CLINICAL STUDY
Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure
A randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol
Marco Metra, MD*,*,
Savina Nodari, MD*,
Antonio D’Aloia, MD*,
Claudio Muneretto, MD ,
Alastair D. Robertson, PhD ,
Michael R. Bristow, MD, PhD and
Livio Dei Cas, MD*
* Cattedra di Cardiologia, Università di Brescia, Brescia, Italy
Cattedra di Cardiochirurgia, Università di Brescia; Brescia, Italy
Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado, USA
Manuscript received December 28, 2001;
revised manuscript received May 7, 2002,
accepted June 27, 2002.
* Reprint requests and correspondence: Prof. Marco Metra, Cattedra di Cardiologia, c/o Spedali Civili, Piazza Spedali Civili, 25100 Brescia, Italy.
metramarco{at}libero.it
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Abstract
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OBJECTIVES: We compared the hemodynamic effects of dobutamine and enoximone administration before and after long-term beta-blocker therapy with metoprolol or carvedilol in patients with chronic heart failure (HF).
BACKGROUND: Patients with HF on beta-blocker therapy may need hemodynamic support with inotropic agents, and the hemodynamic response may be influenced by both the inotropic agent and the beta-blocker used.
METHODS: The hemodynamic effects of dobutamine (5 to 20 µg/kg/min intravenously) and enoximone (0.5 to 2 mg/kg intravenously) were assessed by pulmonary artery catheterization in 29 patients with chronic HF before and after 9 to 12 months of treatment with metoprolol or carvedilol at standard target maintenance oral doses. Hemodynamic studies were performed after  12 h of wash-out from all cardiovascular medications, except the beta-blockers that were administered 3 h before the second study.
RESULTS: Compared with before beta-blocker therapy, metoprolol treatment decreased the magnitude of mean pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP) decline during dobutamine infusion and increased the cardiac index (CI) and stroke volume index (SVI) response to enoximone administration, without any effect on other hemodynamic parameters. Carvedilol treatment abolished the increase in heart rate, SVI, and CI and caused a rise, rather than a decline, in PAP, PWP, systemic vascular resistance, and pulmonary vascular resistance during dobutamine infusion. The hemodynamic response to enoximone, however, was maintained or enhanced in the presence of carvedilol.
CONCLUSIONS: In contrast with its effects on enoximone, carvedilol and, to a lesser extent, metoprolol treatment may significantly inhibit the favorable hemodynamic response to dobutamine. No such beta-blocker–related attenuation of hemodynamic effects occurs with enoximone.
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Abbreviations and Acronyms
| | ACEI | | angiotensin-converting enzyme inhibitor | | ANOVA | | analysis of variance | | CI | | cardiac index | | HF | | heart failure | | HR | | heart rate | | LVEF | | left ventricular ejection fraction | | MAP | | mean arterial pressure | | NYHA | | New York Heart Association | | PAP | | mean pulmonary artery pressure | | PDE | | phosphodiesterase | | PVR | | pulmonary vascular resistance | | PWP | | pulmonary wedge pressure | | SVI | | stroke volume index | | SVR | | systemic vascular resistance |
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Despite the improvement obtained with the administration of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers, the natural history of chronic heart failure (HF) remains progressive, and many patients eventually develop decompensation. During decompensation, patients with HF are limited by dyspnea and fatigue at rest or with minimal exertion, require frequent hospitalizations, have a higher mortality rate, and both symptoms and prognosis become critically dependent on hemodynamic conditions (1–3). Treatment with inotropic agents may, thus, become necessary (4,5). In addition, beta-blockers, which are indicated for their long-term favorable actions (6–8), may be less well-tolerated in advanced HF patients because of their initial negative inotropic activity resulting from withdrawal of adrenergic support (9,10). The concomitant administration of an inotropic agent and a beta-blocker, therefore, may be necessary both in patients already on maintenance beta-blocker treatment who have progressed to decompensated HF and in patients with advanced HF who do not tolerate the initiation of beta-blockade (11,12). However, few studies have assessed the hemodynamic effects of different types of inotropic agents in patients on beta-blocker therapy (12–14).
The most common inotropic agents presenting clinical practice are the beta-adrenergic receptor agonist dobutamine and the type III phosphodiesterase (PDE) inhibitors, milrinone and enoximone. These two classes of drugs have important differences (15,16). In human ventricular myocardium, dobutamine is a partial beta1-receptor agonist (17) but also has action on beta2- and alpha1-postsynaptic adrenergic receptors. Its inotropic effects are, therefore, dependent on the degree of occupancy of the beta-adrenergic receptors and on the activity of beta-adrenergic signal transduction mechanisms (18,19). The type III PDE inhibitors block the breakdown of cyclic adenosine monophosphate, which in myocardial cells results in activation of protein kinase A, phospholamban, and L-type calcium channel phosphorylation. Phoshorylation of phospholamban results in relief of this regulatory protein’s inhibition of calcium adenosine triphosphatase activity, producing positive lusitropic and inotropic effects (15,16). As site of action of the type III PDE inhibitors is distal to beta-adrenergic receptors, their activity is less influenced by the degree of expression and coupling of beta-adrenergic receptors (12,14,19).
The beta-blockers metoprolol and carvedilol have both been shown to favorably affect the prognosis of the patients with HF (6–8). These agents have meaningful pharmacologic differences that might influence the response to inotropic agents (20–22). Metoprolol administration to patients with HF causes the upregulation of beta1-adrenergic receptors and leaves unoccupied, or may even recouple, beta2-adrenergic receptors (21,23). In contrast, carvedilol blocks both beta1- and beta2-adrenergic receptors, and also has alpha1-antagonist activity (21). We hypothesized that these differences would influence the hemodynamic responses to inotropic agents that act on adrenergic receptors, but would have less or no effect on agents that act beyond them. The aim of our study was, thus, to compare the hemodynamic effects of dobutamine and enoximone before and after long-term beta-blocker therapy with metoprolol or carvedilol in patients with chronic HF.
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Methods
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Patients.
We studied patients with chronic HF caused by an ischemic or nonischemic cardiomyopathy who had New York Heart Association (NYHA) functional class II to IV symptoms, a left ventricular ejection fraction (LVEF)  35% by radionuclide ventriculography, and ongoing treatment with furosemide and an ACEI. We excluded patients with an acute ischemic event or a coronary revascularization procedure within three months; a history of alcohol abuse, primary valve disease or congenital heart disease; frequent ventricular premature beats and/or runs of ventricular tachycardia; contraindications to beta-blocker therapy (e.g., bronchial asthma sensitive to the administration of beta-agonists); concomitant treatment with other beta-blockers, alpha-antagonists, calcium antagonists, or antiarrhythmic agents (except amiodarone). The protocol was approved by the Ethics Committee of the Hospital of Brescia. Written informed consent was obtained from all study patients.
Protocol
Hemodynamic measurements were obtained using a balloon-tipped, flow-directed pulmonary artery catheter inserted percutaneously into the right internal jugular vein. Cardiac output was assessed by the thermodilution method with the mean of three consecutive measurements with <15% variations between each other used for data analysis. Derived hemodynamic variables were calculated using standard formulas.
Once a reproducible baseline was obtained, the hemodynamic response to the inotropic agents was assessed. Because of its shorter elimination half-life, dobutamine was infused first, followed by a re-equilibration period of at least 1 h, then by enoximone administration. Dobutamine was infused at the increasing doses of 5, 10, 15, and 20 µg/kg/min with hemodynamic values measured after 15 min of infusion at each dose level. Dobutamine infusion was then discontinued, and hemodynamic variables were allowed to return to within 10% of the initial baseline values during the re-equilibration period. The second baseline, pre-enoximone measurements were obtained in triplicate, and enoximone was then administered as intravenous bolus injections in increasing increments of 0.5 mg/kg, repeated every 20 min to a maximal final dose of 2.0 mg/kg.
After the initial hemodynamic study, each patient was randomized to metoprolol tartrate or carvedilol, added to the ongoing therapy for HF, according to a protocol described previously (22). A second hemodynamic study that included the assessment of the response to dobutamine and enoximone administration was performed after 9 to 12 months of beta-blocker therapy, using the same protocol of the first study. In order to detect the maximal effects of the beta-blocker treatment on the hemodynamic response to the inotropic agents, the second hemodynamic study was performed 3 h after the last administration of either metoprolol or carvedilol at the standard doses used during chronic maintenance therapy. In contrast, all other cardiovascular medications were withdrawn at least 12 h before both the hemodynamic studies.
In addition to pulmonary artery catheterization, all patients were assessed by the NYHA functional classification and by radionuclide ventriculography, for the assessment of LVEF and volumes, before and after 9 to 12 months of beta-blocker therapy at maintenance doses.
Statistical analysis
Each of the 29 subjects was treated chronically with a beta-blocker (carvedilol or metoprolol) and acutely with two inotropes (dobutamine and enoximone) before and after beta-blocker treatment. There were no missing values. Using mean and variance data for the patients included in a previous study (14) and assuming a within-subject correlation of +0.50 and two-sided alpha of 0.05, a sample size of 13 carvedilol-treated subjects was calculated to have 90% power to detect a difference from baseline to end of study of 0.05 l/min/m2 per µg/kg/min in slope (over dobutamine dose of 0 to 20 µg/kg/min) of cardiac index (CI). This difference corresponds to a 45% relative decrease in slope, comparable to the 53% decrease seen in the previous study (14). Comparison of baseline data between the beta-blocker groups was by unpaired t test and chi-square test, as appropriate. Effects of chronic treatment were assessed by paired t test within-group and by analysis of variance (ANOVA) to compare between-group changes. Effects of acute treatment were assessed as changes from before dobutamine or enoximone administration, separately by each beta-blocker and inotrope. The paired t test was used to assess the within-visit effect of dose. Taking the design as that of the split-split-plot experiment (24,25), three-way repeated measures ANOVA was used to assess differences in linear slope of the dose-response curves. The paired t test was used to assess the within-dose effect of visit, when the slope differences were significant. A two-tailed p value <0.05 was considered significant. Results are expressed as mean ± SD unless otherwise specified. Reported p values are not adjusted for multiple comparisons.
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Results
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Patient characteristics and response to beta-blocker treatment.
We studied 34 patients, 27 males and 7 females, age 58 ± 10 years, with chronic HF caused by idiopathic dilated cardiomyopathy (22 patients) or by previous myocardial infarction (12 patients). Eight patients were NYHA functional class II, 25 were class III, and 1 was class IV. The patients had severe left ventricular dysfunction with a mean LVEF of 18.3 ± 6.6% and a moderate-severe impairment of maximal functional capacity, with a mean peak oxygen consumption of 13.3 ± 3.5 ml/kg/min. At end of study, all patients were treated with furosemide and an ACEI, 27 were on digoxin, 21 on spironolactone, and 2 patients were receiving amiodarone.
Patients randomized to metoprolol and to carvedilol were similar with respect to all pretreatment characteristics (Table 1). Five patients died before the end of the study, three suddenly (two in the metoprolol and one in the carvedilol group) and two for worsening HF. The remaining 29 patients completed the protocol and were reassessed after 10.4 ± 1.2 months (median time, 10 months) of beta-blocker therapy. Long-term therapy with metoprolol (mean dose, 129 ± 38 mg daily) or carvedilol (mean dose, 43 ± 11 mg daily) was associated with a significant improvement in clinical symptoms, left ventricular function, and hemodynamic parameters, with no significant difference in these parameters between the two study groups (Table 2).
Hemodynamic response to the inotropic agents
No significant difference in any parameter was detected before dobutamine compared to before enoximone infusion. The changes from baseline in the main hemodynamic parameters caused by dobutamine and enoximone administration, before and after metoprolol or carvedilol treatment, respectively, are shown in Figures 1 to 5. Before beta-blocker administration, CI increased after both dobutamine and enoximone infusions, in both treatment groups. Metoprolol treatment did not change the response to dobutamine, whereas the response to enoximone was augmented. Carvedilol treatment was associated with a significant inhibition of the CI response to dobutamine but not to enoximone administration (Fig. 1). Similarly, metoprolol treatment had no effect on the heart rate (HR) and stroke volume index (SVI) responses to dobutamine and slightly increased them after enoximone; carvedilol significantly inhibited these responses to dobutamine but not to enoximone (Fig. 2).
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Figure 1 Absolute changes (mean ± SEM) from baseline in cardiac index after dobutamine (left figures) or enoximone (right figures) administration, before (open symbols) and after (closed symbols) long-term beta-blocker treatment with metoprolol (upper figures) or carvedilol (lower figures). Asterisks immediately above or below the standard error bars indicate significance of dose-specific differences from baseline. Asterisks between the dose-response curves indicate significance of dose-specific differences in the changes from baseline between before and after beta-blocker therapy. Significance values at the bottom of each graph indicate differences between the slopes of the dose response curves before and after metoprolol or carvedilol treatment. *p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 2 Absolute changes (mean ± SEM) from baseline in heart rate and stroke volume index after dobutamine or enoximone administration, before (open symbols) and after (closed symbols) long-term beta-blocker treatment with metoprolol (upper figures) or carvedilol (lower figures). Significance of symbols as in Figure 1.
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Figure 3 Absolute changes (mean ± SEM) from baseline in the pulmonary wedge pressure and right atrial pressure after dobutamine or enoximone administration before (open symbols) and after (closed symbols) long-term beta-blocker treatment with metoprolol (upper figures) or carvedilol (lower figures). Significance of symbols as in Figure 1.
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Figure 4 Absolute changes (mean ± SEM) from baseline in the mean arterial pressure and systemic vascular resistance after dobutamine or enoximone administration before (open symbols) and after (closed symbols) long-term beta-blocker treatment with metoprolol (upper figures) or carvedilol (lower figures). Significance of symbols as in Figure 1.
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Figure 5 Absolute changes (mean ± SEM) from baseline in the mean pulmonary artery pressure and pulmonary vascular resistance after dobutamine or enoximone administration before (open symbols) and after (closed symbols) long-term beta-blocker treatment with metoprolol (upper figures) or carvedilol (lower figures). Significance of symbols as in Figure 1.
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Before beta-blocker therapy, dobutamine or enoximone administration caused a decline in both the pulmonary wedge pressure (PWP) and mean right atrial pressure. Metoprolol treatment was associated with a reduction in the magnitude of the PWP decline without any change in the direction of this response. Carvedilol treatment had a greater effect than metoprolol on the PWP lowering response of dobutamine as, in its presence, dobutamine infusion was associated with an increase, rather than a decline, in PWP. In contrast, the response to enoximone administration was not influenced by either metoprolol or carvedilol treatment (Fig. 3).
Before either metoprolol or carvedilol treatment, the mean arterial pressure (MAP) was not significantly changed by dobutamine infusion (Fig. 4). After metoprolol treatment MAP slightly, but significantly, increased from preinfusion values during dobutamine infusions of 15 and 20 µg/kg/min, respectively. This MAP increase was likely related to the increase in the CI, as it was accompanied by a dose-dependent decline in systemic vascular resistance (SVR). In contrast, enoximone caused a dose-dependent decline in MAP and SVR, both before and after metoprolol therapy. The MAP and SVR response to dobutamine was significantly affected by carvedilol treatment. In the presence of carvedilol, dobutamine infusion caused a dose-dependent increase in the MAP, which was accompanied by a similar increase in the SVR, in contrast with the decline observed before carvedilol treatment. In contrast, the MAP and SVR decline during enoximone administration was augmented by carvedilol therapy (Fig. 4).
Compared with effects on MAP and SVR, similar responses were observed with respect to mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) (Fig. 5). Before treatment with beta-blocking agents, these parameters declined during the administration of both inotropic agents. After metoprolol therapy dobutamine produced a directionally similar, but somewhat blunted, PAP and PVR response, while the enoximone PAP and PVR responses were unchanged. In contrast, after carvedilol treatment dobutamine infusion caused a significant, dose-dependent increase in the PAP and PVR, while the response to enoximone was similar to the pre-carvedilol treatment effects (Fig. 5).
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Discussion
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Potential need of concomitant beta-blocker and inotropic therapy.
Because of its beneficial effects on prognosis, beta-blocker therapy is now indicated in all the patients with chronic HF who do not have major contraindications. As a result, the number of patients on beta-blocker therapy who develop decompensated HF and who need inotropic therapy is likely to increase. Second, although the beneficial effects of beta-blockade have been shown in selected groups of patients with advanced HF (8), beta-blockers may be poorly tolerated, and the initiation of therapy may be particularly difficult in these patients (9,21). Thus, the concomitant administration of the inotropic agents and beta-blockers may become necessary both in the patients who develop decompensated HF while on chronic beta-blocker therapy and in patients who cannot tolerate the initiation of beta-blockers. However, meaningful differences are present among beta-blockers used to treat HF, as well as in inotropic agents. Thus, it is important to know whether these differences account for significant degrees of interaction between individual inotropes and beta-blockers when these two classes of compounds are used in combination. With this aim, we assessed the response to the two inotropic agents dobutamine and enoximone in a group of patients with HF, before and after long-term treatment with metoprolol or carvedilol. We excluded patients with advanced HF and in unstable clinical conditions in whom the initiation of beta-blocker treatment might be difficult and the hemodynamic responses may be affected by the instability of the clinical and hemodynamic conditions. However, we maintain that our results may be extrapolated to patients with advanced HF, whose response to beta-adrenergic agonists may be compromised to an even a greater extent because of even greater impairment of beta-adrenergic signal transduction mechanisms (14,18,19).
Dobutamine-metoprolol interaction
Our study demonstrates that the hemodynamic response to different inotropic agents may be profoundly influenced by the type of ongoing beta-blocker therapy. In particular, the hemodynamic response to the beta-adrenergic agonist dobutamine was affected only slightly by metoprolol, but to a far greater extent by carvedilol therapy. Before beta-blocker therapy, dobutamine infusion was associated with the expected hemodynamic effects, consisting of a dose-dependent increase in CI, HR, and SVI and a decrease in ventricular filling pressures (15,16,18). The SVR and PVR also showed a dose-dependent decline, mainly related to the increase in the CI as the alpha1-agonist vasoconstrictive activity of dobutamine is counteracted by its peripheral beta2-receptor–mediated vasodilating action (16).
Consistent with previous data (14), metoprolol only slightly affected the hemodynamic response to dobutamine infusion. This may be explained by many mechanisms. First, long-term metoprolol therapy may increase the beta1-adrenergic receptors density and improve beta-adrenergic signal transduction mechanisms, for instance, through the inhibition of the beta-adrenergic receptor kinase or downregulation in G i (12,13,18,20). These adjustments may sensitize the heart to beta1-adrenergic stimulation so that, when metoprolol is removed from the beta-receptors by mass action, the dobutamine response is preserved or even accentuated. Second, dobutamine has reasonably high affinity for myocardial beta2-adrenergic receptors (15,16), which have significant inotropic and chronotropic effects and are left unoccupied by the selective beta1-antagonist metoprolol. In addition, during the chronic administration of beta1-selective agents such as metoprolol, myocardial beta2-receptors exhibit improved coupling to intracellular signal transduction mechanisms, through cross-regulation (23). On the other hand, the slight reduction in the response of the PWP and PAP to dobutamine infusion that was observed after metoprolol therapy was likely related to beta1-receptor occupancy by metoprolol, and is consistent with a slight inhibition of the inotropic response to the beta1-agonist effects of dobutamine.
Dobutamine-carvedilol interaction
Unlike metoprolol, carvedilol profoundly affected the hemodynamic responses to dobutamine. The increases in the CI, HR, and SVI produced by the baseline dobutamine infusion were almost completely inhibited after carvedilol administration. This striking difference between the effects of the two beta-blockers may be ascribed to their different mechanisms of action. Unlike metoprolol, carvedilol does not cause operational beta1-adrenergic receptor upregulation and also blocks beta2-adrenergic receptors (21). These properties, although potentially useful in the long-term (22), may cause a greater inhibition of the effects of dobutamine. In addition to its more comprehensive antiadrenergic action, carvedilol also exhibits "tight binding" to beta-adrenergic receptors, making it more difficult for an agonist to displace it (26).
Concomitant carvedilol therapy also affected the dobutamine vascular resistance responses. In contrast with the decreases in SVR and PVR observed in patients treated with metoprolol, dobutamine infusion was associated with a dose-dependent increase in SVR and PVR in carvedilol-treated subjects. This effect has also been described in previous studies (12,14), and may be explained by persistent blockade of vascular beta2-adrenergic receptors, but not alpha1-adrenergic receptors, by carvedilol. In fact, carvedilol has a greater dissociation constant for alpha1- compared with beta1-adrenergic receptors (21). In addition, the alpha1-antagonist activity of carvedilol tends to decrease during long-term treatment, similarly to that shown with pure alpha1-adrenergic antagonists in the patients with HF (27). The persistent blockade of the beta1- and the beta2-adrenergic receptors with a concomitant stimulation of the peripheral alpha1-adrenergic receptors, thus, may explain the increase in the peripheral vascular resistance and PVR caused by dobutamine after long-term carvedilol administration.
Enoximone-beta-blocker interactions
In contrast with dobutamine, the hemodynamic responses to enoximone were less affected and, in the case of some parameters, even enhanced after long-term beta-blockade with either metoprolol or carvedilol. These data are in accordance with previous studies showing the favorable hemodynamic effects of milrinone administration during concomitant carvedilol treatment (12,14). The maintenance of the effects of the PDE inhibitors during carvedilol therapy is consistent with their mechanism of action, which is distal to and independent of occupancy of the beta-adrenergic receptors (15,16,19). These results also support the potential utility of combined therapy with a beta-blocker and a PDE inhibitor when it is necessary to improve hemodynamics while maintaining the long-term beneficial effects of beta-blockade in patients with advanced HF (28–30).
Conclusions
In conclusion, our study shows that the hemodynamic response to dobutamine may be influenced by the type of concomitant beta-blocker therapy. Prior and ongoing metoprolol therapy was only associated with an attenuation of the decrease in PWP and PAP produced by dobutamine infusion. In contrast with carvedilol treatment, the administration of dobutamine was associated with an almost complete inhibition of the increases in CI, HR, and SVI, and a tendency to a increase, rather than decrease, in MAP, SVR, PWP, PAP, and PVR. In marked contrast with dobutamine, the hemodynamic response to enoximone was not significantly inhibited by either concomitantly administered beta-blocking agent, and some responses were enhanced. These data favor the use of a PDE inhibitor over dobutamine when it is necessary to administer an inotropic agent to a patient on beta-blockade, particularly carvedilol.
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Footnotes
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This study was partially supported by CARIPLO funds from "Centro per lo Studio del Trattamento dello Scompenso Cardiaco" of the University of Brescia.
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A. Mebazaa, M. S. Nieminen, G. S. Filippatos, J. G. Cleland, J. E. Salon, R. Thakkar, R. J. Padley, B. Huang, and A. Cohen-Solal
Levosimendan vs. dobutamine: outcomes for acute heart failure patients on {beta}-blockers in SURVIVE
Eur J Heart Fail,
March 1, 2009;
11(3):
304 - 311.
[Abstract]
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F. Orso, S. Baldasseroni, G. Fabbri, L. Gonzini, D. Lucci, C. D'Ambrosi, M. Gobbi, G. Lecchi, S. Randazzo, G. Masotti, et al.
Role of beta-blockers in patients admitted for worsening heart failure in a real world setting: data from the Italian Survey on Acute Heart Failure
Eur J Heart Fail,
January 1, 2009;
11(1):
77 - 84.
[Abstract]
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A. Kotze and S. J. Howell
Heart failure: pathophysiology, risk assessment, community management and anaesthesia
CEACCP,
October 1, 2008;
8(5):
161 - 166.
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Authors/Task Force Members, K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J.V. McMurray, P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. van Veldhuisen, D. Atar, et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM)
Eur. Heart J.,
October 1, 2008;
29(19):
2388 - 2442.
[Full Text]
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K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J.V. McMurray, P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. van Veldhuisen, D. Atar, A. W. Hoes, et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM)
Eur J Heart Fail,
October 1, 2008;
10(10):
933 - 989.
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M. Metra, P. Ponikowski, K. Dickstein, J. J.V. McMurray, A. Gavazzi, C.-H. Bergh, A. G. Fraser, T. Jaarsma, A. Pitsis, P. Mohacsi, et al.
Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology
Eur J Heart Fail,
June 1, 2007;
9(6-7):
684 - 694.
[Abstract]
[Full Text]
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A. Mebazaa, M. S. Nieminen, M. Packer, A. Cohen-Solal, F. X. Kleber, S. J. Pocock, R. Thakkar, R. J. Padley, P. Poder, M. Kivikko, et al.
Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: The SURVIVE Randomized Trial
JAMA,
May 2, 2007;
297(17):
1883 - 1891.
[Abstract]
[Full Text]
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L. A. Allen and C. M. O'Connor
Management of acute decompensated heart failure
Can. Med. Assoc. J.,
March 13, 2007;
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[Abstract]
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M. M. Givertz, C. Andreou, C. H. Conrad, and W. S. Colucci
Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships
Circulation,
March 13, 2007;
115(10):
1218 - 1224.
[Abstract]
[Full Text]
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P. Molenaar, T. Christ, U. Ravens, and A. Kaumann
Carvedilol blocks {beta}2- more than {beta}1-adrenoceptors in human heart
Cardiovasc Res,
January 1, 2006;
69(1):
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[Abstract]
[Full Text]
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Endorsed by the European Society of Intensive Care, Authors/Task Force Members, M. S. Nieminen, M. Bohm, M. R. Cowie, H. Drexler, G. S. Filippatos, G. Jondeau, Y. Hasin, J. Lopez-Sendon, et al.
Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The Task Force on Acute Heart Failure of the European Society of Cardiology
Eur. Heart J.,
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A. T. Yan, R. T. Yan, and P. P. Liu
Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials
Ann Intern Med,
January 18, 2005;
142(2):
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[Abstract]
[Full Text]
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J. Boldt, C. Brosch, A. Lehmann, S. Suttner, and F. Isgro
The Prophylactic Use of the {beta}-Blocker Esmolol in Combination with Phosphodiesterase III Inhibitor Enoximone in Elderly Cardiac Surgery Patients
Anesth. Analg.,
October 1, 2004;
99(4):
1009 - 1017.
[Abstract]
[Full Text]
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M. Kindermann, C. Maack, S. Schaller, N. Finkler, K. I. Schmidt, S. Laer, H. Wuttke, H.-J. Schafers, and M. Bohm
Carvedilol but Not Metoprolol Reduces {beta}-Adrenergic Responsiveness After Complete Elimination From Plasma In Vivo
Circulation,
June 29, 2004;
109(25):
3182 - 3190.
[Abstract]
[Full Text]
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M. J. Lohse, S. Engelhardt, and T. Eschenhagen
What Is the Role of {beta}-Adrenergic Signaling in Heart Failure?
Circ. Res.,
November 14, 2003;
93(10):
896 - 906.
[Abstract]
[Full Text]
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J.-H. Kim, B. M. Ham, Y. L. Kim, J.-H. Bahk, H.-G. Ryu, Y.-S. Jeon, and K.-B. Kim
Prophylactic milrinone during OPCAB of posterior vessels: implication in angina patients taking {beta}-blockers
Eur. J. Cardiothorac. Surg.,
November 1, 2003;
24(5):
770 - 776.
[Abstract]
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