Beta-blockers inhibit the long-term deleterious effects of

Myocardial Contractile Reserve by Dobutamine Stress Echocardiography Predicts Improvement in Ejection Fraction With -Blockade in Patients With Heart Failure The -Blocker Evaluation of Survival Trial (BEST) Eric J. Eichhorn, MD; Paul A. Grayburn, MD; Susan A. Mayer, MD; Martin St John Sutton, MD; Christopher Appleton, MD; Jonathan Plehn, MD; Jae Oh, MD; Barry Greenberg, MD; Anthony DeMaria, MD; Robert Frantz, MD; Heidi Krause-Steinrauf, MS; for the BEST Investigators Background -Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n 41) or placebo (n 38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r 0.72, P 0.0001) and was the most significant multivariate predictor of change in LVEF (P 0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687 333 versus 420 246 pg/ml, P 0.05) and greater decrease in plasma norepinephrine in response to bucindolol ( 249 171 versus 35 277 pg/ml, P 0.05). Conclusions This study suggests a direct relationship between contractile reserve and improvement in LVEF with -blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol. (Circulation. 2003;108:2336-2341.) Key Words: heart failure receptors, adrenergic, beta bucindolol norepinephrine contractility Beta-blockers inhibit the long-term deleterious effects of the adrenergic nervous system on the heart and thereby improve the biological functioning of the myocyte and ventricular chamber. 1 4 This results in improved ventricular function, an increase in myocardial chamber efficiency, and a reversal in the pathological remodeling process. 1 4 In many cases, this translates into a survival benefit, 5 8 but in the BEST study, there was no clear survival benefit, despite an improvement in left ventricular ejection fraction (LVEF) with bucindolol. 9 However, not all patients have improved LVEF with -blocker therapy. 8,10 A retrospective substudy of the Cardiac Insufficiency BIsoprolol Study (CIBIS) suggested that patients with reduced shortening fraction after 5 months of -blocker therapy may actually have increased mortality compared with placebo. 8 This phenomenon may occur because -blockers have 2 effects: pharmacological withdrawal of adrenergic support that tends to reduce LVEF and biological improvement in myocyte and chamber function that tends to improve LVEF. 1,3 If there is little contractile reserve, the negative inotropic effects of pharmacological adrenergic withdrawal may predominate, and LVEF may fall. Conversely, in patients with contractile reserve, the biological improvement in myocyte and chamber function predominates over the negative inotropic (pharmacological) effect of Received August 19, 2002; de novo received April 8, 2003; revision received July 30, 2003; accepted August 1, 2003. From the Department of Internal Medicine (Cardiology Division), the University of Texas Southwestern and Dallas VA Medical Centers, Dallas (E.J.E., P.A.G., S.A.M.); the University of Pennsylvania, Philadelphia (M.S.S.); the Mayo Clinic Scottsdale, Scottsdale, Ariz (C.A.); the Cardiovascular Branch of the National Institutes of Health and National Heart, Lung, and Blood Institute, Bethesda, Md (J.P.); the Mayo Clinic, Rochester, Minn (J.O., R.F.); the University of California at San Diego (B.G., A.D.); and the National Heart, Lung, and Blood Institute, Bethesda, Md, and the Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif (H.K.-S.). Correspondence to Eric J. Eichhorn, MD, Cardiopulmonary Research Science and Technology Institute, 7777 Forest Lane, Suite C-742, Dallas, TX 75230. E-mail eeichhorn@csant.com 2003 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000097111.00170.7B 2336

Eichhorn et al Myocardial Contractile Reserve by DSE 2337 -blockade. This study was designed to test the hypothesis that myocardial contractile reserve, as determined by dobutamine stress echocardiography (DSE), would predict improvement in LVEF with -blocker therapy. Methods This was a prospective substudy of the -Blocker Evaluation of Survival Trial (BEST). 9 Inclusion criteria for BEST required that the patient be in NYHA class III or IV despite optimal medical therapy (including angiotensin-converting enzyme inhibitors) and have an LVEF 0.35. 9 Eight centers participating in BEST on the basis of their experience and publication record in performing DSE recruited patients for this DSE substudy. Seventy-nine patients gave written informed consent and underwent DSE at baseline before treatment with bucindolol or placebo. All patients underwent DSE according to a low-dose infusion protocol. 11,12 Patients underwent DSE while taking all prescribed medications. Standard echocardiographic images were acquired with care so as not to foreshorten the apical views. Patients received 5, 10, 15, and 20 g kg 1 min 1 of dobutamine in 3-minute stages, with echocardiographic images recorded after each stage. Heart rate and blood pressure were monitored during each stage. Criteria for stopping the dobutamine infusion included (1) hypotension (systolic blood pressure 90 mm Hg), (2) angina, (3) significant arrhythmias (atrial fibrillation, bigeminy, ventricular tachycardia), (4) attainment of 85% maximal predicted heart rate, or (5) a new or worsened abnormality in systolic wall thickening in 2 segments. DSE was recorded on videotape and sent to the Echocardiographic Core Laboratory (Dallas Veterans Affairs Medical Center). Each study was interpreted by 2 blinded observers using a standard quad-screen format. Regional wall motion was assessed by the 16-segment model recommended by the American Society of Echocardiography. 13 Thus, a normal or hyperkinetic segment was graded as 1, hypokinetic as 2, akinetic as 3, and dyskinetic as 4. A segment was considered to have contractile reserve if after dobutamine the wall motion improved and was scored as 2. The stress image at the dobutamine dose showing maximum augmentation of wall motion was compared with baseline images. A regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. LV volumes and LVEF were quantified by biplane Simpson s rule, and LV mass was measured as recommended by the American Society of Echocardiography. 13 Interobserver and intraobserver variability for the BEST echocardiography core laboratory has been published previously with a correlation coefficient of 0.98 and a coefficient of variation of 10% for both interobserver and intraobserver variation. 12 Thus, a 20% reduction in WMSI represents the 95% confidence level for detecting a significant difference between resting and stress images in this laboratory. Change in LVEF from baseline to 3 months after randomization was performed by gated radionuclide techniques in each center. 14 Quality assurance of gated radionuclide ventriculography was performed for each center by a core laboratory that overread the first 5 scans in each center and random scans thereafter. Interobserver variability was tested in 518 scans read by the individual sites and core laboratory in BEST. The Pearson correlation coefficient was 0.84 (P 0.001), with a standard error of 0.02. Neurohormonal Analysis All patients entering the BEST trial had a supine plasma norepinephrine (PNE) drawn at baseline and at 3 months of therapy as part of the protocol. In addition, 57 patients who participated in this DSE study also participated in the neurohormonal substudy, in which B-type natriuretic peptide (BNP) was measured at baseline. PNE was drawn after the patient had remained in a supine position for 30 to 40 minutes. The blood was immediately immersed in ice and centrifuged for 20 minutes at 2 to 4 C at 1000 100g. Analysis was performed with high-pressure liquid chromatography with electrochemical detection. BNP was drawn at the same time in participating centers. Plasma BNP was measured by radioimmunoassay (Shinogi) as described previously. 15 Analysis Continuous variables were compared by t test and Wilcoxon rank sum test; categorical variables were compared by the 2 and Fisher s exact tests. In the group of patients randomized to bucindolol, change in LVEF after 3 months of therapy as measured by gated radionuclide imaging was compared with the response to DSE by use of 3 different measurements: (1) change in LVEF, (2) change in WMSI, and (3) number of viable segments. Regression analysis was used to examine the relationship between these measurements and both baseline LVEF and change in LVEF at 3 months. Regression analysis was used to determine univariate predictors of change in LVEF after 3 months of bucindolol therapy, including systolic blood pressure, change in WMSI with dobutamine, pretreatment resting LVEF and right ventricular ejection fraction (RVEF) (assessed by radionuclide technique), heart rate, LV mass (assessed echocardiographically), and end-systolic volume (assessed echocardiographically). A multivariate model was developed using the most significant univariate predictors of improvement in LVEF with bucindolol (ie, those with a value of P 0.10). For the assessment of outcome in the bucindolol-treated patients with and without contractile reserve, contractile reserve was defined as a change in the WMSI of 0.2 or less. This definition was based on the median change in WMSI ( 0.2). A probability value of P 0.05 was used for statistical significance. Results Patient Characteristics Of the 79 patients in the DSE substudy, 41 were assigned to placebo and 38 assigned to treatment with bucindolol. The baseline characteristics of the patients in the substudy are shown in Table 1. Patients were comparable with respect to age, sex, body habitus, and pathogenesis of heart failure. TABLE 1. Baseline Characteristics of the Studied Patients Placebo Bucindolol No. of patients 41 38 Mean age, y (range) 60 12.5 (31 81) 61 11.6 (27 79) Sex, M/F, n (%) 34 (83)/7 (17) 31 (82)/7 (18) Weight, lb 187 42.4 177 32.2 Height, in 69 3.6 69 3.6 Race White, not Hispanic 32 (78) 26 (68) Black, not Hispanic 6 (15) 8 (21) Other 3 (7) 4 (10) NYHA class III 31 (76) 30 (79) IV 10 (24) 8 (21) Heart failure pathogenesis Ischemic 25 (61) 25 (66) Nonischemic 16 (39) 13 (34) Heart rate, bpm 84 11.4 82 9.7 Systolic blood pressure, mm Hg 118 16.3 114 18.5 LVEF, % 22 8.2 20 6.7 PNE, pg/ml 429 242 527 309

2338 Circulation November 11, 2003 TABLE 2. Association Between Baseline Characteristics and Contractile Reserve Characteristic With Contractile Reserve (n 44) No Contractile Reserve (n 35) Overall (n 79) P Age 59 12 62 12 60 12 0.373 Sex, M/F, n (%) 34 (77)/10 (23) 31 (89)/4 (11) 65 (82)/14 (18) 0.191 Ischemic pathogenesis 21 (48) 29 (83) 50 (63) 0.001 NYHA class IV 7 (16) 11 (31) 18 (23) 0.102 Heart rate, bpm 81 9 86 12 83 11 0.055 Systolic blood pressure, mm Hg 117 17 114 18 116 17 0.420 Median CHF duration, mo 38 24 29 0.346* PNE, pg/ml Median 344 538 409 0.002* Mean SD 394 223 587 310 476 279 LVEF Median 22 19 19 0.236* Mean SD 22 7.7 20 7.1 21 7.5 RVEF Median 29 30 29 0.932* Mean SD 30 12.0 29 13.2 30 12.4 JVD Minimal or no JVD 38 (86) 24 (69) 62 (78) 0.056 JVD halfway up 6 (14) 11 (31) 17 (22) Edema No or feet only 40 (91) 27 (77) 67 (85) 0.090 Feet, ankles, or pretibial 4 (9) 8 (23) 12 (15) Rales None 39 (89) 30 (86) 69 (87) 0.743 Bases only 5 (11) 5 (14) 10 (13) S3 gallop 19 (43) 20 (57) 39 (49) 0.218 JVD indicates jugular venous distension. *Wilcoxon rank sum test. There were 44 patients who had contractile reserve by DSE as defined by change in WMSI of 0.2 or less. Patients with and without contractile reserve did not differ with regard to LVEF, RVEF, median heart failure duration, rales, or S3 gallop (Table 2). However, there was a trend for patients without contractile reserve to have significant edema (23%) compared with patients with contractile reserve (9%) (P 0.090) and to have significant jugular venous distension (31%) compared with patients with contractile reserve (14%) (P 0.056). Relationship of Baseline LVEF and Contractile Reserve to 3-Month LVEF Changes A significant correlation was estimated from regression analysis between change in WMSI in response to dobutamine, a measure of contractile reserve, and resting LVEF (by radionuclide) before bucindolol therapy (r 0.36, P 0.0011) (Figure 1). Although patients with higher resting LVEF had greater contractile reserve, there was great variability in this relationship. Resting baseline systolic blood pressure was correlated significantly with all 3 measures of contractile reserve. Systolic blood pressure was correlated inversely with change in WMSI (r 0.33, P 0.042) and correlated positively with change in LVEF (r 0.36, P 0.036) and number of viable segments (r 0.34, P 0.037). There was a significant correlation between the change in LVEF (as determined by gated radionuclide) at 3 months of bucindolol therapy and all 3 measures of contractile reserve estimated by regression analysis (Table 3). The change in Figure 1. Regression analysis for baseline LVEF by radionuclide assessment and change in WMSI with DSE. Although a statistically significant relation exists, large variability in this relationship is present. MUGA indicates multigated acquisition scan.

Eichhorn et al Myocardial Contractile Reserve by DSE 2339 TABLE 3. Pearson s Correlation Coefficient and Associated P Value for Change in Ejection Fraction at 3 Months of Treatment and Baseline Measures of Contractile Reserve Measure of contractile reserve r P Bucindolol group (n 35) Change in LVEF 0.35 0.041 Change in WMSI 0.72 0.0001 No. of viable segments 0.66 0.0001 Placebo group (n 38) Change in LVEF 0.28 0.084 Change in WMSI 0.29 0.080 No. of viable segments 0.30 0.065 WMSI in response to dobutamine had the most significant association with improvement in LVEF in response to -blockade (r 0.72, P 0.0001) (Figures 2 and 3). However, all 3 measures correlated well with change in LVEF. On the basis of the estimated regression line, a change in WMSI of 0.2 correlates with an improvement in LVEF of 5 EF units. By contrast, patients randomized to placebo had no relationship between measures of contractile reserve and change in LVEF (Table 3). Univariate and multivariate predictors of improvement in LVEF after 3 months of bucindolol therapy were examined (Table 4). End-systolic volume, systolic blood pressure at baseline, and change in WMSI with dobutamine were significantly correlated with improvement in LVEF with bucindolol in univariate models. When these 3 variables were present in a multivariate model, only the change in WMSI (ie, contractile reserve) was a significant independent predictor of change in LVEF (P 0.0001). The mean dose of bucindolol at 3 months was 78 29 mg BID in patients with contractile reserve versus 65 31 mg BID in those without contractile reserve (P 0.19); at 12 months of follow-up, the mean dose of bucindolol in survivors was 82 30 versus 69 25 mg BID (P 0.14) for patients with and without contractile reserve, respectively. Neurohormonal Analysis Mean BNP in patients with contractile reserve (n 31) was 261 377 pg/ml, versus 345 323 pg/ml in those without contractile reserve (n 26, P 0.085) for the cohort studied. Mean PNE in patients with contractile reserve (n 42) was Figure 2. Regression analysis for change in WMSI with DSE and change in LVEF at 3 months of therapy with bucindolol. Figure 3. Regression analysis for number of viable segments with DSE and change in LVEF at 3 months of therapy with bucindolol. 394 223 pg/ml, versus 587 310 pg/ml in those without contractile reserve (n 31, P 0.002) for the cohort studied. Mean PNE levels were 420 246 pg/ml in patients with contractile reserve (n 21), versus 687 333 pg/ml in those without contractile reserve (n 14) in the bucindolol group (P 0.006). The patients without contractile reserve experienced a greater fall in PNE at 3 months in response to the sympatholytic effects of bucindolol than those with contractile reserve ( 249 171 versus 35 277 pg/ml, P 0.0125). Safety of DSE Side effects of dobutamine were reported in 24 patients (30%) and included nonsustained ventricular tachycardia (n 1), ventricular ectopic beats (n 14), bigeminy (n 4), hypotension (n 3), and angina (n 2). The dobutamine dose was stopped at 10 g kg 1 min 1 in 4 patients and at 15 g kg 1 min 1 in 7 patients (asymptomatic hypotension, 2 patients; bigeminy, 1 patient; 5-beat runs of ventricular TABLE 4. Baseline Univariate and Multivariate Predictors of Change in LVEF at 3 Months for Bucindolol Patients Predictor R P Univariate analysis* Systolic blood pressure 0.356 0.036 Change in WMSI 0.725 0.0001 LVEF 0.100 0.565 RVEF 0.180 0.309 Heart rate 0.099 0.569 LV mass 0.156 0.377 End-systolic volume 0.434 0.010 Edema 0.304 0.076 JVD 0.192 0.271 Multivariate analysis Change in WMSI 0.0001 End-systolic volume 0.151 Systolic blood pressure 0.269 JVD indicates jugular venous distension. *Sample sizes are as follows: n 35 for systolic blood pressure, change in WMSI, LVEF, heart rate, edema, and JVD; n 34 for RVEF, LV mass, and end-systolic volume. Sample size is n 34.

2340 Circulation November 11, 2003 tachycardia, 2 patients; frequent ectopy, 2 patients; atrial fibrillation, 1 patient; no reason reported, 3 patients). Discussion This study demonstrates a direct relation between myocardial contractile reserve by DSE and the degree of ventricular function improvement seen with -blockade. -Blockade improves LVEF by biologically augmenting myocyte and chamber contractility. 1 4 This improvement does not occur immediately but rather between 1 and 3 months of therapy. 3 A partial explanation of biological improvement in LVEF may be upregulation of sarcoplasmic reticulum calcium ATPase (SERCA2), a protein that controls calcium sequestration, and an increase in the relative amount of -myosin heavy chain. 16 In the absence of contractile reserve (ie, when myocytes have been supplanted by replacement fibrosis because of cell death and interstitial remodeling 1,17 ), ventricular function cannot improve by this biological mechanism because there are not enough contractile units. In support of this hypothesis, a previous study of patients with dilated cardiomyopathy taking -blockers showed an inverse relationship between the amount of replacement fibrosis present on endomyocardial biopsy and amount of improvement in LVEF with therapy. 18 In addition to improvement in energetics, reduction in ischemia, and a shift in phenotype, which may lead to improved function, -blockers may slow the rate of myocyte apoptosis, 19 thus preserving myocardial contractile reserve. Contractile reserve itself appears to improve after LVEF has improved with -blocker therapy. 20 Thus, the benefit of -blockade in heart failure patients relates not only to improvement in resting ventricular function but also to improved contractile reserve and ability to respond to stress such as that found during exercise. However, we did not measure contractile reserve after bucindolol therapy in this study. As shown in Figure 1, some patients with relatively preserved LVEF do not have improved WMSI with dobutamine, whereas others with very poor LVEF have significant contractile reserve. Thus, a low resting LVEF does not preclude a good response to -blocker therapy. Distinguishing responders from nonresponders is important, because pharmacological reduction in LVEF by adrenergic withdrawal that is not offset by biological improvement in contractile function may result in a net decrease in LVEF. 8 In the long term, this has been shown to be a poor prognostic sign for -blocker effect and may in some cases result in an increase in mortality. 8 In general, heart failure prognosis may be altered significantly by biologically improving ventricular function 8,21 but depends on other concomitant factors such as status of the adrenergic nervous system and arrhythmogenic substrate. Because other factors may mitigate the benefits of improving ventricular function, improvement in LVEF does not guarantee a better prognosis for the patient. 22 Systolic blood pressure correlated weakly with contractile reserve and was a univariate predictor of improvement in LVEF after bucindolol therapy. Previous investigators have noted systolic blood pressure to be a good predictor of response to -blockade, 10 and it is probably a poor man s measure of contractile reserve. In BEST, in the cohort of patients taking bucindolol who underwent radionuclide angiography at baseline and 3 months (n 1216), there was a strong relationship of systolic blood pressure to improvement in LVEF (change in LVEF at 3 months, 2.1461 0.065 systolic blood pressure; P value for ANOVA 0.0001). The greater drop in PNE in response to bucindolol therapy in patients without contractile reserve may be a result of greater adrenergic activity at baseline (as reflected by higher resting baseline PNE). However, this greater drop in central adrenergic activity may represent a greater risk to this population. Patients without contractile reserve have the highest baseline sympathetic activity and are most dependent on that activity to maintain circulatory compensation. Previous studies with moxonidine, a central sympatholytic agent with no -adrenergic receptor blocking properties, have shown similar reductions in PNE with a large increase in mortality. 23 Unlike receptor blockade, sympatholysis produces an irreversible loss of adrenergic support to the failing heart, which may be deleterious early in the course of therapy in advanced heart failure. The fact that deleterious mortality effects of sympatholysis offset the benefits of -blockade in patients with advanced heart failure may explain why BEST had no clear effect on survival 10 compared with the clear survival benefit of other -blocking agents that do not produce sympatholysis. 5 7 Limitations We did not use high-dose DSE to evaluate the biphasic response, in which contractile reserve occurs at low-dose and ischemia at high-dose dobutamine. 24,25 However, we were concerned about the possibility of provoking arrhythmias with high-dose dobutamine. In fact, dobutamine was stopped early in 13 patients (16%) because of frequent ventricular ectopy. This complication rate is considerably higher than that reported for the use of DSE for evaluating known or suspected coronary artery disease 26 and emphasizes the need for caution when using DSE in patients with CHF. The small sample size of this substudy precludes subgroup analysis of patients with and without ischemic pathogenesis of heart failure. Future studies should reexamine this issue with a larger sample size and long-term follow-up. On the basis of these findings, earlier intervention with -blockers in patients who still have contractile reserve is warranted. When contractile reserve is depleted, adrenergic activity increases (as reflected by PNE), systolic blood pressure diminishes as contractile reserve is exhausted, and there is less hemodynamic response to -blockade. Further studies are warranted to determine whether contractile reserve translates into more beneficial outcomes in heart failure patients treated with -blockers. Acknowledgments BEST was sponsored by the Division of Epidemiology and Clinical Applications of the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs Cooperative Studies Program through an interagency agreement. Additional support was provided by Incara Pharmaceuticals Corporation, which supplied bucindolol and placebo.

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