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European Journal of Heart Failure 2002 4(3):269-276; doi:10.1016/S1388-9842(01)00239-2
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© 2002 European Society of Cardiology

Myocardial contractile reserve under low doses of dobutamine and improvement of left ventricular ejection fraction with treatment by carvedilol

P. Jourdaina,*, F. Funcka, Y. Fullab, A. Hagegec, M. Bellorinia, N. Guillarda, J. Loireta, B. Thebaulta and M. Desnosc

a Service de Cardiologie Hôpital R. Dubos 6 avenue d’île de France, 95300 Pontoise, France
b Service de Médecine Nucléaire Hôpital Cochin Paris, France
c Service de Cardiologie Hôpital Georges Pompidou Paris, France

* Corresponding author. Tel.: +33-13075-4186; fax: +33-13075-4433


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
To examine the ability of myocardial contractile reserve (MCR) assessment to predict the improvement of left ventricular ejection fraction with treatment by carvedilol, a prospective study was undertaken in 85 patients with chronic heart failure and left ventricular ejection fraction <45%. Low dose dobutamine echocardiography (DSE), a 6-min walk test and measured brain natriuretic peptide (BNP) were assessed in all the patients. Patients were separated into two groups. Group A were patients without any myocardial reserve and group B patients with a myocardial contractile reserve defined as an increment of more than 20% of the resting left ventricular ejection fraction during dobutamine infusion. The two groups differed for percentage of ischemic cardiomyopathy (67.8 in group A vs. 29.7% in group B P=0.028), 6-min walk test performance (respectively, 343 vs. 415 meters P<0.05) and BNP plasma levels (respectively, 184.5 vs. 70.1 P<0.02) but not for left ventricular ejection fraction or NYHA class. During DSE, MCR and heart rate variation was higher in group B than in group A. At the end of the follow up, LVEF increased and NYHA class decreased in group B but not in group A. In multivariate analysis the existence of MCR could predict the improvement of LVEF with treatment by carvedilol. In our study, studying MCR could help to predict patients who will improve their LVEF with carvedilol prior to the administration of the treatment.

Key Words: Myocardial contractile reserve • Heart failure • Beta-blocker therapy

Received February 15, 2001; Revised August 29, 2001; Accepted September 12, 2001


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure is a disease with a severe prognosis. The average survival is 55% after 4 years [1]. Some studies have proved the beneficial effect of beta-blockers on mortality of patients suffering from heart failure [2–4]. However, some patients do not improve their left ventricular ejection fraction (LVEF) or develop some deleterious secondary effects.

Determination of myocardial contractile reserve (MCR) seems to be useful for determining prognosis in patients suffering from ischemic or non-ischemic cardiomyopathy [5,6]. This determination can be done using dobutamine stress echocardiography (DSE) [5–9].

At the present time, it is impossible to identify patients who will be ‘good responders’ in terms of improvement of LVEF to beta-blocker therapy [10] and we have not found any study about MCR and carvedilol therapy.

The goal of this study was to determine if the study of MCR could identify, among patients with a chronic systolic heart failure, those who would improve their LVEF under beta-blocker therapy.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
We have included prospectively, 85 consecutive patients between February 1999 and May 2000. Ischemic cardiomyopathy was defined as the existence of at least one stenosis >70% in at least two incidences during a selective coronary angiography carried out on all patients using the Sedlinger method.

The inclusion/exclusion criteria were:

Patients with a clinical systolic heart failure for more than 2 months. Diagnosis of heart failure was based on the association of clinical and functional signs associated with an LVEF <45% and a telediastolic diameter in trans thoracic echocardiography >55 mm.

All the patients were in sinus rhythm. All were stable for more than 1 month and had no contra-indication to the use of beta-blockers or dobutamine. Patients with systolic arterial pressure <85 mmHg and a heart rate <55 were excluded.

Patients receiving intravenous or oral positive inotropes other than digitalis were also excluded. All patients also had to have been treated for 2 months with stable and optimal doses of ACEI. No patient was treated with {alpha} or β-blockers prior to inclusion.

Six patients were excluded from the study at this stage of selection. Four were in atrial fibrillation and echogenicity was too bad to perform dobutamine echocardiography in two patients.

This protocol was accepted by the CPPRB (ethical committee) of Boucicaut's Hospital and conforms to the Helsinki principles.

Echocardiography was performed in left lateral decubitus with a Hewlett-Packard 3500 echocardiograph using American Society of Echocardiography (ASE) methodology [11]. Left ventricular ejection fraction (LVEF) was measured using a modified Simpson method in apical 4 and 2 cavities position. Peak velocity of E and A waves and deceleration time of the E wave were measured with a pulsed Doppler.

Dobutamine stress echocardiography (DSE) was carried out by a qualified echocardiographer with a nurse before the introduction of carvedilol. Arterial pressure and heart rate were monitored continuously by a H.P system. We used limited doses of dobutamine following the recommendation for detection of myocardial viability. We used 5, 10 and 20 {gamma}/kg per min of dobutamine administered by an intravenous catheter. Doses were increased every 4 min. All measurements were taken at the basal state and at each dose stage. At every stage, arterial pressure, heart rate and a 12-lead electrocardiogram were measured and recorded. Dobutamine perfusion was stopped after 20 {gamma}/kg per min of dobutamine administered for 4 min. We have not targeted any theoretical maximal heart rate because we wanted to appreciate viability and not ischemia. All the patients reached the target dose of dobutamine. After DSE, patients were placed under observation for 15 min. An ECG was performed at 6 and 15 min after the end of the test. Arterial pressure and heart rate were measured at the same time. Intra-observer variability was <5% for determining LVEF.

Myocardial contractile reserve or response under 20 {gamma}/kg per min of dobutamine was defined in our study as the existence of an increment of more than 20% of resting LVEF under dobutamine. This definition was based on the intra-observer variability. In the case of patients with ischemic cardiomyopathy, we took the ‘best response’ under dobutamine, so that we avoided to minimize response to dobutamine in case of biphasic response of ischemic segments. The doses of dobutamine were lower than some other studies in order to minimize the adverse effects.

The 6-min walk test was carried out on flat ground. We measured the maximal distance covered by the patient in 6 min, following Roul's recommendations [12]. The first time, the test was carried out twice (two tests separated by at least 30 min) to minimize patients’ misunderstanding. We have recorded only the second test.

Samples to measure brain natriuretic peptide plasma levels were taken with EDTA and aprotinin. They were centrifuged at –4 °C/4000 rev. per min and stored at –80 °C. Assay of plasma BNP levels was done using a commercial radioimmunoassay (Cis Bio International Kit under Shionogi license) in the Nuclear Medicine Department, Cochin Hospital.

2.1. Statistical analysis
All data were stored using Excel 98. Statistical analysis was carried out using Sigmastat 2.0 and Statview 5.0 software. Parametric data were compared using Student's test. Non-parametric data were studied using the Mann–Whitney test. All data were as mean±standard deviation. A P<0.05 was considered as statistically significant. Rates were compared using the {chi}2 test. Multivariate analysis was done with multiple linear regression analysis.

2.2. Treatment by carvedilol
Patients were hospitalized for the selection visit. DSE, 6-min walk test and BNP levels were evaluated. Test doses of 3.125 mg of carvedilol were given to the patient and heart rate and arterial pressure were monitored for 4 h. Every 15 days the patient came back to the hospital to increase dosage of carvedilol. At each visit, we carried out a 6-min walk test, measured BNP plasma levels, and monitored heart rate and arterial pressure for 2 h. The target dose of carvedilol was 50 mg/day for patients <80 kg and 100 mg/day in patients >80 kg. Eighty percent of patients reached this ‘optimal defined’ dose of carvedilol. The duration of the titration period was 2 months in all the patients who reached the optimal daily dose of carvedilol.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. At the inclusion
We classified patients into two groups according to their MCR function. Group A contained patients without any MCR in DSE and group B contained patients with an MCR in DSE. Characteristics of the two groups are given in Table 1. Under DSE, we noticed an important increase of LVEF in group B with a LVEF of approximately 46% under 20 {gamma}/kg per min of dobutamine (P<0.001). In group A there was no increase of rest LVEF (NS). Under DSE, the two groups differed for maximal LVEF and maximal heart rate which were significantly higher in group B (respectively, 46.6±13.4% vs. 33.2±17% and 102±14 vs. 80.1±18.1) (P<0.001). LVEF under DSE was correlated to rest LVEF (Fig. 1). There was more ischemic cardiomyopathy in A group than in B group (71 vs. 33.3%) (P=0.016). Plasma BNP levels were lower in B group than in A group (70.1±62 pg/ml vs. 184.5±89) (P=0.016). However, 6-min walk test performance and basal heart rate were higher in B group than in A group (respectively, 415±65 m vs. 343.4±90 m and 79.4±11 vs. 71.2±10) (P<0.05). There was no difference in terms of mean daily dose of carvedilol between the two groups (40.2±10 mg vs. 38.7±9 mg, respectively) (Fig. 2).


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  		Table 1 Population characteristics

 


Figure 1
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  		Fig. 1 Relation between LVEF at rest and under DSE.

 


Figure 2
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  		Fig. 2 Evolution of hemodynamic and echographic parameters during DSE.

 
As to the basal state, variation between the two groups was statistically significant for MCR (52±29% in B group and –4±14.5% in A group) and the heart rate variation (HRV) (30±14 b.p.m. in B group vs. 12.8±10) (P<0.001).

We did not observe any severe secondary events during DSE. Some patients related some non-serious adverse events which are reported in Table 2. No event led to stopping the DSE and no patient was hospitalized at the end of the DSE. All the patients tolerated the test dose of carvedilol.


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  		Table 2 Side effects of DSE

 
3.2. Follow-up
Therapeutics other than diuretics were not modified during the follow-up period (Table 3). Diuretics were optimized in function of congestion. Target doses of carvedilol were defined as 50 mg daily for patients <80 kg and 100 mg daily for patients >80 kg. Seventy-five percent of patients reached the target doses of carvedilol. The follow up visit took place 6.8±0.5 months after optimal treatment by carvedilol. Total duration of the study, including titration period was 8.6±2 months. Concomitant treatments at the end of the follow up are reported in Table 4. Patients without any MCR had more diuretics than patients with MCR (P<0.05) (Fig. 3).


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  		Table 3 Follow up

 


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  		Table 4 Treatments

 


Figure 3
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  		Fig. 3 Evolution of clinical evaluation by NYHA classification.

 
At the end of the follow up period, one patient died from heart failure. Three patients were hospitalized for heart failure (two in A group and one in B group.) Follow-up data are reported in Table 3. The two groups differed for NYHA class and BNP plasma level which were significantly lower in B group and for rest LVEF and 6-min walk test performances which were higher in B than in A group (Table 3).

In multivariate analysis (age, rest LVEF, MCR, rest E/A ratio, rest heart rate, systolic arterial pressure, BNP plasma level, 6-min walk test performance), the sole existence of MCR could predict the improvement of rest LVEF under carvedilol treatment in patients with chronic heart failure (P<0.0001).


   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
4.1. MCR and β-blocker therapy
In our study, the existence of a MCR at the DSE could predict the improvement of LVEF under treatment by carvedilol. This is important information given the high percentage of bad responders to β-blocker therapy. The proportion of bad responders to β-blocker therapy is estimated to range from 20 to 30% of patients for clinical criteria, 24% in NYHA class II vs. 43% in NYHA class IV) [13]. Effectiveness of carvedilol treatment comes through unknown factors but also by well-known criteria such as LVEF. The possibility of bad tolerance could slow the use of this type of treatment. Unfortunately, clinical and paraclinical rest criteria could not identify the patients who would improve their LVEF under treatment with carvedilol. In this case, determination of MCR could really help the physician to identify good responders prior to introducing carvedilol (Fig. 4).


Figure 4
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  		Fig. 4 Evolution of LVEF under treatment by carvedilol.

 
The definition of MCR is different from one author to the other [6–8]. In some studies, it is calculated as a percentage of improvement of rest LVEF. It is the definition that we have retained because it seems to be more relevant in patients with low LVEF. Some authors have defined MCR as an increase of absolute value of rest LVEF under dobutamine. In this study, adopting the first or the second definition did not cause any cross-over from one group to another. We used lower doses of dobutamine than other studies, in particular in studies about identification of hibernating myocardium but we wanted to minimize adverse events and appreciate global ejection fraction and not segmental improvement under DSE.

The mechanisms which underly this MCR are still unclear. Heart failure regardless of its etiology leads to a neuro-adrenergic activation [14]. Increase of sympathetic tone increases secretion of renin and angiotensin, which itself leads to salt and water retention. This also implies an arterio-venous vasoconstriction leading to an increase of pre and post charge and an increase in ventricular wall stress. Chronic heart failure also leads to a down regulation of β1 receptors in direct relation to the severity of ventricular dysfunction [14,15].

The study of MCR consists of analyzing the response of the adrenergic system to a β-agonist stimuli reflecting the desensitisation of these systems. It therefore reflects the degree of adrenergic cardiomyopathy induced by chronic heart failure. Indeed, in patients with the most severe chronic heart failure, it is clear that plasma catecholamine levels are very high and are correlated with less β receptors and a greater myocardial denervation showed by metaiodobenzylguanidine (MIBG) scintigraphy [16]. Patients without any MCR are those who have less β receptors and who have more adrenergic cardiomyopathy.

In 1989 Waagstein described the beneficial effects of β blockade in patients with non-ischemic cardiomyopathy [4]. These patients presented an increase of their LVEF and an up regulation of their β receptors under treatment with metoprolol. Carvedilol reduces plasma levels of norepinephrine in venous coronary sinus [17]. This could be the sign of a decrease in neuro-adrenergic activation.

However, carvedilol does not seem to modify β receptor density or β1/β2 ratio, in contrast with other β-blockers such as metoprolol (at the same level of β blockade) [16].

In fact, in chronic heart failure, mechanisms which underly this adrenergic hyperactivation are multiple. The high level of catecholamines causes a down regulation of β1 receptors [18]. Their desensitization is consecutive to an increase of synthesis of β ARK (receptor kinase) [19] and to a diminution of synthesis of m ARN coding for β receptors.

β2 receptors are not desensitized but are partially decoupled from adenylate cyclase. Receptor activity and increase of inhibitive G protein (Gi protein) synthesis are symmetric. Carvedilol as well as bucindolol stick on a high affinity site on β2 receptor modulated by these Gi protein, inducing in that manner an effect of ‘low affinity’ for this receptor desensitization [20]. The indirect effect on β receptors could be linked to an inverse agonist effect which diminishes the production of cyclic AMP.

Dobutamine is a β agonist which mainly acts through the β2 and {alpha}1 adrenergic receptors. Its effect is proportional to the dosage used. [21]. Its positive inotropic effect comes via an increase of cyclic AMP secondary to the action of adenylate cyclase. In a transgenic mouse model, the increase of adenylate cyclase is parallel to the response to dobutamine [22].

Some authors have shown a link between response to dobutamine and beta-blockers. Heilbrunn has argued that introduction of treatment with metoprolol in patients with chronic heart failure could have a contractile response appear to dobutamine [23]. For Dubois rande, the existence of MCR could predict the improvement of clinical parameters under medical therapy (excluding β-blockers) [24]. In an experimental model of cardiomyopathy induced by free radicals, treatment by carvedilol or its main metabolite could restore the inotropic response induced by Ca2+ at the difference of metoprolol [25]. The effect of carvedilol could be linked to its anti oxidative properties [26], which could explain the effect on the circulating catecholamines without any direct effect on β receptor density.

Nevertheless, many different hypotheses could be suggested to explain this link between MCR and carvedilol therapy. The absence of MCR in some patients could be secondary to:

  • A very important percentage of fibrosis. This percentage of fibrosis is correlated to a bad prognosis [27]. It is correlated to hormonal activation in particular for renin and angiotensin [28]. An important fibrosis could diminish the myocardial contractility [29] and reduce the vascularization of the myocytes. It could also decrease response to dobutamine [30].
  • A high degree of myocardial apoptosis or necrosis. If there is just a small number of myocytes, their response to dobutamine is too little to be identified with DSE, so studying MCR comes to identify ventricular viability. It could explain the link between lack of MCR and bad prognosis. Apoptosis is still an important prognostic factor, the problem is that it is difficult to appreciate its importance [31,32]. In patients without left ventricular dysfunction who were treated with anthracyclines for cancer in childhood; MCR is lower than in control patients. This fact could link myocytic death, mitochondrial destruction and MCR [33,34].
  • Existence of an adrenergic activation leading to an autonomic cardiomyopathy with a down regulation of β receptors as mentioned above. In this case, the action of carvedilol is not a β receptor up regulation but probably a neuro-hormonal effect on renin angiotensin catecholamine systems [24], on β ARK systems or on Gi proteins like metoprolol [35] rather than directly on β receptors [19].

It is possible that these hypotheses have different relevance and more detailed studies are needed to give further explanations of this phenomenon.

In this study, B type natriuretic peptide levels were lower in patients with MCR. This association between MCR and BNP was noted first by Kitaoka et al. [36]. BNP plasma levels are dependent on many factors including left ventricular diastolic pressure; it is possible that LVEDP is linked to MCR regardless of LVEF as shown by Dubois rande et al. [24].

4.2. Limits
This study was not carried out like a classical double blind study which could improve the degree of scientific proof. It is difficult, because of ethical considerations, to randomize patients to β-blocker and placebo groups.

We have studied a small number of patients but this study was a preliminary one, aimed at identifying a link between MCR and β-blocker therapy efficacy, in order to target patients who will get the maximum benefit from this type of treatment. We think that it is time to begin some morbidity/mortality studies to support our conclusions.

We have not performed myocardial biopsy because of the risk for the patient. We have not measured the plasma levels of catecholamines because of the relative lack of correlation between the concentrations in the coronary sinus and in peripheral blood.


   5. Conclusion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
β-Blocker therapy in chronic heart failure is presently known as one of the most effective therapies of heart failure as ACE inhibitors or spironolactone. Actually, however, we cannot target patients who will improve their LVEF under carvedilol. Myocardial contractile reserve with low doses of DSE could allow identification of patients who will be good responders, in terms of LVEF and NYHA classification, to treatment with carvedilol. Studying MCR could target patients who will obtain benefit from β-blocker therapy and could optimize treatment with carvedilol in patients with chronic heart failure.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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