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European Journal of Heart Failure 2003 5(5):621-627; doi:10.1016/S1388-9842(03)00054-0
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© 2003 European Society of Cardiology

β-Blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol

Savina Nodari*, Marco Metra and Livio Dei Cas

Cattedra di Cardiologia, Università di Brescia c/o Spedali Civili, P.zza Spedali Civili, 25100 Brescia, Italy

* Corresponding author. Tel.: +39-30-307221; fax: +39-30-3700359. E-mail address: savina.nodari{at}tin.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
We compared the effects of 6 months administration of atenolol or nebivolol on resting and exercise hemodynamic parameters and maximal exercise capacity, in 26 patients with hypertension and left ventricular (LV) diastolic dysfunction (ejection fraction >50%, end-diastolic diameter <60 mm and increased pulmonary wedge pressure at rest and/or at peak exercise). Both atenolol and nebivolol administration was associated with a significant decrease in the resting and peak exercise heart rate and blood pressure and in LV mass, with an increase in the E/A ratio. This latter effect was greater with nebivolol. Nebivolol was associated with an increase in the peak VO2, VO2 at the anaerobic threshold and with a decrease in the VE/VCO2 ratio. With regards to the hemodynamic parameters, compared to patients on atenolol, those on nebivolol showed a lower reduction in the cardiac index, a greater increase in the stroke volume index and a decline in the mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and peak exercise. Thus, although the two β-blockers have a similar antihypertensive action, nebivolol administration was associated with a greater hemodynamic improvement, compared to atenolol.

Key Words: β-Blockers • Diastolic function • Heart failure

Received August 21, 2002; Revised January 17, 2003; Accepted April 23, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Predominant left ventricular (LV) diastolic dysfunction is the cause of heart failure in more than one third of patients and its prevalence increases among the elderly, females, and patients with hypertension and/or coronary artery disease [1,2]. Even in the absence of a clinical history of heart failure, impaired LV early diastolic relaxation, detected by pulsed Doppler echocardiography, is predictive of an higher incidence of major cardiovascular events both in the general population [3] and in hypertensive patients [4], with a relation independent of age, gender, LV mass and ambulatory blood pressure [4]. Thus, an improvement in LV diastolic function is an important goal of both the treatment of heart failure and the prevention of cardiovascular events. Treatment of LV diastolic dysfunction remains, however, empirical [5–7]. β-Blockers have many potentially useful effects. They reduce the heart rate and myocardial ischemia and cause regression of myocardial hypertrophy in patients with hypertension. However, no study to date has specifically assessed the effects of their long-term administration in patients with diastolic heart failure.

Nebivolol is a β-blocker with associated vasodilator activity mediated through increased nitric oxide (NO) release [8–12]. This mechanism has many potentially beneficial effects for the treatment of the patients with hypertension and diastolic heart failure. First, peripheral vasodilatation may contribute to the antihypertensive effect of this agent [13]. Second, increased NO release in the vessels of the skeletal muscle may increase their dilatatory capacity and thus allow better muscle perfusion during exercise. Lastly, NO is one of the most powerful endogenous lusitropic agents [14]. Its increased release shifts the LV pressure–volume curve downward and to the right and augments the LV pre-load reserve with, hence, a greater stroke volume [15–17]. Moreover, patients with LV hypertrophy seem to be particularly sensitive to the beneficial effects of NO on diastolic function [18]. Studies in patients with LV systolic dysfunction have shown a greater improvement in the parameters of diastolic function, associated with an increase in exercise capacity, with nebivolol administration, compared with the traditional β-blockers [19–22]. The aim of our study was, therefore, to compare the effects of the long-term administration of either atenolol or nebivolol on hemodynamic parameters, assessed both at rest and during maximal exercise, and the exercise capacity of a group of patients with hypertension and diastolic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
We studied 30 patients with mild arterial hypertension and chronic heart failure due to LV diastolic dysfunction. Entry criteria included New York Heart Association (NYHA) class II or III symptoms of heart failure for ≥6 months, a peak VO2 <=25 ml/kg/min by cardiopulmonary exercise testing, evidence of normal LV systolic function, defined by an ejection fraction ≥0.50 and an end-diastolic diameter <32 mm/m2 by 2D echocardiography, and of diastolic dysfunction, defined by a mitral valve Doppler flow velocity pattern with peak E wave less than peak A wave velocity (E/A<1.0) and/or by a pulmonary wedge pressure >12 mmHg at rest and/or>20 mmHg at peak exercise [23–25]. Patients were excluded if they had evidence of myocardial ischemia at stress myocardial perfusion scintigraphy or of coronary artery disease at coronary angiography; primary valve disease or congenital heart disease; resting systolic blood pressure >200 mmHg or diastolic blood pressure >100 mmHg; atrial fibrillation; concomitant diseases that might adversely influence prognosis or impair exercise capacity (e.g. malignancy, musculoskeletal diseases); contraindications to β-blocker therapy, (e.g. asthma, advanced heart block or bradyarrhythmias); and concomitant treatment with other β-blockers. Four patients were not reassessed after β-blocker therapy (refusal to undergo the second hemodynamic study in 3 patients and β-blockade intolerance for bronchial wheezing in one) and were therefore excluded from the study.

The investigation conformed to the principles outlined in the Declaration of Helsinki and the protocol was approved by the local ethics committee. Written informed consent was obtained from all study patients.

2.2. Protocol
A prospective, parallel design was used with 1:1 randomization to either atenolol or nebivolol using a permuted block design. Each patient underwent maximal cardiopulmonary exercise testing with hemodynamic monitoring, resting 2D echocardiogram, Doppler measurements of mitral valve flow velocities and clinical symptom assessment at baseline, before the initiation of β-blocker therapy, and after 6 months of treatment with atenolol or nebivolol.

Atenolol and nebivolol were started at the doses of 50 and 2.5 mg once a day, respectively, with an up-titration after 2 weeks to the doses of 100 mg daily for atenolol and 5 mg daily for nebivolol. Titration could be increased to higher doses when needed, to achieve a better control of blood pressure. Dose titration was deferred, interrupted or stepped back in the case of an increase in heart failure symptoms, dizziness, hypotension (systolic blood pressure <=80 mmHg), bradycardia (resting heart rate <=60 b/min) or other untoward effects possibly related to β-blockade. Concomitant treatment was maintained constant throughout the study.

2.3. Procedures
At least 1 h before performance of the maximal cardiopulmonary exercise test, a triple lumen Swan–Ganz catheter was inserted percutaneously through the right internal jugular vein and positioned in the pulmonary artery to obtain hemodynamic measurements. Cardiac output was measured using the thermodilution method. Resting hemodynamic data were obtained both in the supine position, after an equilibration period of at least 15 min. Bicycle exercise testing was then performed in the sitting position with simultaneous expiratory gas exchange and hemodynamic monitoring, starting at a workload of 20 W with increments of 20 W every 2 min up to limiting dyspnea or fatigue according to a protocol previously described in detail [26]. All patients had performed at least two preliminary cardiopulmonary exercise tests in order to be familiar with the procedure and to ensure stability of the results, defined as a <=1 ml/kg/min change in peak VO2 between two consecutive tests. The slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2 slope) [27] and the half-time of the VO2 recovery after exercise [28] were also calculated.

Echocardiographic studies were performed at rest, with the patient in the left lateral position, using commercially available instruments with a mechanical transducer of 2.5 MHz, by two experienced echocardiographers who were blinded to the clinical data and ongoing therapy. Two-dimensional guided M-mode measurements of the left atrial and LV internal dimensions, and septum and posterior wall thickness were made at the LV minor axis at the level of the chordae tendinae just beyond the mitral leaflet tips, as recommended by the American Society of Echocardiography [29]. LV mass was calculated using the Penn convention [30] according to the equation: LV mass=1.04 ((LV end-diastolic diameter+posterior wall thickness+interventricular septum thickness)3–(LV end-diastolic diameter)3)–13.6 g, and normalized for body surface area. The transmitral flow velocity was measured using pulsed-wave Doppler with the sample volume positioned between the mitral leaflet tips during diastole. The E wave and A wave peak velocities and the ratio of the E wave to the A wave peak velocities (E/A ratio) were measured on three separate beats and then averaged [31].

2.4. Statistical analysis
Since, in patients with chronic diastolic heart failure, the LV filling pressure may be normal at rest and increase only during exercise [25,32], the primary objective of our study was to compare the effects of nebivolol and atenolol on the pulmonary wedge pressure assessed at peak exercise. The secondary objectives were to compare the effects of the two β-blockers on the other hemodynamic parameters, assessed at rest and peak exercise, and on the maximal exercise tolerance. Based on the changes in exercise hemodynamic variables observed in earlier studies [33,34] and assuming a dropout rate of 20%, we calculated that the enrollment of 30 patients would have provided 95% power to detect an absolute difference of 5 mmHg in the change from baseline of the peak exercise PWP between the atenolol and the nebivolol treatment groups ({alpha}=0.05).

Results are expressed as mean±S.D. Baseline data were compared using Student's t test for continuous variables and by {chi}2 test for categorical variables. Changes from baseline were compared between the atenolol and the nebivolol treatment group by two-way analysis of variance (ANOVA) and, within each treatment group, by Student's t test for paired samples. In all analyses, a value of P<0.05 in a two-tailed distribution was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline characteristics
The studied patients had mild hypertension (systolic blood pressure, 149±21 mmHg; diastolic blood pressure, 92±7 mmHg), symptoms of heart failure (NYHA functional class, 2.42±0.50) and an impairment in functional capacity (peak VO2, 18.0±4.8 ml/kg/min) with a normal LV systolic function (LV ejection fraction, 56±7%; LV end-diastolic diameter index, 28±2 mm/m2) and signs of LV diastolic dysfunction (mitral E/A ratio, 0.82±0.12; mean pulmonary wedge pressure, 14±5 mmHg at rest and 24±4 mmHg at peak exercise). The patients randomized to atenolol and nebivolol were similar with respect to all pretreatment characteristics. Their mean age was 65±9 and 62±13 years, respectively. There were 8 males in the atenolol group and 7 in the nebivolol treatment group. With regards to concomitant therapy, oral furosemide was administered to all but one patient treated with atenolol (mean dose, 26±16 mg daily), and to all patients on nebivolol (29±10 mg daily). An angiotensin converting enzyme inhibitor or, when not tolerated, an angiotensin II antagonist, was administered to 11 patients on atenolol and 12 on nebivolol. Lastly, 7 patients on atenolol and 8 patients on nebivolol were on amlodipine (10 mg daily). Following completion of the up-titration period, all patients randomized to atenolol received the dose of 100 mg daily while the final dose of nebivolol was of 5 mg daily in all but one patient who received 10 mg daily.

3.2. Effects on functional capacity, echocardiographic and Doppler parameters
Compared with baseline, both the β-blockers improved clinical symptoms, assessed by NYHA class. Only nebivolol was associated with a significant improvement from baseline in exercise capacity, assessed by peak VO2, VO2 at the anaerobic threshold, and the VE/VCO2 slope (Table 1). Peak VO2 and VO2 at the anaerobic threshold increased by 1.2±1.6 ml/k/min and 1.6±2.1 ml/k/min, respectively, (both P<0.01 vs. baseline) in the patients treated with nebivolol while no significant change (0.1±2.3 ml/k/min and 0.1±1.5 ml/k/min) was observed in those on atenolol. Similarly, the VE/VCO2 slope decreased by 2.3±1.3 (P<0.05) in the patients who received nebivolol but not in those on atenolol. However, these differences did not reach statistical significance with between-group ANOVA.


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  		Table 1 Effect on clinical status, exercise capacity and echo-Doppler parameters

 
The LV ejection fraction and end-diastolic diameter did not change from baseline with either atenolol or nebivolol. Both the β-blockers were associated with a significant decrease from baseline in the LV end-diastolic septal wall thickness and the LV mass index with an improvement in the transmitral flow E/A ratio. Nebivolol administration was also associated with a decrease from baseline in the LV end-diastolic posterior wall thickness. No significant difference in the magnitude of these changes was found between the two β-blockers, except for the E/A ratio, which increased to a greater extent in the nebivolol group (Table 1).

3.3. Effects on the hemodynamic parameters
Hemodynamic data obtained at rest, in the supine position, and at peak exercise are shown in Tables 2 and 3. Compared with baseline, both agents significantly decreased heart rate and blood pressure. The reduction in heart rate also caused a decrease in the cardiac index which was of greater magnitude after atenolol, compared to nebivolol administration. Nebivolol, was also associated with a significant increase from baseline in the stroke volume index and a decline in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and peak exercise, and with a decrease in the peak exercise systemic vascular resistance. In contrast, atenolol administration was only associated with an increase from baseline in the peak exercise stroke volume index, with no change in the other parameters. The changes from baseline in the cardiac index, systemic vascular resistance, mean pulmonary artery pressure and pulmonary wedge pressure were significantly different, both at rest and peak exercise, between the atenolol and the nebivolol treated group (Tables 2 and 3). At peak exercise, the changes in the stroke volume index and stroke work index were also significantly different between the two patient groups (Table 3). Percentage change from baseline in the main hemodynamic parameters is shown in Fig. 1.


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  		Table 2 Hemodynamic data at rest

 


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  		Table 3 Hemodynamic responses at peak exercise

 


Figure 1
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  		Fig. 1 Percentage changes from baseline (mean±S.E.M.) in hemodynamic variables at rest and during peak exercise after treatment with atenolol (white bars) or nebivolol (black bars) for 6 months. Symbols immediately above or below the columns designate significance of differences from baseline, whereas symbols between the columns designate significance of differences between groups. *P<0.05, **P<0.01, ***P<0.0001. HR denotes heart rate, MAP mean arterial pressure, CI cardiac index, SVI stroke volume index, SVR systemic vascular resistance, PWP pulmonary wedge pressure and PVR pulmonary vascular resistance.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1. Major findings
Our data show that long-term therapy with β-blockers in patients with arterial hypertension and diastolic heart failure is associated with a significant improvement in many parameters of LV function with, however, meaningful differences between the different agents. In particular, nebivolol administration was associated with a greater improvement in the E/A ratio, a greater decline in pulmonary wedge pressure and mean pulmonary artery pressure and a smaller reduction in cardiac index, both at rest and at peak exercise, and with a decline in systemic vascular resistance and an increase in the stroke volume index and stroke work index at peak exercise. Lastly, only the patients on nebivolol showed an increase from baseline in the peak VO2, VO2 at the anaerobic threshold, and a decrease in the VE/VCO2 slope.

4.2. Mechanisms of the different effects of atenolol and nebivolol
Four possible mechanisms may account for the differences observed between the nebivolol and atenolol treatment groups: the chronotropic response to exercise, the regression of LV hypertrophy and the effects on peripheral resistance and on LV diastolic function.

The chronotropic response to exercise is known to be an accurate measure of the cardiac response to adrenergic drive. Previous studies in patients with LV systolic dysfunction, have related the differences in the effects on maximal exercise capacity between different β-blockers to the magnitude of their negative chronotropic effects and hence to their degree of antiadrenergic activity [34,35]. However, this mechanism may not be applied to our results. In fact, the magnitude of the reduction in heart rate was similar between the atenolol and the nebivolol group, both at rest and during exercise, consistent with their similar, selective, action on β1 adrenergic receptors. Other studies have shown a lower negative chronotropic activity of nebivolol, compared to atenolol, in normal subjects [36].

With regards to the effects of the two β-blockers on LV hypertrophy, both atenolol and nebivolol administration was associated with a decrease in LV septal wall thickness and LV mass, with a concomitant improvement in the E/A ratio. These results are consistent with previous studies [37–40]. Compared to atenolol, nebivolol administration was associated with a more significant decrease in the end-diastolic septal wall thickness and LV mass index and with a decrease in the LV end-diastolic posterior wall thickness. Although the magnitude of these changes was not significant by ANOVA, it is consistent with the greater improvement in the E/A ratio and in the LV filling pressures after nebivolol, compared to atenolol administration.

The differences observed between the two β-blockers may also be ascribed to the peripheral vasodilatatory action and the increase in NO release associated with nebivolol administration [8–11]. Our results are similar to those previously obtained in comparative studies between traditional β-blockers and β-blockers with associated vasodilating activity [41–43]. Differently from these studies, we directly assessed both the resting and peak exercise ventricular filling pressures and maximal exercise capacity and specifically studied patients with symptoms of chronic heart failure caused by LV diastolic dysfunction.

The hemodynamic improvement and the increase in exercise tolerance after nebivolol, may be explained by its peculiar effects on NO release. NO release may cause both vasodilatation and perfusion of the exercising skeletal muscle and a greater improvement in LV diastolic function [12–14]. The improvement in early diastolic relaxation, likely associated with NO release, may explain the decline in LV filling pressure, with better LV filling and hence a greater stroke volume, both at rest and during exercise. As the impairment in LV diastolic filling and pre-load recruitment is the primary mechanism of exercise intolerance in patients with diastolic heart failure [32], this increase in LV NO release may explain the increase from baseline in the exercise capacity observed in the patients treated with nebivolol.

In conclusion, our study demonstrates that the chronic administration of nebivolol is associated with a greater hemodynamic improvement, both at rest and during exercise, when compared to atenolol administration, in the patients with arterial hypertension and diastolic heart failure. These differences are likely related to a greater improvement in LV diastolic function related to the ancillary properties of nebivolol.


   Acknowledgements
 
This article was partially supported by CARIPLO funds from ‘Centro per lo studio del trattamento dello scompenso cardiaco’ of the University of Brescia.


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

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