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European Journal of Heart Failure 2005 7(4):618-623; doi:10.1016/j.ejheart.2004.04.015
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© 2005 European Society of Cardiology

Selective versus nonselective β-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization

Abdul Al-Hesayena, Eduardo R. Azevedoa, John S. Florasa, Shauna Hollingsheadb, Gary D. Lopaschukb and John D. Parkera,*

a Division of Cardiology, Department of Medicine, Mount Sinai Hospital and University Health Network Hospitals, University of Toronto 600 University Avenue, Suite 1609, Toronto, Ontario, Canada, M5G 1X5
b The Department of Pediatrics, Faculty of Medicine and Dentistry, University Hospital, University of Alberta Edmonton, Canada

* Corresponding author. Tel.: +1-416-586-4794; Fax: +1-416-586-8413. E-mail address: jdp{at}ca.inter.net


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Non-selective and selective β-blockers have been shown to improve outcomes in chronic heart failure (CHF). Recent data suggests the non-selective β-blockers have a more favourable effect on outcomes than β1-selective agents. We sought to examine the differential effects of non-selective versus selective β-blockade on myocardial substrate utilization in patients with CHF.

Methods and results: Twenty-two patients with CHF were randomised to the non-selective β-blocker carvedilol or the selective β-blocker metoprolol (double-blind). Measurement of hemodynamics, arterial and coronary sinus free fatty acid (FFA) and lactate levels, and cardiac norepinephrine spillover (CANESP) were made before and after 4 months of therapy. In the carvedilol group (n=11), there was a significant reduction in myocardial FFA uptake (0.12±0.02 to 0.1±0.02 mmol/l, P<0.03). By contrast, in the metoprolol group (n=11) there was no change in myocardial FFA extraction. Carvedilol therapy tended to increase myocardial lactate extraction (0.24±0.05 to 0.35±0.08 mmol/l, P=0.08) while metoprolol therapy resulted in a trend in the opposite direction (0.18±0.03 to 0.11±0.04 mmol/l, P=0.09). The change in lactate extraction in the carvedilol group was significantly different from that in the metoprolol group (+0.11±0.06 vs. –0.09±0.04 mmol/l, P<0.01). Carvedilol treatment caused a significant reduction in CANESP while metoprolol had a neutral effect (–95±27 vs. 25±42 pmol/min, carvedilol vs. metoprolol P<0.03).

Conclusion: Carvedilol treatment caused a 20% reduction in myocardial free fatty acid extraction while metoprolol had a neutral effect. These differences are most probably related to the differential effects of these two agents on efferent cardiac sympathetic activity and may be relevant to the reported differential effects of these drugs on clinical outcomes.

Key Words: Heart failure • Receptors • Adrenergic • Beta • Nervous system • Sympathetic • Metabolism • Al-Hesayen • β-Blockers • Myocardial substrate utilization

Received February 14, 2004; Revised March 3, 2004; Accepted April 28, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The benefit of β-blocker therapy in the setting of chronic heart failure (CHF) is well established [1–4]. However, whether all β-blockers confer the same degree of benefit is a still a point of controversy [5]. The possibility that there may be significant differences in the treatment effects of different β-blockers is emphasized by the results of the BEST and COMET trials [6,7].

The mechanism of benefit with β-blockade in the setting of CHF is not clearly established. However, there is increasing interest in their impact on myocardial energy substrate utilization and efficiency in CHF [8]. This interest is driven by the concept that a potentially important outcome of sympathetic activation in the setting of CHF is an increased reliance on free fatty acids (FFA) as a metabolic substrate for myocardial work with a concurrent suppression of glucose metabolism [9,10]. Although this concept is still controversial, with in vitro studies showing a reduction in gene expression and enzyme activity of key elements of mitochondrial β-oxidation, multiple in vivo studies in animals models and humans with heart failure have documented (employing different techniques) this switch to FFA oxidation as a major source of energy [10–14]. While FFA oxidation provides the highest yield of ATP per molecule oxidized, it requires more oxygen than ATP production from glucose metabolism. This translates into approximately 10% more oxygen to produce an equivalent amount of ATP from FFA compared to ATP from glucose metabolism [15]. Therefore, myocardial FFA oxidation will result in increased oxygen consumption and reduced efficiency. β-blocker treatment could potentially prevent these adverse effects of sympathetic activation and improve myocardial efficiency. Investigations in animal models of CHF suggest that β-blockers may reduce myocardial utilization of free fatty acids. In humans with CHF, information concerning the impact of β-blockers on energy substrate utilization and efficiency remains limited and, to some extent, contradictory [16–18]. To date, no studies have compared the impact of different β-blockers on these parameters in patients with CHF.

In the present study we examined the impact of chronic treatment with non-selective versus selective β-blockers on myocardial substrate utilization. We hypothesized that non-selective β-blockade will result in more complete suppression of lipolysis resulting in a shift from FFA oxidation towards carbohydrate metabolism.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
The study population consisted of 22 patients with congestive heart failure. Inclusion criteria included age between 18 and 80 years old, with symptomatic CHF and left ventricular ejection fraction ≤35%, who had been on stable medical therapy for more than 1 month. We excluded all patients with an acute coronary syndrome or myocardial revascularization within the preceding three months, those who had a contraindication to β-blocker therapy, primary valvular heart disease or systolic blood pressure <85 mm Hg. Eleven patients were in the carvedilol group (age 54±3 years, LVEF 18±2%) and 11 patients were in the metoprolol group (age 54±4 years, LVEF 21±3%). In the carvedilol group, nine patients were on an angiotensin converting enzyme inhibitor (ACEI), two patients were on an angiotensin receptor blocker (ARB), and seven patients were on a loop diuretic. In the metoprolol group, 10 patients were on an ACEI, one patient on an ARB, and 10 patients on a loop diuretic.

The University of Toronto Ethical Review Committee for experimentation involving human subjects approved the protocol. Written informed consent was obtained from all participants.

2.2. Study protocol
Patients who agreed to participate in this study were submitted to a right heart catheterization during which baseline hemodynamic recordings were performed. Subsequently arterial and coronary sinus blood samples were collected to measure FFA and lactate levels. Once all baseline measurements were obtained, patients were randomized to carvedilol or metoprolol in a double-blind fashion. All patients were initiated on 3.125 mg of carvedilol or 6.25 mg of metoprolol, twice a day, and slowly uptitrated to a maximum dose of 25 mg of carvedilol or 50 mg of metoprolol twice a day. After 4 months of therapy patients underwent a repeat right heart catheterization for measurement of hemodynamics, free fatty acid and lactate levels. Once all tests were completed the study medication of the patient was identified and they were started on open label carvedilol or metoprolol as appropriate (Fig. 1).


Figure 1
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  		Fig. 1 Change in free fatty acid extraction in the carvedilol (Car) and metoprolol (Met) groups after 4 months of therapy. *P<0.05 vs. baseline.

 
2.3. Hemodynamic measurements
Instrumentation for hemodynamic measurements included the insertion of a pulmonary artery catheter for recording of right heart pressures and cardiac output. An arterial line was placed in the femoral or radial artery for blood sampling and measurement of arterial pressure. All pressures and electrocardiographic tracings were registered in a strip chart recorder. A coronary sinus catheter was inserted through the internal jugular vein or the brachial vein and positioned under fluoroscopic guidance. A small injection of radiocontrast dye was used to confirm the location of the catheter. Total body and cardiac norepinephrine spillover were measured as previously described [19].

2.4. Biochemical analysis
Free fatty acid concentrations were measured by spectrophotometric enzymatic assay. Lactate concentrations were determined using enzymatic spectrophotometric methods. Sympathetic efferent neuronal outflow was estimated by the measurement of cardiac and total body norepinephrine spillover, using techniques that are well established in our laboratory [19,20].

2.5. Statistical analysis
All data are presented as mean value±SEM. Statistical analysis was performed in Statview. Between group comparison of baseline characteristics were made using unpaired t-test. Paired t-tests were used for within group comparisons. A P value of less than 0.05 was required for statistical significance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline characteristics
All patients had New York Heart Association functional class II or III symptoms. Baseline heart rate was higher in the carvedilol group (82±2 bpm vs. 70±4 bpm, P<0.02). There were no other significant differences in baseline systemic or pulmonary hemodynamics between the two groups. Arterial and coronary sinus FFA and lactate concentrations were similar in both groups at baseline (Tables 1 and 2).


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  		Table 1 Hemodynamic responses

 


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  		Table 2 Biochemical responses

 
3.2. Hemodynamic responses
Carvedilol was uptitrated to a mean dose of 44±4 mg/day. After 4 months of therapy, carvedilol caused a significant reduction in heart rate (82±3 bpm to 66±2 bpm, P<0.0001). There were no changes in cardiac filling pressures, pulmonary artery pressure or systemic arterial blood pressure after 4 months of therapy with carvedilol (Table1).

Metoprolol was uptitrated to a mean dose of 60±8 mg/day. Heart rate was reduced significantly with metoprolol (70±4 bpm to 62±4 bpm, P<0.03). As with carvedilol, metoprolol therapy was associated with no significant changes in pulmonary artery pressure. However, there was a small but statistically significant reduction in cardiac index (2.6±0.1 to 2.4±0.1 l/min/m2, P<0.05).

3.3. Biochemical responses
There was no significant change in arterial FFA concentration during therapy with carvedilol (0.33±0.04 to 0.29±0.05 mmol/l, P=NS). There was, however, a significant reduction in cardiac FFA extraction (systemic arterial versus coronary sinus concentration) during therapy with carvedilol (0.12±0.02 to 0.1±0.02 mmol/l/l, P<0.03). Therapy with metoprolol resulted in a non-significant trend in the opposite direction in cardiac FFA extraction (0.09±0.02 to 0.11±0.03 mmol/l, P=NS). Despite these divergent effects on FFA extraction there was no significant difference on the effect of carvedilol versus metoprolol in this end point (–0.03±0.01 mmol/l vs.+0.02±0.03 mmol/l, carvedilol vs. metoprolol, P=NS) (Table 2).

After 4 months of therapy, carvedilol tended to increase cardiac lactate extraction (0.24±0.05 to 0.35±0.08 mmol/l, P=0.08) while with metoprolol the trend was in the opposite direction (0.18±0.03 to 0.11±0.04 mmol/l, P=0.09). Analysis of the between group differences of these changes revealed a significant difference in lactate extraction between them (+0.11±0.06 vs. –0.09±0.04 mmol/l, carvedilol vs. metoprolol, P<0.01) (Fig. 2).


Figure 2
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  		Fig. 2 Change in lactate extraction in the carvedilol (Car) and metoprolol (Met) groups after 4 months of therapy. *P<0.05 vs. change in metoprolol group.

 
The patients reported here represent a subgroup of a larger study, the results of which have been reported previously, examining the impact of therapy with metoprolol versus carvedilol on total body and systemic sympathetic activity in patients with chronic CHF [20]. In that study, therapy with carvedilol caused a significant reduction on both total body and cardiac specific sympathetic activity. In contrast, therapy with metoprolol caused no change in these parameters. In the study subjects presented in the present report the neurochemical responses to therapy with metoprolol and carvedilol were similar to our previous report. In the metoprolol group there was no significant change in total body or cardiac norepinephrine spillover after 4 months of β-blocker therapy (0.1±0.9 nmol/min and 24.8±42.2 pmol/min respectively, P=NS for both). In those treated with carvedilol, significant reductions in both of these endpoints were observed. Total body norepinephrine spillover was significantly reduced (–2.4±0.5 nmol/min, P=0.001) while cardiac norepinephrine spillover fell from 245±31 to 150±25 pmol/min (P=0.005) after 4 months of therapy. These changes observed in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.03).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this report we describe the differential effects of selective versus non-selective β-blockade on myocardial substrate utilization. We have demonstrated that 4 months of therapy with carvedilol caused a shift from FFA utilization to lactate utilization in patients with NYHA classes II–III heart failure. In contrast, metoprolol had a neutral effect on FFA utilization accompanied by a reduction in lactate consumption.

Congestive heart failure is characterized by increased reliance on FFA oxidation as a source of energy, an effect mediated by sympathetic activation through both β1- and β2-adrenegic receptors [9,10]. Furthermore, sympathetic activation could increase myocardial FFA oxidation by reducing myocardial malonyl coenzyme A levels, with the subsequent activation of carnitine palmityl transferase-1 (CPT-1). These biochemical perturbations would be associated with an increase in mitochondrial FFA uptake and oxidation [16,17]. Indeed, β-blocker therapy in a dog model of heart failure was associated with attenuation of CPT-1 activity and a reduction on myocardial FFA oxidation [21].

In this report, chronic non-selective β-blockade with carvedilol caused a 20% reduction in FFA extraction and a 50% increase in lactate extraction, while metoprolol had a neutral effect on FFA utilization and reduced lactate extraction by 35%. These important differences between carvedilol and metoprolol could have resulted from differential effects of these agents on peripheral lipolysis. The non-selective β-adrenergic receptor blocking activity of carvedilol might provide a more complete suppression of lipolysis given its ability to block both β1- and β2-receptors [18,22,23]. The associated reduction in serum FFA could lower cardiac extraction of FFA since the uptake of FFA has been shown to be concentration dependent [24]. Although this concept has mechanistic appeal, it does not explain the results obtained in the current study since arterial FFA concentration did not change during therapy with either β-blocker.

We hypothesized that the differential impact of carvedilol and metoprolol on cardiac FFA utilization results from their discrepant effects on cardiac sympathetic activity. In prior reports, our laboratory has documented the ability of non-selective β-adrenergic blockers to reduce cardiac sympathetic activity both when given acutely, and during sustained therapy [19,20]. In these studies, the selective β-adrenergic blocker metoprolol had different effects on cardiac sympathetic activity, increasing it with acute administration, while having a neutral effect during chronic therapy [19]. The mechanism of this differential effect appears to result from the ability of carvedilol to block prejunctional β2-adrenergic receptors thus inhibiting norepinephrine release [25]. Support for the prejunctional nature of this effect comes from extensive animal experimentation as well as from the observation in humans that carvedilol reduces norepinephrine spillover while having no impact on peripheral sympathetic nerve firing rates [20,25–27]. In the present cohort of patients similar results were obtained. Although carvedilol also reduced total body sympathetic activity (a measure of generalized sympathetic activity) this effect did not lead to a reduction in arterial FFA concentrations suggesting that carvedilol did not have an important effect on peripheral lipolysis. Therefore, our observations suggest that the impact of non-selective β-adrenergic receptor blockade on myocardial FFA utilization is driven by the impact of a reduction in cardiac sympathetic activity on myocardial metabolism. Whether this was mediated by downregulation of myocardial enzymes involved in FFA oxidation cannot be determined from the results of the present study, however observations made in animal models suggests that this is a plausible hypothesis [21].

This is the first human in vivo study examining the effects of β-blockade on myocardial substrate extraction as assessed by steady state measures of transcardiac substrate concentrations. Previous studies have addressed this question using positron emission tomography (PET) scanning to measure myocardial uptake of radiolabeled FFA and glucose. Our findings are consistent with the observations of Wallhaus et al. [28], in their report, 3 months of carvedilol treatment in patients with CHF was associated with a 57% reduction in FFA uptake. In another report, Beanlands et al. [29] used PET scanning to determine the impact of metoprolol on myocardial kinetics of C-11 acetate as a measure of oxidative metabolism. Therapy with metoprolol in patients with CHF was associated with a significant decrease in cardiac oxidative metabolism and an improvement of myocardial efficiency. This finding confirmed previous reports which suggested that β-blockers could improve myocardial efficiency in patients with CHF [30]. Importantly this data does not contradict our observations since they found an improvement in myocardial efficiency but did not examine the impact of metoprolol on FFA or carbohydrate utilization. Indeed, our study is the first report where the impact of a non-selective versus a selective β-blocker on myocardial energy substrate extraction was compared in a randomized manner in patients with CHF. The results of the current study and previous in vivo observations suggest a decrease in myocardial FFA utilization in response to β-blocker therapy in the setting of CHF. This observation appears inconsistent with in vitro studies suggesting a reduction in gene expression and enzyme activity of key elements of mitochondrial beta-oxidation [11]. Although we cannot provide an explanation for this discrepancy, it is recognized that changes in steady state cardiac extraction of energy substrates may not necessarily reflect changes in substrate utilization.

It is important to discuss some limitations of our study. First, the arterial FFA concentrations were within the normal range. In other studies involving patients with CHF, FFA levels were elevated when compared to non-CHF controls [28]. Although our patient group had severe left ventricular dysfunction with a mean EF of 20±2%, they had well compensated hemodynamics and only mild to moderate symptoms. This represents the most likely explanation for the normal FFA concentrations observed in these patients. Although the shift from FFA to lactate utilization should theoretically translate into improved myocardial efficiency, we cannot make any definitive statements about myocardial energetics because myocardial oxygen consumption was not measured. Finally, The metoprolol dose achieved seems small compared to the doses reached in the COMET trial [7]. This may be related to the lower heart rate in the metoprolol group at baseline. Furthermore, following β-blocker titration similar heart rates were achieved in the two groups suggesting that similar degrees of β-blockade had been reached.

In conclusion, our results demonstrate a differential effect of carvedilol and metoprolol on cardiac substrate utilization. Chronic treatment with carvedilol caused a shift from beta-oxidation towards lactate consumption. These differential effects might translate into differences in the impact of these drugs on myocardial oxygen consumption and efficiency. Furthermore, they might provide a potential mechanism to explain the mortality differences between metoprolol and carvedilol reported in the COMET trial [7].


   Acknowledgements
 
Dr. Al-Hesayen holds a research fellowship award form the Heart and Stroke Foundation of Ontario. This study was funded by an operating grant from the Heart and Stroke Foundation of Ontario, Glaxo Smith Kline and from Bayer. The authors wish to thank the staff of the Bayer Cardiovascular Clinical Research Laboratory of Mount Sinai Hospital for their help in the completion of these studies.


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

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