(Hypertension. 2001;37:1216.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Mechanisms of Carvedilol Action in Human Congestive Heart Failure
From the Department of Cardiovascular Medicine, Alfred Hospital and Baker Medical Research Institute, Melbourne, Australia.
Correspondence to Dr David M. Kaye, Baker Medical Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail david.kaye{at}baker.edu.au
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Abstract |
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Abstract—The precise mechanism by which ß-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, ß2-adrenoceptor–mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17±1% to 28±3%; P<0.01) and left ventricular stroke work (87±13 to 119±21 g · m per beat; P<0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33±0.04 to 0.42±0.04; P=0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.
Key Words: heart failure • norepinephrine • beta-antagonists • myocardium • energy metabolism
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Introduction |
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Congestive heart failure has been extensively characterized as a disorder arising from a complex interaction between impaired ventricular performance and neurohormonal activation. Over the past decade, clinical trials have highlighted the beneficial actions of pharmacological approaches to modulating the renin-angiotensin system in congestive heart failure, and more recently the value of antagonizing the effects of sympathetic overactivity has emerged.
While the precise mechanism of the beneficial clinical and hemodynamic actions of ß-adrenoceptor blockers remains unclear, several possibilities have been proposed, including heart rate reduction, modulation of systemic neurohormonal activity, antagonism of the toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. Although it had been proposed that nonselective ß-antagonists may be more beneficial in the management of heart failure because of potential presynaptic modulation of catecholamine release,1 recent reports of the use of bisoprolol and metoprolol have clouded this issue.2 3
In the present study we sought to evaluate whether the beneficial hemodynamic actions of carvedilol in patients with congestive heart failure could be explained by alterations in sympathetic nervous tone or myocardial metabolism.
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Methods |
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The study population consisted of 10 consecutive patients (all male; mean age, 55±3 years) with stable congestive heart failure who were commencing carvedilol therapy. In 6 patients heart failure was due to a nonischemic dilated cardiomyopathy, and in the remaining 4 it was due to ischemic heart disease. All patients were treated with an angiotensin-converting enzyme inhibitor and a diuretic, and all but 1 patient were on digoxin. The mean left and right ventricular ejection fractions, assessed by radionuclide ventriculography, were 17±1% and 45±5%, respectively. Before the commencement of carvedilol therapy, patients underwent invasive hemodynamic evaluation, neurochemical assessment of cardiac and total systemic sympathetic function, and biochemical assessment of myocardial energetics. After baseline catheterization studies, carvedilol therapy was commenced and up-titrated to 50 mg/d as tolerated, according to previously published guidelines.4 After 3 months of stable carvedilol therapy, repeated radionuclide ventriculography and cardiac catheterization were performed. All patients gave written informed consent, and the study was performed with the approval of the Alfred Hospital Ethics Review Committee.
Study Outline and
Catheterization Protocol
All studies were performed in the morning, and
medications were continued in all cases to avoid
hemodynamic instability. A balloon-tipped
thermodilution catheter (7F Arrow, Arrow International) was inserted
via an introducer sheath placed in the right internal jugular vein for
the determination of pulmonary arterial pressures,
wedge pressure, and cardiac output. A right radial arterial
line was placed for arterial blood pressure measurement and
blood sampling.
After the hemodynamic assessment, a coronary sinus thermodilution catheter (Webster Laboratories) was positioned in the coronary sinus under fluoroscopic control. The tip of the catheter was positioned at least 2 cm proximal to the orifice of the coronary sinus, as confirmed by injection of radiographic contrast. Coronary sinus blood flow was estimated by thermodilution, and an average was determined from at least 2 measurements.
Radiotracer Determination of Adrenergic
Activity
Cardiac and total systemic norepinephrine
and epinephrine kinetics were determined by isotope dilution,
as originally reported by our
group.5 6 7
In brief, radiolabeled
L-[7-3H]norepinephrine
and
L-[N-methyl-3H]epinephrine
were continuously infused (0.5 to 1 µCi/min) into a
peripheral vein to achieve a steady state plasma
concentration. The total systemic spillover rate for
norepinephrine and epinephrine was calculated as
the ratio of the radiotracer infusion rate to the plasma specific
activity of norepinephrine and epinephrine in
plasma, respectively. The rate of clearance of
norepinephrine and epinephrine from the circulation
was calculated as the ratio of the infusion rate of each radiotracer to
the concentration of norepinephrine and
epinephrine, respectively, in arterial plasma. The
rate of norepinephrine (or epinephrine)
spillover from the heart was calculated by the modified Fick
equation
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Measurement of Left Ventricular
Energetics
Myocardial oxygen consumption
(MVO2) and carbon dioxide production
(MVCO2) were calculated as the product of
the coronary sinus blood flow and the coronary
sinus–arterial concentration difference for each gas. The
concentration of oxygen and carbon dioxide in blood was calculated by
standard
methods.8 9 Left
ventricular work (LVW) was determined from the following
formula8 : LVW=Cardiac
Outputx(Arterial Systolic Pressure-Wedge
Pressure)x0.0136. Ventricular mechanical efficiency (MEF)
was calculated as the ratio of LVW to the myocardial energy expenditure
(MEE). MEE was calculated according to the following calorimetric
relationship10 : MEE
(J · min-1)=(0.08xMVO2+0.034xMVCO2)x4.18.
Calculation of the MEF was also confirmed by the following
relationship: MEF=LVW/(MVO2x2.059). Myocardial
respiratory quotient (RQ) was calculated as
RQ=MVCO2/MVO2.
Biochemical Assays
Blood samples collected for catecholamine
assay were immediately transferred to ice-chilled tubes containing EGTA
and reduced glutathione. Samples were stored on ice, and plasma was
subsequently separated by centrifugation at 4°C.
Plasma samples were stored at -70°C until assay. Plasma
norepinephrine and epinephrine concentrations were
determined by high-performance liquid
chromatography, as previously
described.11 The plasma
specific activity of tritiated norepinephrine and
epinephrine was determined by performing timed fraction
collections of the eluant leaving the detector cell. Cross
contamination of the tritiated fractions was minimal (typically
<0.1%). Radioactivity was subsequently determined by liquid
scintillation spectroscopy.
Statistical Methods
Data are presented as mean±SEM. When
normally distributed, paired data analysis was performed by a
paired t test. Paired
analysis of data that was not normally distributed was
conducted with the Wilcoxon signed rank test. A
P value <0.05 was considered
statistically significant.
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Results |
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After 3 months of enrollment in the study, the average total daily dose of carvedilol was 42.5 mg/d. Carvedilol therapy was individually titrated according to heart rate, blood pressure, and features of congestive heart failure. Carvedilol therapy was associated with an improvement in New York Heart Association class from 2.9±0.1 to 2.1±0.2 (P<0.01).
Hemodynamic Response to
Carvedilol
As outlined in
Table 1, 3 months of carvedilol therapy was associated with
a significant reduction in the resting heart rate, consistent
with adrenergic blockade. No significant changes in systemic or
pulmonary arterial pressures were evident. The
study group demonstrated a significant improvement in both left and
right ventricular ejection fraction. While the resting
cardiac output was unchanged by carvedilol therapy, a substantial rise
in stroke volume was evident (57±6 to 75±7 mL;
P<0.05). Although the resting
left ventricular work was not significantly altered by
carvedilol therapy, this was achieved at a lower heart rate in the
presence of carvedilol. Accordingly, calculation of the left
ventricular stroke work demonstrated a significant
improvement from 87±13 to 119±21 g · m per beat
(P<0.05) with carvedilol
therapy.
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Adrenergic Response to Carvedilol
Therapy
Consistent with the diagnosis of heart
failure, the baseline plasma norepinephrine and
epinephrine concentrations were elevated, at 2.5±0.3 nmol/L
and 456±121 pmol/L
respectively.7 12
After 3 months carvedilol therapy, we were unable to detect any change
in the plasma concentrations of norepinephrine or
epinephrine. In conjunction, we did not detect any change in
the total systemic spillover rate or clearance for either
norepinephrine or epinephrine
(Figures 1 and 2). Although patients had
symptomatically and hemodynamically only
moderate heart failure, measurement of the cardiac
norepinephrine spillover rate at baseline revealed
marked sympathetic nervous activation
(Figure 3). At the end of the 3-month treatment period, no
evidence of an effect on the cardiac spillover rate for either
norepinephrine or epinephrine or the respective
transcardiac extraction was apparent
(Figure 3).
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Ventricular Mechanics and Oxygen
Consumption
To evaluate the influence of carvedilol on the
myocardial metabolism and mechanical efficiency on the
failing heart, we also performed simultaneous
arterial and coronary sinus blood gas
analysis. In conjunction with the rise in left
ventricular stroke work, carvedilol therapy was associated
with an increase in myocardial oxygen consumption, when indexed to
heart rate
(Table 2). No changes in the myocardial efficiency or
respiratory quotient were apparent. Although the myocardial energy
expenditure remained unchanged overall, there was a trend toward higher
energy expenditure per beat
(Table 2).
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Discussion |
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The adverse influence of sustained sympathetic nervous overactivity on both myocardial function and survival is now well recognized both experimentally and clinically.13 14 15 16 17 In combination with these findings, recent reports describe favorable effects of ß-adrenoceptor antagonists on symptomatic status and mortality in patients with congestive heart failure.2 4 18 19 Together, these observations highlight the importance of the sympathetic nervous system as a therapeutic target in heart failure.
The exact mechanism responsible for the favorable hemodynamic actions of ß-adrenoceptor blockers remains unclear. For carvedilol specifically, ß1-adrenoceptors could yield beneficial actions via heart rate reduction, antagonism of the toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics.20 21 The presence of ß2-adrenoceptor antagonism may also be of importance because of a potential role in the presynaptic modulation of catecholamine release.1 Finally, carvedilol also displays antioxidant actions, although the relevance of this property remains uncertain.
While the beneficial effects of ß-adrenoceptor blockade are increasingly appreciated, controversy continues to surround the relative merits of nonselective compared with ß1-selective adrenoceptor antagonists.19 22 On the basis of these differences, it has been proposed that the additional ß2-adrenoecptor antagonism provided by agents such as carvedilol may be of clinical relevance. In this context, it has been reported that activation of myocardial ß2-adrenoecptors increases contractility and under certain circumstances may facilitate the development of ventricular arrhythmias.23 24 25 The potential clinical importance of the myocardial ß2-adrenoceptor in the failing heart has been highlighted by observations that it does not undergo downregulation, as displayed by the ß1-adrenoceptor. The ß2-adrenoceptor has also been identified both experimentally and clinically in sympathetic ganglia and in postganglionic sympathetic nerve terminals,1 26 27 28 29 30 where it appears to facilitate the release of norepinephrine.
While the reported beneficial actions of long-term administration of nonselective ß-adrenoceptor antagonists, such as carvedilol, could potentially be explained by multiple actions, the precise mechanism remains unclear. Accordingly, the aim of this study was to evaluate the influence of long-term carvedilol therapy on systemic and cardiac adrenergic state, measured by the isotope dilution method, and ventricular function and metabolism.
In agreement with previous reports, carvedilol therapy in the present study was associated with a significant improvement in left ventricular ejection fraction.19 31 32 As with other studies,31 no change in cardiac output was evident. The pulmonary capillary wedge pressure did not fall in our study, being only modestly elevated compared with some other studies. As such, the results of our study may differ from those of others on the basis of a relatively milder degree of hemodynamic impairment. Resting heart rate was significantly reduced by carvedilol, consistent with a significant degree of ß-adrenoceptor blockade, although it did not correlate with the improvement in left ventricular ejection fraction. In the present study we did not include a control group because the principal aim of the study was to examine the relationship between the apparent improvement in ß-adrenoceptor blockade–mediated improvement in ejection fraction and potential candidate mechanisms.
In the present study we could not demonstrate any effect of carvedilol on either plasma norepinephrine or epinephrine or their respective rates of spillover to plasma from the heart or total circulation. In previous studies, we and others12 33 34 have shown that the elevation of plasma norepinephrine represents the combined influence of reduced clearance and increased spillover from the sympathetic nervous system to plasma. The lack of change of the total clearance rate of norepinephrine from plasma is readily explained by the absence of a change in cardiac output after therapy. Previous work demonstrates that norepinephrine clearance is particularly dependent on cardiac output.6 35 The total systemic spillover rate of norepinephrine to plasma in patients with heart failure, as an integrated index of sympathetic nervous activity, is particularly influenced acutely by arterial hypotension.35 The lack of change of the total norepinephrine spillover rate is consistent with the absence of a change in arterial blood pressure and, furthermore, contradicts the notion that the lipophilic ß-adrenoceptor blocking agents might exert some of their actions via actions in the central nervous regulation of sympathetic outflow.36
Despite the introduction of carvedilol, the average cardiac norepinephrine spillover rate of our study group remained approximately 3 times that of previously described healthy subjects.12 Although recent observations by Newton and colleagues1 34 suggest that acute alterations in the release or norepinephrine from cardiac sympathetic nerve terminals can be effected by pharmacological manipulation of presynaptic ß2-adrenoceptors, the present study does not support this notion. Unlike our study, in their acute studies significant changes in ventricular contractility and coronary sinus blood flow were possible confounding factors. Previously, Gilbert and colleagues31 reported that carvedilol, unlike metoprolol, was associated with a reduction in the transcardiac norepinephrine concentration gradient, although coronary sinus blood flow and norepinephrine extraction were not accounted for. Unlike our study, carvedilol treatment was associated with a significant fall in pulmonary capillary wedge pressure, and accordingly the fall in cardiac norepinephrine release may have been due in part to hemodynamic factors per se.35 Alternatively, Cousineau et al,37 using a multiple indicator methodology, showed that although an apparent reduction in the local release rate for norepinephrine was apparent after ß-blockade, this phenomenon was the result of altered local permeability rather than a true change in the release rate. In the present study we also observed net release of epinephrine from the failing heart, as previously reported by us,7 and carvedilol did not appreciably alter the rate of release.
In the present study we also tested the proposed notion that one of the favorable effects of ß-adrenoceptor blockade in heart failure was due to a reduction in oxygen consumption, as proposed by Eichhorn et al.38 In the present study carvedilol therapy was associated with no overall change in myocardial oxygen consumption, although when heart rate changes are considered, a significant rise in oxygen consumption per beat was detected. This rise may be explained by the increase in stroke work, while mechanical efficiency was unchanged. Of interest, Yamakawa and coworkers21 showed that acute ß-blockade in patients with heart failure was not accompanied by a fall in total myocardial oxygen consumption, but rather by a selective reduction in the oxygen consumed for nonmechanical work. Furthermore, this study did not demonstrate any beneficial effects on mechanical efficiency. The antioxidant properties of carvedilol could also potentially explain the beneficial actions of the drug. In an attempt to examine this possibility, we sought to determine the transcardiac concentration gradient of the lipid peroxidation product malondialdehyde. However, we could not detect a net malondialdehyde gradient, making this measurement unsuitable for further exploration of the antioxidant property of carvedilol (data not shown).
In summary, the present study confirms the favorable effects of carvedilol on left ventricular ejection fraction and stroke work in patents with congestive heart failure. Despite these improvements, no significant alterations in global or cardiac adrenergic drive were evident, suggesting that modulation of catecholamine release does not explain the beneficial effect of carvedilol. Furthermore, although carvedilol treatment was associated with a rise in oxygen consumption, it did not substantially alter mechanical efficiency. These findings therefore suggest that the principal mode of action of ß-blockade in heart failure is probably via protection against the toxic effect of catecholamines on the heart.
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Acknowledgments |
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This study was supported by an institute grant from the National Health and Medical Research Council of Australia. Dr Kaye is the recipient of a Wellcome Trust Senior Research Fellowship. The expert technical assistance of Cleo Martin, RN, and Karen Murchie, BSc, is gratefully acknowledged.
Received September 27, 2000; first decision October 24, 2000; accepted October 24, 2000.
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