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(Circulation. 2000;102:2070.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

The Effects of ß₁-Blockade on Oxidative Metabolism and the Metabolic Cost of Ventricular Work in Patients With Left Ventricular Dysfunction

A Double-Blind, Placebo-Controlled, Positron-Emission Tomography Study

R. S. B. Beanlands, MD; C. Nahmias, PhD; E. Gordon, MD; G. Coates, MD; R. deKemp, PhD; G. Firnau, PhD; E. Fallen, MD

From the Department of Nuclear Medicine, ES Garnett Memorial PET Centre, the Division of Cardiology, McMaster University Medical Centre (C.N., E.G., G.C., E.F., G.F.), Hamilton, Canada, and the Cardiac PET Centre in the Division of Cardiology at the University of Ottawa Heart Institute (R.B., R.d.K., G.F.), Ottawa, Canada.

Correspondence to Rob Beanlands, MD, FRCP(C), Director of Cardiac Imaging, University of Ottawa Heart Institute, H149-40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. E-mail rbeanlands{at}ottawaheart.ca

	Abstract

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Background—The mechanism for the beneficial effect of ß-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MO₂). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency.

Methods and Results—The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11-acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work-metabolic index was calculated as follows: (systolic blood pressurexSVIxheart rate)/k. No significant change in oxidative metabolism occurred with placebo (k=0.061±0.022 to 0.054±0.012 per minute). Metoprolol reduced oxidative metabolism (k=0.062±0.024 to 0.045±0.015 per minute; P=0.002). The work-metabolic index did not change with placebo (from 5.29±2.46x10⁶ to 5.14±2.06x10⁶ mm Hg · mL/m²), but it increased with metoprolol (from 5.31±2.15x10⁶ to 7.08±2.36x10⁶ mm Hg · mL/m²; P<0.001).

Conclusions—Selective ß-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with LV dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with ß-blocker therapy in this patient population.

Key Words: heart failure • acetates • metabolism

	Introduction

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Heart failure due to left ventricular (LV) dysfunction represents the final common pathway for most forms of heart disease and continues to be recognized as a major clinical problem.¹ Despite their negative inotropic effect, ß-blocker drugs improve symptoms, LV function,^{2 3 4 5 6 7} and survival^{8 9 10} in patients with heart failure. The mechanism for this seemingly paradoxical effect is unclear. Katz¹ suggested that it may relate to an energy-sparing effect of these agents. However, the independent effect of selective ß-blocker therapy on myocardial energetics and metabolism has not been widely studied.

An evaluation of myocardial oxygen consumption (MO₂) in conjunction with measurements of ventricular performance (mechanical efficiency) would give insight into the beneficial effect of ß-blockade in heart failure. Unfortunately, the need for invasive means to determine oxygen consumption has limited such investigations in the past. However, the myocardial kinetics of radiolabeled C-11 acetate, which can be determined noninvasively using positron-emission tomography (PET), have been used to measure rates of oxidative metabolism, and they have a direct relationship with MO₂.^{11 12 13 14 15} This approach has been combined with echocardiography (to measure ventricular function) as a noninvasive means to determine myocardial efficiency and evaluate the effects of drug therapies on the metabolic costs of ventricular work.^{14 15 16 17}

The principal aim of this study was to determine the effect of selective ß-blockade with metoprolol on oxidative metabolism and on the work-metabolic index (WMI; a noninvasive estimate of myocardial efficiency) in patients with chronic stable heart failure and LV dysfunction.

	Methods

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Patient Population
Patients were enrolled between September 1995 and December 1997. They were included if they had impaired LV function with an ejection fraction <40% (measured by radionuclide angiogram, echocardiogram, or LV angiogram) and had been on stable therapy for 4 weeks before randomization. Exclusion criteria were as follows: (1) on ß-blocker therapy; (2) contraindications to ß-blocker therapy, including obstructive pulmonary disease or advanced heart block; (3) myocardial infarction or stroke within the preceding 3 months; (4) serious medical condition that could alter outcome; (5) unstable angina; (6) unstable ventricular arrhythmias; and/or (7) hypertrophic cardiomyopathy or constrictive pericarditis. The protocol was reviewed and approved by the institutional ethics review boards of the 2 participating centers (McMaster University Medical Center site of the Hamilton Health Sciences Corporation and the University of Ottawa Heart Institute in the Ottawa Civic Hospital).

Experimental Protocol
Before entering the study, patients underwent a metoprolol test dose challenge of 5 mg. Patients were evaluated before and 2 hours after challenge for clinical decompensation and worsening symptoms, increasing heart failure, hypotension, or bronchospasm. Patients were contacted 24 hours later to ensure that no new symptoms had developed.

At least 1 week after the test dose, eligible patients were enrolled in the study, which was divided into the following 3 phases: (1) a 2-week stabilization period during which time the patient was on a stable medical regimen before randomization, (2) a 7-week metoprolol/placebo dose titration phase, and (3) a 3-month metoprolol/placebo maintenance phase.

Baseline Studies
A clinical examination, C-11 acetate PET imaging, echocardiography, 6-minute walk test, and a quality-of-life questionnaire were performed at the end of the stabilization phase before randomization.

Randomization
Patients were randomly assigned to receive metoprolol or placebo. Each tablet had a similar appearance, and both patient and investigator were blinded regarding treatment group. Randomization was stratified for different causes of ventricular dysfunction (ischemic and nonischemic). Patients were considered to have an ischemic cause if they had 1 coronary artery with >50% stenosis on coronary angiography, a documented history of myocardial infarction, and/or a moderate to severe perfusion abnormality on nuclear imaging.

Metoprolol/Placebo Dose Titration
The metoprolol or placebo dose was increased on a weekly basis from 5.0 mg BID on week 1 to 50 mg TID on week 7. The therapeutic end point was a total dose of 150 mg, a systolic blood pressure 85 mm Hg, or a resting heart rate of 50 to 70 beats/min.^{2 3} Patients were evaluated before and for 2 hours after the administration of the first dose and then at the time of each dose change. After drug titration, the patients had clinical evaluations every month, or sooner if clinical deterioration occurred. Compliance was evaluated by careful questioning and pill count. Patients were continued on the same doses of all their initial cardiac medications except diuretics, which were adjusted as needed by the attending physician.

After the study had been underway for >1 year, a parallel, multicenter, randomized-placebo control study (Randomized Evaluation of Strategies for Left Ventricular Dysfunction [RESOLVD]) evaluating ß-blocker therapy with metoprolol in patients with congestive heart failure was initiated in the 2 centers participating in our study.¹⁸ The dose titration and follow-up regimen were virtually identical to those in our study, with the maximum dose reaching 200 mg of metoprolol or placebo per day. To avoid competing for patient recruitment and because the dosing regimens were similar, a minor modification of the maximum dose to 200 mg was made. This was considered reasonable and was approved by the institutional ethics review boards at the centers. Of the total of 40 patients randomized, 8 were randomized to the higher maximal dose protocol and were balanced between metoprolol (n=4) and placebo (n=4).

Follow-Up Studies
Baseline measurements were repeated after the 3 months of maintenance (total, 19 weeks of therapy including the 7-week titration phase).

PET
The patients were positioned in a whole-body PET scanner (either ECAT 953 CTI/Siemens or ECAT ART CTI/Siemens) at McMaster University Medical Center. A 20-minute transmission scan was performed to correct the emission images for photon attenuation. PET studies were scheduled in the morning after an overnight fast.

C-11 Acetate PET Imaging
Immediately after the transmission scan, 15 to 20 mCi (550 to 740 MBq) of C-11 acetate was administered intravenously, and a dynamic PET acquisition was initiated (10x10, 1x60, 5x100, and 3x180 seconds).^{15 16}

C-11 Acetate PET Data Analysis
Regions of interest were defined over the LV myocardium and blood pool on the midventricular transaxial image plane. These regions were then applied to the corresponding images in the dynamic sequence, yielding myocardial and blood pool time versus activity curves.

A monoexponential function was fit to the myocardial time-activity data (Figure 1), and the clearance rate constant k was determined as described previously^{13 16 17} (also termed k-mono). The monoexponential fit begins at the point when the blood pool is stable (usually 2 to 4 minutes after injection).

View larger version (11K): [in this window] [in a new window]   Figure 1. Example of myocardial time-activity data for C-11 acetate PET acquisition. A monoexponential function fit to the myocardial clearance beginning at 2 minutes (when much of the blood pool has cleared) yields a clearance rate constant k that represents the rate of oxidative metabolism and also reflects MO2. In this case, k was 0.064 per minute.

Echocardiography
Immediately before the C-11 acetate PET study, a 2D echocardiogram was performed. All images were acquired on a commercially available cardiac ultrasound system (HP1000) and analyzed offline using the HP software package for 2D quantitation. All measurements were made in triplicate, and the average was used for analysis.

Echocardiography Data Analysis
LV volumes were measured using the single-plane method of disc.¹⁹ The stroke volume was calculated from the difference between the end-diastolic and end-systolic volumes. The stroke volume index (SVI) was used to estimate stroke work index (SWI) as follows: SWI=SVIxPSP, where PSP indicates peak systolic blood pressure.^{15 16 17} Mitral regurgitation, which was identified using color flow Doppler, was graded visually for each study by an investigator blinded to clinical and PET data. A standard 0 to 4 scoring system was used, where 0 indicated none or trivial regurgitation and 4 indicated severe regurgitation.²⁰ All echocardiographic and PET data were analyzed by individuals blinded to the clinical data and treatment arm.

WMI Determination
The C-11 clearance data were combined with the stroke work data to determine the LV WMI, as follows^{15 16 17} :

This equation is a modification of the minute work-to-oxygen consumption relationship originally defined as mechanical efficiency by Bing et al.²¹

Evaluation of Functional Capacity and Quality of Life
The Minnesota Living with Heart Failure questionnaire was used to assess quality of life.²² Functional score using this approach ranges from 0 (good) to 105 (poor). Submaximal exercise capacity was determined using the 6-minute walk test.²³

Statistical Analysis
All measurements were expressed as mean±1SD. Baseline and follow-up data were compared by paired Student’s t tests. Metoprolol and placebo groups were compared for baseline, follow-up, and percent change between baseline and follow-up using unpaired Student’s t tests.

	Results

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Patient Enrollment and Patient Characteristics
Forty patients were enrolled in the study between August 1995 and December 1997 (metoprolol group, n=19; placebo group, n=21). Patients were stratified according to cause of heart disease (ischemic, n=29; nonischemic, n=11). Seven patients either withdrew, had incomplete follow-up, or had nonanalyzable PET data. Of these 7, 1 patient withdrew after 1 week of therapy because of fatigue (patient was on metoprolol), 1 patient developed bradycardia and heart block and was withdrawn (patient was on placebo), 2 patients withdrew from follow-up PET scans because of claustrophobia or severe arthritis, and 3 patients completed drug follow-up but had PET data that were not analyzable for technical reasons. One additional patient developed abdominal discomfort but did complete the protocol and imaging. In retrospect, the patient was thought to have developed ischemic bowel symptoms on metoprolol, which was later confirmed on colonoscopy. All other patients tolerated the medication well.

Thus, 33 patients had complete PET data for analysis (placebo, 19; metoprolol, 14). The baseline characteristics for the patients with complete PET data are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Hemodynamic and Echocardiographic Parameters
Hemodynamic and echocardiographic parameters are summarized in Table 2. Baseline parameters were similar between groups. Heart rate did not change with placebo but decreased with metoprolol (P=0.02). A slight trend existed for the SVI to increase with ß-blockade, but this did not reach statistical significance. The degree of mitral regurgitation was similar between the groups at baseline (1.5±1.0 for metoprolol versus 1.3±1.0 for placebo) and did not significantly change with follow-up (1.3±1.0 versus 1.4±1.1). Echocardiographic data were not analyzable in 1 patient on metoprolol. This patient was not included in the echocardiographic (or WMI) data analysis.

View this table: [in this window] [in a new window]   Table 2. Heart Rate, Blood Pressure, and Echocardiographic Data

C-11 Acetate Kinetic Data
Figure 2 shows the rate of myocardial oxidative metabolism as measured by the rate constant k at baseline and follow-up. No significant change occurred with placebo (k=0.061± 0.022 per minute at baseline versus 0.054±0.012 per minute at follow-up), whereas metoprolol led to a significant reduction (from k=0.062±0.024 per minute at baseline to k=0.045±0.015 per minute at follow-up; P=0.002). The percent change in k for the metoprolol group was -24±23%. This was significantly greater than the change with placebo (-5±25%; P=0.027).

View larger version (23K): [in this window] [in a new window]   Figure 2. Myocardial oxidative metabolism rate, as measured by the C-11 clearance rate constant, for placebo (n=19) and metoprolol patients (n=14). *P<0.05 vs baseline.

WMI
Figure 3 shows the baseline and follow-up WMI. No significant change occurred with placebo (5.29±2.46x10⁶ mm Hg · mL/m² at baseline versus 5.14±2.06x10⁶ mm Hg · mL/m² at follow-up). With metoprolol, the WMI increased significantly, from 5.31±2.15x10⁶ to 7.08±2.36x10⁶ mm Hg · mL/m² (P<0.001). Metoprolol led to a change in WMI of 39±32%, which was significantly greater than that with placebo (5±39%; P=0.016).

View larger version (26K): [in this window] [in a new window]   Figure 3. WMI, an estimate of myocardial efficiency, in placebo (n=19) and metoprolol patients (n=13). *P<0.02 vs baseline and placebo.

Functional Parameters
Quality-of-life score increased slightly with ß-blockade from 21±14 at baseline to 25±13 at follow-up, but this change is not statistically significant. There was minimal change with placebo (20±16 at baseline versus 21±20 at follow-up). No significant changes occurred in the 6-minute walk test distance with metoprolol (454±105 m at baseline versus 453±94 m at follow-up) or with placebo (437±73 m at baseline and 435±74 m at follow-up).

Ischemic Cardiomyopathy Subgroup
The study was stratified at randomization to allow for subgroup analysis. The ischemic cardiomyopathy subgroup was considered of sufficient size to allow for subgroup analysis. Eleven patients in the metoprolol group and 15 patients in the placebo group had ischemic cardiomyopathy. Metoprolol significantly reduced the rate of oxidative metabolism (from k=0.066±0.025 per minute at baseline to 0.044±0.017 per minute at follow-up; P=0.001). With placebo, no significant change occurred (from k=0.062±0.024 per minute to k=0.054±0.012 per minute; P=NS). The mean percent change in k with metoprolol was -31±19%, in comparison with -5±28% with placebo (P=0.014).

Metoprolol significantly increased the WMI, from 4.79±1.90x10⁶ to 6.72±2.40x10⁶ mm Hg · mL/m² (P<0.001). No change occurred with placebo (5.47±2.70x10⁶ versus 5.35±2.16x10⁶ mm Hg · mL/m²). The mean percentage increase from baseline with metoprolol was 44±32%, compared 9±43% for placebo (P=0.03).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Selective ß-blocker therapy with metoprolol led to a significant reduction in oxidative metabolism and an improvement in cardiac efficiency compared with placebo. A novel aspect of this study was that these findings were determined using noninvasive techniques, namely, C-11 acetate PET and echocardiography. A reduction in oxidative metabolism and improved cardiac efficiency with metoprolol were also observed in a subgroup with ischemic cardiomyopathy. Randomized studies evaluating cardiac efficiency with ß-blockade have been limited and, to our knowledge, have not randomized patients with ischemic heart disease.

Potential Role of an Energy-Sparing Effect of ß-Blockade
Adrenergic activation is now recognized as an important factor in the pathogenesis of heart failure.^{24 25} Adrenergic stimulation leads to increased oxygen consumption, which initially may be compensatory but, over the long-term, results in an energy-depleted state²⁶ and cell injury. In addition, direct myocardial toxicity and stimulation of remodeling may occur.^{24 27 28} Katz¹ proposed that the improved survival with ß-blocker therapy may relate to their energy-sparing effects; however, this has not been well studied. By reducing heart rate and inotropy, ß-blockers should reduce myocardial energy demands and oxygen consumption.²⁹ Reduction in demand from ß-blockade would permit the repletion of energy stores.⁶ This may allow energy to be directed to repairing cell injury and restoring contractile elements.³⁰ Although initially this may not be expected to improve efficiency, the improvement in cell function may also begin to reverse ventricular remodeling (which has been observed with ß-blockade).^{24 25 28} The pharmacological effect of ß-blockade in reducing energy demands may thus facilitate the biological recovery of the myocytes,²⁴ which would result in improved efficiency.

In the current study, a definite reduction in oxidative metabolism was observed with metoprolol. However, only a small, nonsignificant increase in ejection fraction was observed, and no change occurred in functional capacity or quality of life. One explanation for this may relate to our population, which included more patients with an ischemic cause of disease. The recovery of LV function in those with a ischemic cardiomyopathy may be less than that in those with a nonischemic cause of disease, and recovery may show no change in many cases.³¹ Also, our patients had a somewhat less severe impairment of LV function and symptoms than those in other studies.⁸ This may reduce the degree of recovery that can be observed.^{8 31} In addition, not all studies have demonstrated better LV and functional parameters with ß-blockade compared with placebo.^{4 8} In fact, LV function and symptoms may get worse initially before getting better because of the withdrawal of adrenergic support.^{24 25 32} A parallel reduction in LV function and oxygen consumption would also be expected early in therapy.²⁹

In the current study LV function was maintained with metoprolol at a lower rate of oxidative metabolism, supporting the idea that some recovery occurred and that there is an energy-sparing effect of ß-blocker therapy. Longer follow-up (beyond 3 months) may have shown an improved ejection fraction as well. Future studies with noninvasive determination of efficiency using PET and echocardiography would allow serial evaluation of this process to determine the time sequence of changes in metabolism, function, and efficiency recovery.

The concept of an energy-sparing effect is also supported by the known ß-adrenergic stimulation of lipolysis.^{6 33} The resulting increased fatty acid utilization is less efficient for a given level of MO₂.³⁴ Thus, in addition to the effects described above, ß-blockade in the presence of high catecholamines could alter metabolic substrate utilization, further permitting more efficient oxygen utilization.⁶

Previous Studies on ß-Blockade and Energetics
Investigations into the effects of ß-blockade on myocardial metabolism, oxygen consumption, and efficiency in heart failure have been limited. This is partly because of the previous need for invasive methods to measure these parameters, which is often difficult.⁵ In 2 small, nonrandomized studies of ischemic and nonischemic cardiomyopathy, bucindolol improved ventricular work without significantly affecting oxygen consumption,⁶ whereas metoprolol tended to reduce MO₂.⁵ In the latter study, efficiency was not determined.

In 24 randomized patients with nonischemic cardiomyopathy, metoprolol decreased MO₂ and increased stroke volume and efficiency compared with baseline. Compared with placebo, metoprolol decreased oxygen consumption and showed a trend toward increasing stroke volume and efficiency that did not reach statistical significance.

In the current study, a slight trend existed toward an increased stroke index (this was not statistically significant). However, metoprolol significantly reduced oxidative metabolism and increased WMI compared with baseline and placebo. As noted above, the differences between the current study and others likely relates in part to the type and severity of LV dysfunction and the population studied. Unlike the previous randomized study,⁷ the current study included an ischemic subgroup that also demonstrated changes in oxidative metabolism and WMI.

C-11 Acetate PET, Oxidative Metabolism, and WMI
After acetate is extracted by the myocardial cell, 80% to 90% of it undergoes oxidation via the tricarboxylic acid cycle.^{11 12 35} The principal metabolite of acetate, CO₂, is cleared rapidly from the cell. Thus, when acetate is radiolabeled, the myocardial clearance of radiolabeled CO₂ directly reflects tricarboxylic acid cycle flux and oxidative metabolism.^{11 12} This correlates well with direct and indirect measures of MO₂ in animal models and human studies.^{11 12 13 14 15}

The contribution of other acetate metabolite pools in the cell to this rapid clearance is generally small, even with varying metabolic conditions and substrates.^{11 12 13} This is also supported by the strong relationship between C-11 acetate clearance kinetics and MO₂.^{11 12 13 14 15} Thus, it is likely that any contribution of the metabolite pool to the large 24% reduction in oxidative metabolism observed with metoprolol was minimal.

Any analysis of cardiac energetics must consider the 2-fold task of the heart to deliver adequate stroke work and to perform this at a low oxygen cost. When combined with echocardiography or MRI to measure cardiac function, C-11 acetate PET can be applied as a noninvasive means to measure the metabolic cost of ventricular work, an estimate of cardiac efficiency.^{14 15 16 17}

Conclusions
In patients with LV dysfunction, 3 months of ß₁-selective blockade with metoprolol significantly reduced the rate of oxidative metabolism, as measured using C-11 acetate PET. Metoprolol significantly decreased the metabolic cost of ventricular work, as measured by an increase in the WMI, a noninvasive estimate of myocardial efficiency. This reflects an energy-sparing effect of ß₁-blockade. When LV dysfunction was due to ischemic heart disease, a similar reduction in the rate of oxidative metabolism and an improvement in efficiency were observed.

These improvements in myocardial energetics may account for some of the benefits observed with ß-blocker therapy in this patient population and support the use of these agents. Whether these improvements in oxidative metabolism and efficiency are maintained over longer periods of time and whether they are associated with eventual improvements in functional capacity and quality of life over time will require further study of long-term therapy.

	Acknowledgments

 
Supported in part by the Heart and Stroke Foundation of Ontario (grant NA2812/B3325), with supplemental support from Astra Canada. R.S.B. Beanlands is a research scientist supported by the Medical Research Council of Canada. The authors thank G. Woodcock, B. Aubrey, and M. Thompson for nursing assistance, Dr Salem Yusuf and his staff for their support and collaboration, which facilitated recruitment and completion of the protocol, and Ms Sherri Nipius for her excellent help in preparing the manuscript.

Received April 13, 2000; revision received May 30, 2000; accepted June 8, 2000.

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