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(Circulation. 1996;94:340-345.)
© 1996 American Heart Association, Inc.

Articles

Negative Chronotropic Effect of ß-Blockade Therapy Reduces Myocardial Oxygen Expenditure for Nonmechanical Work

Hideyuki Yamakawa, MD; Motoshi Takeuchi, MD; Hideyuki Takaoka, MD; Katsuya Hata, MD; Masuki Mori, MD; Mitsuhiro Yokoyama, MD

the First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.

Correspondence to Motoshi Takeuchi, MD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650, Japan.

	Abstract

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Background The negative chronotropic effect of ß-blocking agents is likely to provide hemodynamic and energetic advantages. However, the negative chronotropic effect on cardiac energetics observed on the initiation of ß-blockade therapy has not been fully elucidated.

Methods and Results In 18 patients with heart failure, left ventricular pressure and volume, external work (EW), myocardial oxygen consumption per beat (total O₂), mechanical efficiency (EW/total O₂), and O₂ for nonmechanical work (total O₂-2·EW) were measured with the use of conductance catheter and Webster catheter at the following three states: under control conditions and after ß-blockade (0.15±0.07 mg/kg propranolol IV) with and without atrial pacing to keep the heart rate at control levels. Heart rate decreased after atrial pacing was stopped. EW decreased during ß-blockade with pacing and returned to the control level after pacing was stopped. Total O₂ did not change during ß-blockade with or without pacing, whereas O₂ for nonmechanical work increased with pacing and returned to the control level after pacing was stopped. As a result, mechanical efficiency decreased during ß-blockade with pacing and returned to the control level after pacing was stopped.

Conclusions The negative chronotropic effect of a ß-blocking agent may offset the mechanoenergetical deterioration resulting from its negative inotropic effect through a reduction in oxygen expenditure for nonmechanical work. These findings suggest that the negative chronotropic effect is an important aspect of ß-blockade therapy.

Key Words: heart failure • ß-adrenergic receptor blockade • heart rate • energetics

	Introduction

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ß-Adrenoceptor blockade therapy, first described as a treatment for patients with heart failure in 1975,¹ has been widely accepted because of its clinical, hemodynamic, and neurohormonal benefits.^{1 2 3 4 5 6 7 8 9} Many clinical trials have indicated that most patients with heart failure are able to tolerate ß-blockade therapy and show little clinical and hemodynamic deterioration.^{2 3 4 5 6 7 8} Several mechanisms have been postulated to account for the beneficial effects of ß-blockade therapy: attenuation in neurohormonal activation,^{9 10 11} upregulation of ß-adrenoceptor,^{3 12} reduction in O₂,^{9 13 14} prevention of catecholamine-induced cardiac necrosis,^{15 16} and reduction in heart rate.^{1 2 17 18} Among these postulated mechanisms, the negative chronotropic effect is likely to have hemodynamic and energetic advantages.^{2 17 18 19} However, the influences of negative chronotropic effect per se, especially on cardiac energetics during initiation of ß-blockade therapy, have not been fully elucidated. A previous investigation has shown that myocardial energy expenditure consists of a mechanical work component, related to cross-bridge cycling, and a nonmechanical work component, related to excitation-contraction coupling.²⁰ Accordingly, to better understand the effects of ß-blockade on myocardial energetics, it is useful to discriminate between O₂ for mechanical work and O₂ for nonmechanical work.

In the present study, we focus on negative chronotropic effects on cardiac mechanoenergetics during acute ß-blockade. We compared the alterations in hemodynamics and energetics before and after intravenous administration of a ß-blocking agent, with and without right atrial pacing. The results suggest that the reduction in the component of O₂ associated with nonmechanical work, which results from the negative chronotropic effect, is an important part of the therapeutic benefit of ß-blockade therapy in patients with heart failure.

	Methods

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Patient Population
Eighteen patients (mean age, 57±10 years; 15 men and 3 women; 16 patients with previous myocardial infarction and 2 patients with dilated cardiomyopathy) undergoing cardiac catheterization for the evaluation of heart disease were enrolled in the study (Table 1). Patients with acute myocardial infarction, unstable angina pectoris, valvular heart disease, or high-risk hemodynamic instability were excluded. Mean left ventricular ejection fraction was 39±11%. No patients had dyskinetic left ventricular wall motion. Complete informed, written consent was obtained from each patient before the study, and no unfavorable complications occurred as a result of this investigation. The study protocol was approved by the Institutional Committee on Human Research at Kobe University Hospital.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Patients

Catheterization Procedure
All diuretics and vasodilators were withheld for at least 24 hours before the study. Patients underwent routine catheterization, including coronary angiography and left ventriculography. After completion of routine catheterization, a thermodilution Swan-Ganz catheter (Goodtech) was advanced into the pulmonary artery, a conductance (volume) catheter (CardioDynamics) was advanced into the left ventricle, and a Webster catheter (Wilton Webster Manufacturing Co) was advanced into the coronary sinus as confirmed by injection of contrast medium, as previously described.^{21 22 23}

Left ventricular pressure-volume relations were determined with the use of a conductance catheter attached to a stimulator/processor (Sigma-5, CardioDynamics), with a Millar catheter (Millar Instruments) advanced into the left ventricle through the lumen of the conductance catheter. This technique has been described previously.^{22 23 24 25}

Measurements of Pressure-Volume Parameters
After completion of calibrations, a balloon catheter (Baxter) was advanced to the right atrium just above the inferior vena cava to occlude venous return. After caval occlusion, pressure-volume loops were recorded over 8 to 10 beats to obtain the end-systolic pressure-volume relation (Fig 1A). Left ventricular pressure-volume data during the decrease in left ventricular pressure were fitted with the use of the linear least-squares technique to determine the following:

where E_max is a relatively load-independent index of myocardial contractility.

View larger version (40K): [in this window] [in a new window]   Figure 1. A, Pressure-volume loops obtained with the use of a conductance catheter during inferior vena caval occlusion. The end-systolic pressure-volume relation (ESPVR) was obtained through linear least-squares fitting of the end-systolic pressure-volume points during reduction in preload with inferior vena caval occlusion. Vo is the volume intercept of ESPVR. B, Emax is the slope of ESPVR. Ea is approximated by the ratio of ESP to SV. EW was calculated as an area bounded by the pressure-volume trajectory of one beat. PVA was calculated as an area bounded by ESPVR, the end-diastolic pressure-volume relation, and the systolic pressure-volume trajectory of the contraction. PE was calculated by subtracting EW from PVA.

E_a incorporates the principal elements of vascular load, including peripheral resistance, vascular compliance, characteristic impedance, and systolic and diastolic time intervals. This variable can be approximated by the steady state ratio ESP/SV, as shown schematically in Fig 1B. The ratio E_a/E_max represents ventriculoarterial coupling. EW was calculated as the area that is bounded by the pressure-volume trajectory of one beat, PVA was calculated as the area that is bounded by the end-systolic pressure-volume relation, the end-diastolic pressure-volume relation, and the systolic pressure-volume trajectory of each beat.²³ PE was calculated by subtracting EW from PVA.²³

Measurements of Cardiac Energetics
The coronary sinus catheter was advanced percutaneously through a left jugular vein to the great cardiac vein. In each instance, the catheter tip was angiographically verified to be beyond the origin of any visible intermediate or lateral branches and in proximity to the anterior cardiac vein. Coronary sinus blood flow was measured at least twice with a Webster catheter.^{26 27} Coronary venous blood samples were taken from the distal lumen of the Webster catheter for oximetry. O₂ per minute was calculated as the product of coronary sinus flow (mL/min) and the arterial-coronary sinus oxygen-content difference (vol%) and was divided by heart rate to yield O₂ per beat (mL O₂/beat).^{21 27 28} We calculated mechanical efficiency as the ratio of EW (J/beat) to O₂ per beat (J/beat), where 1 mm Hg·mL of EW and 1 mL O₂ of O2 correspond to 1.33x10^-4 and 20 J, respectively. The converting efficiency from metabolic energy to mechanical energy has been found to be 40% to 50%.^{20 21 29} Therefore, O₂ for EW was calculated as 2xEW. O₂ for nonmechanical work (O_2,non) was calculated as the following:

Because O_2,non consists of O₂ for PE (O_2,PE) and PVA-independent O₂,²⁰ O_2,non was also calculated as the following:

Study Protocol
Patients were divided into the two groups (with different order of protocol) to allow us to determine the possible influences of the study design. The study protocol for 10 patients was as follows. (1) In the control study, routine heart catheterization and calibrations were carried out; hemodynamic variables, pressure-volume loops, and coronary sinus blood flow were measured; and blood gas samples were collected from the coronary sinus and femoral artery during spontaneous sinus rhythm. Inferior vena cava occlusions were performed several times to obtain the end-systolic pressure-volume relation. (2) For the ß-blockade–with–pacing study, after control measurements were made, right atrial pacing was started to maintain heart rate at the control rate. An intravenous bolus of propranolol was injected carefully to decrease peak positive dP/dt by 10%. The mean dose of propranolol administered was 0.15±0.07 mg/kg. We repeated the same measurements as in the control study. (3) In the ß-blockade–without–pacing study, after all measurements with atrial pacing during acute ß-blockade were completed, atrial pacing was stopped. Five minutes later, we repeated the same measurements as performed previously at the slowed heart rate.

The study protocol for an additional eight patients was as follows: (1) control study, (2) ß-blockade–without–pacing study, and (3) ß-blockade–with–pacing study.

Because the results for the two groups of the other order of study protocol did not differ from each other, the combined data for 18 patients have been given ("Results").

Statistical Analysis
We obtained end-systolic pressure-volume relations with the use of linear regression analysis. ANOVA was applied to compare the alterations in hemodynamics and energetics during the three studies. When ANOVA demonstrated statistical significance, the Wilcoxon method with Bonferroni's correction was applied to compare the paired variables among the three studies. Differences were considered significant at a value of P<.05.

	Results

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The changes in cardiac hemodynamics are summarized in Table 2. During ß-blockade with pacing, heart rate and ESP remained unchanged, and EDP increased. After atrial pacing was stopped, heart rate decreased (-15.2±5.0%, P<.001), and ESP and EDP remained unchanged. Peak positive dP/dt decreased during ß-blockade with pacing and declined considerably after pacing was stopped. During ß-blockade with pacing, EDVI and ESVI did not change significantly, but SVI decreased. After atrial pacing was stopped, EDVI and ESVI increased, and SVI returned to the control level. Ejection fraction decreased during ß-blockade with pacing but remained unchanged after pacing was stopped.

View this table: [in this window] [in a new window]   Table 2. Changes in Hemodynamics With and Without Atrial Pacing During Acute ß-Blockade

Changes in pressure-volume parameters are shown in Table 3. E_max decreased and E_a increased during ß-blockade with pacing, resulting in deterioration of ventriculoarterial coupling. After pacing was stopped, E_max declined more, and E_a returned to the control level, resulting in improvement of ventriculoarterial coupling. EW decreased during ß-blockade with pacing and returned to the control level after pacing was stopped. PE increased during ß-blockade with pacing and tended to decline after pacing was stopped. As a result, PVA did not change during ß-blockade with pacing and increased after pacing was stopped.

View this table: [in this window] [in a new window]   Table 3. Changes in Mechanoenergetics With and Without Atrial Pacing During Acute ß-Blockade

Fig 2 demonstrates the influence of acute ß-blockade with and without atrial pacing on pressure-volume relations. After pacing was stopped, pressure-volume loop shifted rightward: SV, V₀, EW, and PVA increased, and E_max, E_a, and ventriculoarterial coupling decreased.

View larger version (33K): [in this window] [in a new window]   Figure 2. Schematic representation of the negative chronotropic effect on the pressure-volume relation during acute ß-blockade. The negative chronotropic effect of the ß-blocking agent caused a rightward shift of the pressure-volume loop and increases in SV, EW, and PVA. Vo is the volume intercept of ESPVR. Emax is the slope of ESPVR. Ea is approximated by the ratio of ESP to SV.

Changes in cardiac energetics are given in Table 3. O₂ per minute remained unchanged during acute ß-blockade with pacing and decreased after pacing was stopped. O₂ per beat remained unchanged with and without pacing during acute ß-blockade. As a result, the decrease in EW without a net change in O₂ per beat resulted in decreased mechanical efficiency during ß-blockade with pacing, which was associated with the increase in O₂ for nonmechanical work. After atrial pacing was stopped, mechanical efficiency returned to the control level; O₂ for nonmechanical work was reduced because of the recovery in EW without a net change in O₂ per beat (Fig 3).

View larger version (20K): [in this window] [in a new window]   Figure 3. The influence of acute ß-blockade with and without atrial pacing on mechanical efficiency. The negative chronotropic effect of the ß-blocking agent offset the decrease in mechanical efficiency caused by its negative inotropic action.

Fractional changes in O₂ are demonstrated in Fig 4. Oxygen expenditure for nonmechanical work increased during ß-blockade with pacing and returned to the control level after pacing was stopped. Moreover, O₂ for PE as well as PVA-independent O₂, two components of O₂ for nonmechanical work, tended to decrease after atrial pacing was stopped.

View larger version (58K): [in this window] [in a new window]   Figure 4. Changes in O2 (VO2) with and without atrial pacing during acute ß-blockade. Both O2 for PE and PVA-independent O2 were decreased by the negative chronotropic effect of the ß-blocking agent, resulting in a decrease in O2 for nonmechanical work. Thus, the negative chronotropic effect offset the oxygen expenditure for nonmechanical work due to the negative inotropic action.

	Discussion

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In the present study, we hypothesized that the negative chronotropic effect of ß-blocking agents is an advantageous aspect of ß-blockade therapy in terms of cardiac mechanoenergetics. To test this hypothesis, a ß-blocking agent was administrated, and cardiac mechanoenergetics, with and without right atrial pacing, were compared. When control heart rate was maintained through atrial pacing during acute ß-blockade, EW decreased with no net change in O₂ per beat, indicating a reduction in mechanical efficiency. When heart rate slowed after atrial pacing was stopped, EW increased with no net change in O₂ per beat, indicating that mechanical efficiency had returned to the control level. O₂ for nonmechanical work increased during ß-blockade with pacing and decreased to the control level after pacing was stopped. That is, the negative chronotropic effect of the ß-blocking agent reduced oxygen expenditure for nonmechanical work and, therefore, offset the deterioration in mechanical efficiency caused by its negative inotropic action.

Improvement in mechanical efficiency caused by a negative chronotropic effect occurred due to an increase in EW with no change in O₂ per beat. In the present study, ESP remained unchanged, and SV index was increased. Therefore, the increase in EW can probably be attributed to an increase in SV due to improvement in diastolic filling. Although a mechanism by which the negative chronotropic effect can improve diastolic filling has not been fully explained, prolongation of the diastolic period and a decrease in wall stiffness may contribute to this improvement.²

The constancy of O₂ per beat seen with the negative chronotropic effect, despite an increase in EW, may be related to a decrease in contractility and a reduction in afterload. A decrease in contractility is known to reduce O₂ for nonmechanical work.^{20 30} Suga²⁰ reported that a negative inotropic agent reduced O₂ for nonmechanical work in the isolated canine heart; this decrease was due to a reduction in O₂ for excitation-contraction coupling.^{20 30} In the present study, the peak positive dP/dt and E_max decreased significantly, and the V₀ increased significantly after pacing was stopped (data not shown). Thus, left ventricular contractility was further reduced by the negative chronotropic effect. Accordingly, O₂ for nonmechanical work may be decreased by the negative chronotropic effect of a ß-blocking agent.

Hata et al³¹ reported that appropriate afterload reduction increased EW and decreased PE without changing left ventricular contractility and O₂. Thus, afterload reduction can improve mechanical efficiency. Previous investigations with ventriculoarterial coupling also demonstrated that reduction in afterload rather than in preload plays an important role in restoring optimal ventricular load coupling.^{32 33} Afterload reduction would decrease PE by improving ventriculoarterial coupling. In the present study, the negative chronotropic effect of a ß-blocking agent decreased E_a and optimized ventriculoarterial coupling, thereby decreasing PE, an element of O₂ for nonmechanical work. Unlike our result, Haber et al³⁴ demonstrated that ventriculoarterial coupling was preserved during acute ß-blockade; in their study, the changes in E_max were similar but E_a decreased. The difference may be in part accounted for by the influences of ß-blocking agent on ESP, which remained unchanged in our study but decreased in their study. Ventriculoarterial coupling deteriorated by 20% in their study, which is consistent with our result (E_a/E_max increased by 21%). Thus, the difference in the acute response of ventriculoarterial coupling to ß-blockade does not appear to be crucial, and the alteration in ventriculoarterial coupling appears to be similar in the two studies.

These two beneficial effects of the negative chronotropic effect on cardiac energetics offset the increase in O₂ for EW, resulting in the preservation of the net O₂.

It is noteworthy that the negative chronotropic effect provided a reduction in oxygen expenditure for nonmechanical work per beat. Many studies have demonstrated that the patients with heart failure are already in a critical stage of cardiac energetics.^{35 36 37} Any further energy expenditure may be disastrous to the failing heart. Therefore, it is likely that the reduction in oxygen expenditure for nonmechanical work resulting from the negative chronotropic effect would be an important mechanism to account for the salutary effect of ß-blockade therapy.

There have been several studies of the effects of long-term ß-blockade on cardiac energetics.^{4 5 9 38} The results have been conflicting. Andersson et al³⁸ reported that long-term metoprolol treatment improved hemodynamic status in patients with dilated cardiomyopathy at rest and had a more pronounced effect during exercise, with improved or stable myocardial metabolic data. Mechanical efficiency was shown to be preserved with long-term bucindolol therapy⁴ or improved with long-term metoprolol treatment.⁵ O₂ per minute increased with bucindolol⁴ but did not change with metoprolol,⁵ whereas EW increased in both studies. Further investigation is required to clarify the effects of long-term as well as short-term ß-blockade therapy on cardiac energetics.

Study Limitations
There are several limitations in the present study. First, we used a nonselective ß-blocking agent, propranolol. If we had used a cardioselective ß-blocking agent, the results might have been somewhat different. However, we wanted to demonstrate the benefits and importance of the negative chronotropic effect of propranolol on cardiac mechanoenergetics. Second, the hearts of the patients studied were markedly but not severely depressed. The results might be different in patients with severe heart failure because the adrenergic drive would be greater.^{10 11} Therefore, these findings can be applied to patients with mild-to-moderate heart failure. Finally, we focused on the short-term effects of a ß-blocking agent, not on its long-term effects. We speculate that the negative chronotropic effect may also play an important role in long-term ß-blockade therapy, but further investigation is required.

Conclusions
We evaluated the influences of the negative chronotropic effect on left-ventricular hemodynamics and energetics in patients with heart failure during acute ß-blockade. Our results have demonstrated that by reducing the oxygen expenditure for nonmechanical work, the negative chronotropic effect of a ß-blocking agent may offset mechanoenergetic deterioration caused by its negative inotropic action. These findings suggest that the negative chronotropic effect is an important advantageous aspect of ß-blockade therapy.

	Selected Abbreviations and Acronyms

 

Ea = effective arterial elastance EDP = end-diastolic pressure EDVI = end-diastolic volume index Emax = slope of linear end-systolic pressure-volume relation ESP = end-systolic pressure ESVI = end-systolic volume index EW = external work PE = potential energy PVA = pressure-volume area SVI = stroke volume index V0 = volume-axis intercept of the end-systolic pressure-volume relation O2 = myocardial oxygen consumption

Received November 16, 1995; revision received January 23, 1996; accepted January 29, 1996.

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