91S:55– 61. 14. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, Guida P, Andriani A, Mastropasqua F, Rizzon P. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Card 2002;40:1615–1622. 15. Sogaard P, Egeblad H, Kim WY, Jensen HK, Pedersen AK, Kristensen BO, Mortensen PT. Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J Am Coll Card 2002; 40:723–730. 16. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, Kong SL, Lam YM, Hill MR, Lau CP. Tissue Doppler echocardiography evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438 – 445. 17. Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39:194 –201.