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European Journal of Heart Failure 2000 2(2):183-187; doi:10.1016/S1388-9842(00)00060-X
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© 2000 European Society of Cardiology

Improvement of cardiac output in patients with severe heart failure by use of ACE-inhibitors combined with the AT1-antagonist eprosartan

B. Gremmlera,*, M. Kunerta, H. Schleitinga and L.J. Ulbrichtb

a Department of Cardiology, Marienhospital Josef-Albers-Strasse 70, D 46236 Bottrop, Germany
b University of Witten/Herdecke Germany

* Corresponding author. Fax: +49-2041-1061409.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: The efficacy of ACE-inhibitor therapy is well documented in the treatment of chronic heart failure. As pharmacological mechanisms of ACE-inhibition and angiotensin II AT1-receptor-antagonists differ, an additional positive effect concerning left ventricular function can be expected in combining both classes of drugs.

Methods: Twenty patients (64.9 ± 8.5 years) with advanced chronic heart failure (NYHA class III) receiving long-term medication with digitalis, diuretics and ACE-inhibitors were randomized to either eprosartan (540 ± 96 mg/day) or placebo, according to a blinded protocol. Hemodynamic measurements by impedance cardiography were performed at baseline and after 8.85 ± 1.5 days of study medication treatment.

Results: Additional treatment with eprosartan resulted in a higher cardiac output than in the control group (P < 0.05). While in the active treatment group cardiac output increased significantly from baseline (2.27–3.24 l/min, P = 0.039), there was no change in the control group.

Conclusions: The additional treatment with the AT1-receptor antagonist eprosartan, given to severe heart failure patients, who received digitalis, diuretics and ACE-inhibitors, resulted in a beneficial effect by increasing cardiac output. This effect may be due to eprosartan's additional property of blocking the autocrine interaction of locally and not ACE-generated angiotensin II with their respective vascular and myocardial AT1-receptors as well as the influence on prejunctional AT1-receptors located on sympathetic nerve terminals.

Key Words: ACE-inhibitors • Selective angiotensin II AT1-receptor-antagonist • Chronic heart failure • Norepinephrine • Eprosartan

Received March 4, 1999; Revised September 23, 1999; Accepted January 7, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The efficacy of angiotensin converting-enzyme-inhibitors in the therapy of chronic heart failure is well documented in many studies [1–7]. The therapeutic benefit of ACE-inhibition is mainly explained by a decrease of afterload via reduction of angiotensin II formation in the vascular system and myocardium. Furthermore, ACE-inhibitors increase kinin levels, the importance of which is controversial. However, ACE-inhibitors do not affect non-ACE-generated angiotensin II (in myocardium 80% of angiotensin may be generated by chymase and in a vessel wall by CAGE) [5,6,8–12]. Direct antagonism of angiotensin II may be accomplished by blockade of ATII type 1 (AT1) receptors in the myocardium and the vessel wall [12–16]. This effect is common to all angiotensin II type 1 receptor antagonists. An additional effect of the AT1-receptor antagonists is the reduction of sympathetic outflow by blocking the prejunctional AT1 receptor, located on the sympathetic nerve terminals, especially described in animal experiments for eprosartan [17]. This is important as progression of heart failure is triggered by high-grade sympathetic stimulation. Norepinephrine effects are hazardous to the vessels and the myocardium [18–21].

We hypothesized that the addition of the AT1 antagonist eprosartan to ACE-inhibitor therapy results in cardiovascular benefits, as ACE-inhibition reduces the overall amount of angiotensin II, but does not influence chymase and CAGE-dependent production of this substance. The AT1 antagonist eprosartan blocks AT1 stimulation, but it does not affect AT2 stimulation which could also be beneficial. Supplementary presynaptic release of norepinephrine may be blocked in the sympathetic nerve terminal.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
Twenty patients (14 male, 6 female) were included in the study. The reason for admission to our hospital was severe heart failure in all cases. Each patient scored NYHA Class III; 65% of the patients suffered from chronic ischemic heart disease, 35% from dilated cardiomyopathy (Table 1).


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  		Table 1 Baseline characteristics

 
All patients received long-term treatment of heart failure including digitalis, diuretics and ACE-inhibitors. If patients were already pretreated with a β-blocker by the primary care physician, this therapy was continued.

Heart failure was diagnosed by clinical investigation. Chest X-ray and echocardiography documented severe left ventricular dysfunction in combination with pathological LV dimensions. Cardiac output measured by impedance cardiography had to be low (<3.5 l/min). Patients with renal disorders, hemodynamically important valvular heart disease, or endocrinologically induced heart failure were not included in this study.

Study medication was initiated after clinical recompensation (4–9 days after admission to hospital).

2.2. Echocardiographic measurements
Left ventricular dimensions were determined by standardized M- and B-mode echocardiography (Hewlett Packard Sonos 5500).

2.3. Cardiac output measurements
Cardiac output was measured by means of impedance-cardiography [22,23] [computerized Impedance Cardiograph CTCTM (version 6, 37), Sorba Medical Systems]. Measured data of impedance dZ/dt were automatically calculated as cardiac output. These data were adjusted to the ‘true’ cardiac output as described in the literature [24]. Impedance-cardiography was performed using at least 40 measurements over a period of 20 min after a period of rest. The average of those measurement was taken as the true cardiac output at rest.

The total peripheral resistance was determined by calculation from cardiac output and blood pressure.

2.4. Laboratory measurements
At the start, and after completion of the study, routine blood samples were taken. Specifically, the serum creatinine and the serum potassium level were monitored since interaction of these drugs could possibly impair renal function.

2.5. Study design
According to a blinded protocol, 10 patients were treated with eprosartan additionally (540±96 mg/day) while 10 patients received placebo. In the eprosartan group seven patients received 1x2 eprosartan tablets 300 mg, one patient 1x1.5 tablets 300 mg and two patients 1x1 tablet 300 mg. Previous medication (ACE-inhibitors, diuretics, digitalis, β-blockers) was continued. The number of patients with dilated cardiomyopathy and ischemic heart disease was similar in both groups. After a minimum treatment of 7 days under in-hospital conditions (average 8.85±1.4 days) the final investigations were performed according to the abovementioned protocol. Parameters were evaluated by two independent investigators without knowledge of the administered therapy. Informed consent was signed by all patients. The investigation conforms with the principles outlined in the Declaration of Helsinki.

2.6. Statistics
The statistical analysis was performed applying Student’s t-test for dependent or independent samples, as appropriate. A P-value of <0.05 was considered to be statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Study parameters
The mean cardiac output was 2.36±0.59 l/min in the control group and did not significantly differ from cardiac output in the eprosartan group before starting the additional eprosartan treatment (2.27±0.65 l/min). Left-ventricular dimensions also did not show significant differences in both groups (Control group LVEDD mean 63.5±6.22 mm and LVESD mean 51.99±9.25 mm, eprosartan group LVEDD mean 65.12±5.76 mm, LVESD mean 54.17±5.09 mm). Heart rate at the start of evaluation was comparable in both groups without significant differences [Control group (seven patients treated with β-blockers) mean 82.6±18.12 beats/min and in the eprosartan group (six patients treated with β-blockers) mean 87.3±17.1 beats min–1]. Systolic and diastolic blood pressure did not significantly differ in both groups (control group mean 117.5±11.5 mmHg, eprosartan group mean 122.5±13 mmHg systolic, respectively, diastolic control group mean 67.5±5 mmHg, eprosartan group mean 72±8 mmHg). The total peripheral resistance was comparable in both groups without significant differences (control group mean 2223±669 dyn s cm–5, eprosartan group 2419±682 dyn s cm–5.

Cardiac output of the control group measured at the beginning of the study did not significantly differ compared with the final evaluations (mean 2.36±0.59 l/min vs. 2.29±0.76 l min–1). Additional treatment with eprosartan resulted in a higher cardiac output compared with the control group (P<0.05). In the eprosartan group a statistically significant rise of cardiac output was observed at the end of the study (mean 2.27±0.65 l/min vs. 3.24±1.14 l/min, P=0.039). In comparison to the cardiac output (CO) in the control group at the end of the study, the CO of the eprosartan treated patients also revealed a statistically significant rise. (2.29±0.76 l/min vs. 3.24±1.14 l/min, P<0.05) (Fig. 1). In both groups heart rate at rest decreased slightly during the observation time to a mean of 78.4±13.2 beats/min in the control group and to 79.6±14.4 beats/min in the eprosartan group. The differences between both groups are not statistically significant. The blood pressure did not significantly change at the end of the study vs. the initial values (Control-group systolic mean 119, 5±12, 4 mmHg and diastolic 73±5 mmHg vs. eprosartan group systolic mean 119, 5±10, 6 mmHg and diastolic 75±6 mmHg). The total peripheral resistance in the eprosartan group significantly decreased (P=0.042) to a value of mean 1795±577 dyn s cm–5, while a non-significant increase was observed in the control group. In addition, a significant (P=0.05) decrease of the resistance-value in the eprosartan group was measured in comparison with the control group at the end of study.


Figure 1
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  		Fig. 1 Cardiac output before and under additional eprosartan treatment.

 
Concerning echocardiography parameters, significant changes were not seen in either group. Mean LVEDD in the control group was 64.37±5.77 mm, mean LVESD 53.59±7.59 mm. Eprosartan group: mean LVEDD 62.69±4.58 mm, LVESD 51.36±4.46 mm.

In both groups analysis of serum creatinine revealed no change during the observation period (control group: initially 1.068 mg%, end of study 1.084 mg%; eprosartan group: 1.122 mg% vs. 1.036 mg%, respectively). There was no statistically significant alteration to the serum potassium level, neither at the beginning nor the end of the study (control group mean 4.27±0.46 mmol l–1, end of study 4.38±0.52 mmol l–1; eprosartan group initially 4.35±0.5 mmol l–1 vs. 4.52±0.23 mmol l–1, respectively)

3.2. Adverse side effects
No side effects have been observed. No case of severe hypotension or bradycardia was measured during treatment. A possible gain in physical performance was not tested because of the history of severe heart failure.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The results of our short-term pilot trial indicate a clinical profit in eprosartan therapy, added to ACE-inhibitors.

Since all patients received adequate dosages of ACE inhibition before medication was started, effective inhibition of converting enzymes can be assumed in our patients. The observed increase in cardiac output in the eprosartan group may be a result of multiple effects, which have already been described by experimental working groups.

Antagonism of non-ACE-dependent vascular angiotensin II production led to a further decrease of vascular resistance. This experimental observation has also been found in our investigation by the decrease of total peripheral resistance during eprosartan therapy. Apart from peripheral vascular phenomena, local myocardial effects have to be considered. Blocking intra-myocardial angiotensin II production may reduce AT1 stimulation which could have direct effects on the myocardium or reduce sympathetic activation. In experimental investigations these beneficial effects have been found [16,17] and may explain the decrease of total peripheral resistance and the observed improvement of cardiac output.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our reported clinical data show a statistically significant amelioration of cardiac output in patients treated with ACE-inhibitors plus the AT1 antagonist eprosartan. Our results justify further investigations in a larger population. If the positive trend can be asserted by further studies, combined ACE-inhibitor and AT1 antagonist therapy may be recommended as a standard medication for patients with severe chronic heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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