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European Journal of Heart Failure 2000 2(1):81-90; doi:10.1016/S1388-9842(00)00054-4
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© 2000 European Society of Cardiology

Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure

Mikko Pietiläa,*, Kimmo Malminiemib, Risto Huupponenc, Juha Rouruc, Kari Pulkkid, Erkki Peree and Liisa-Maria Voipio-Pulkkia

a Department of Medicine, Turku University Central Hospital Kiinamyllynk 4-8, 20520 Turku, Finland
b Departments of Internal Medicine and Clinical Pharmacology, Tampere University Hospital Turku, Finland
c Department of Pharmacology and Clinical Pharmacology, University of Turku Turku, Finland
d Department of Clinical Chemistry, Turku University Central Hospital Kiinamyllynk 4-8, 20520 Turku, Finland
e The Social Insurance Institution, Research and Development Centre Turku, Finland

* Corresponding author. Tel.: +358-2-2611-611; fax: +358-2-2612-030.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Purpose: Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating β1-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional β1-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group).

Results: Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2±11.5 to 81.7±10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98±0.05 to 1.10±0.05 mmol/l, P<0.005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0.65, P<0.0001) and body mass index (r=–0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05).

Conclusions: Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating β1- selective adrenoceptor antagonist, potentiates this effect.

Key Words: Insulin sensitivity • Heart failure • Exercise training • Celiprolol • Clinical trial • Euglycaemic clamp

Received June 28, 1999; Revised December 7, 1999; Accepted December 20, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Chronic heart failure is characterized by several abnormalities of the endocrine system. In addition to elevated levels of circulating catecholamines and activation of the renin–angiotensin system, hyperinsulinemia and insulin resistance [1] have also been reported in chronic heart failure. Since exercise is known to improve insulin sensitivity in healthy subjects [2] and in athletes [3], it provides a potentially appealing method to improve insulin sensitivity also in patients with chronic heart failure. Celiprolol, a vasodilating β1-selective adrenoceptor antagonist, has been shown to induce a beneficial effect on insulin sensitivity in hypertensive dyslipidemic subjects [4,5]. Since both treatment with β-adrenoceptor antagonists and exercise training are emerging therapeutic approaches in patients with chronic heart failure, we studied the combined effects of celiprolol and physical exercise on insulin sensitivity and serum lipid levels in patients with chronic, stable heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Subjects and study protocol
The study population consisted of 31 patients with chronic, stable NYHA class II–III heart failure who attended the outpatient clinic of the Turku University Central Hospital. The etiology of heart failure was ischemic heart disease in 25 and dilated cardiomyopathy in 6 patients. The demographic characteristics of the patients are summarized in Table 1. To study insulin sensitivity, 19 of the 31 patients underwent the euglycemic hyperinsulinemic clamp test (n=11 for celiprolol group and n=8 for control group). Subjects with known diabetes (n=8) were excluded from euglycemic clamp testing and in four patients either the baseline or follow-up analysis for insulin sensitivity was not available. For safety reasons, all baseline testing was performed while patients were receiving their original medication. This trial had a double-masked, placebo-controlled and parallel design. It was approved by the Joint Ethical Committee of Turku University and Turku University Hospital. The Finnish National Agency for Medicines was notified before the study as required by national regulations. The investigation confirms with the principles outlined in the Declaration of Helsinki.


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  		Table 1 Patient demographic characteristics at the baseline visit, and number of concomitant medicationsa

 
2.2. Exercise training
All subjects underwent a 6-month exercise training program, consisting of both aerobic and anaerobic training once a day, 6 days a week. This home-based training period was preceded by a 2-week in-house training instruction period. Baseline measurements were performed and a personal training program was created for each participant during the in-house period. Individualized target heart rate levels (varying between 60 and 85% of the maximal heart rate obtained during stress test) below the ischemic threshold were determined using information from a standard stress test and telemetric surveillance of the subjects’ responses during the in-house training. Anaerobic exercise was light intensity circuit muscle training, including dorsal and abdominal musculature as well as muscles of both the upper and lower extremities. Aerobic training consisted of walking, step-board exercise or ergometer training, or any other aerobic exercise method of similar intensity and duration (minimum of 30 min) depending on the subject’s preference. After the institution-based in-house training period, subjects continued training at home for 6 months, with monthly control visits, during which compliance was ascertained using exercise diaries and target exercise intensity was increased whenever possible. Compliance was estimated to be excellent or good, if over 75% or 60% (respectively) of the scheduled training sessions had been performed according to exercise diaries.

2.3. Study medication and concomitant treatments
After completing baseline testing, the participants were randomized to receive either celiprolol or placebo 200 mg once daily. All other medication, including ACE-inhibitors and lipid lowering agents (Table 1) was kept constant during the study. If the patient was already receiving a β-adrenoceptor antagonist, this was gradually discontinued in order to avoid withdrawal symptoms and the dosage of celiprolol or placebo increased within a period of 2 weeks. For safety reasons, administration of an open-label β-adrenoceptor antagonist (metoprolol) was allowed if resting heart rate exceeded 70 b.p.m. This was necessary in 13 of the 20 patients in the celiprolol and to 8 of the 11 patients in the placebo-treated group (P=NS for difference between groups). There was no difference between groups in the use of medication for dyslipidemias: altogether 18 subjects out of 31 were receiving treatment with statins (11/20 in the celiprolol group and 7/11 in the placebo group, P=NS). The use of angiotensin converting enzyme inhibitors was also similar in the two groups; 13/20 in the celiprolol group and 9/11 in the placebo group (P=NS). Also, other concomitant medications were comparable in both groups (Table 1). Compliance to study medication was estimated by regular pill counts.

2.4. Measurement of muscle exercise capacity and cardiopulmonary performance
The effect of the training program on the trunk and lower and upper extremity extensor muscles was measured by dynamic repetition tests [6]. In short, all five tests (abdominal and dorsal muscles, right and left upper extremity extensors and lower extremity extensors) were tested during the same session. Hand-held weights served as resistance for upper extremity extensors and a weight vest for lower extremities. No additional resistance was used in abdominal and dorsal muscle testing. All movements were repeated in peaceful pace until subjective maximum. The maximal number of repetitions in each test was set to be 50. Five minutes of resting was allowed between different tests. The average number of repetitions in the muscle group tests was then calculated.

Pulmonary oxygen uptake was measured using the EOS-Sprint Exercise Test System (Erich JAEGER GmbH&CoKG, Wurtzburg, Germany) while the subject was performing a symptom-limited exercise test with 15 W/min increments on a Ergometrics 800S bicycle ergometer (Ergometersysteme GmbH+CoKG, Bitz, Germany).

2.5. Measurement of whole body glucose uptake
Whole body glucose uptake was measured using a hyperinsulinemic euglycemic clamp test [7], which was carried out after an overnight (12 h) fast. The test was performed both before the in-house training period and after 6 months of exercise training. Patients attended the laboratory at 08.00 h and were not allowed to take their medication for 10 h before the measurements. Patients received insulin (Actrapid, Novo Nordisk A/S, Copenhagen, Denmark) with the infusion rate of 40 mU (288 pmol)/kg/m2 body surface area. Euglycemia, with target blood glucose concentration of 5 mmol/l, was maintained using a variable rate of 20% glucose infusion. The rate of glucose infusion was adjusted according to the whole blood glucose concentration measured from arterialized venous blood, obtained from a superficial vein of the hand kept in a box containing heated air (approx. 65°C). Blood samples were drawn at 10–15-min intervals for the determination of blood glucose (glucose oxidase method with Analox GM7 measuring device, Analox Instruments, London, UK) and serum insulin (Phadeseph Insulin RIA, Pharmacia, Uppsala, Sweden). For glucose duplicates, the intra-assay coefficient of variation (CV) was 1.3% and the interassay CV for standards was 1.7%. For insulin determination, the intra-assay CV was 2.7% and the interassay CV 3.9%.

The average glucose infusion rate between 60 and 120 min was taken as the M-value, and the insulin sensitivity index (ISI) was calculated by dividing the average glucose infusion rate by the steady-state blood glucose and serum insulin levels between 60 and 120 min.

2.6. Serum lipid measurements
Samples for serum lipid measurement were obtained both before the in-house training period and after 6 months of training. All samples were collected after an overnight (12 h) fast. Serum cholesterol and triglycerides were measured using a fully enzymatic CHOD-PAP method for total cholesterol [8] and a GPO-PAP method for serum triglycerides [9]. Serum HDL cholesterol concentrations were measured from the supernatant after precipitation of very low density lipoproteins (VLDL) and low density lipoprotein (LDL) with 10% polyethylene glycol [10]. Coefficients of variation were 2.1% for cholesterol, 3.9% for triglycerides and 2.8% for HDL cholesterol. Serum LDL cholesterol level was calculated using the formula by Friedewald et al. [11].

2.7. Measurement of β1-adrenoreceptor antagonist activity
As an attempt to take into account the confounding effect of different β1-adrenoreceptor antagonist activities in the two groups, the β1-adrenoreceptor antagonist activity in plasma samples was determined with a radioreceptor assay using rabbit lung tissue as a source for β1-adrenoceptors [12]. ICI 118551 (Imperial Chemical Industries, Macclesfield, UK) was added to the membrane preparation at a concentration of 60 ng/ml to block β2-adrenoceptors prior to the analysis. One milliliter of plasma was extracted with 4 ml acetonitrile whereafter 2 ml of the organic phase was evaporated. Diluted rabbit lung preparation (170 µl) in assay buffer (50 mM TRIS, 10 mM MgCl2, pH 7.45) and 30 µl [3H]CGP 12177 (6 nM, Amersham International plc, Buckinghamshire, UK) was added whereafter the mixture was vortexted and incubated for 1 h at room temperature. After incubation the mixture was washed three times with 5 ml of assay buffer and harvested with Brandel Cell Harvester M12-R (Brandel, Gaithesburg, MD, USA) using Gelman Sciences Type A/E Glass Fibre filter (Gelman Sciences, Ann Arbor, MI, USA). A standard curve was constructed using metoprolol concentrations ranging from 5 to 5000 ng/ml in plasma. The results are expressed as acetonitrile extractable metoprolol equivalents (ng/l).

2.8. Statistical analysis
The study effect (physical exercise+study medication) was tested using analysis of variance with repeated measurements (RANOVA) and with the study treatment group as a fixed factor. Here the interaction P-value is the probability of equal change in the celiprolol and control groups during the study. Within-group analysis was carried out using paired t-test based on User contrast analysis (BMDP Solo) after RANOVA. The baseline values between the groups were compared using Student’s t-test for independent samples and Fisher’s exact test for the dichotomal variables. The results of all the patients who completed the study and had successful tests before and after the intervention are presented (per protocol analysis). The possible confounding effects of the pre-study β1-adrenoceptor antagonist therapy and concomitant metoprolol treatment during the intervention were evaluated using covariance analysis. The baseline β1-adrenergic receptor occupancy and the difference between post- and pre-study occupancies were used as covariates.

The descriptive statistics are given as mean±standard error of mean (S.E.M.). Associations between the variables were studied using unweighted linear correlation analyses. Pearson’s correlation coefficients (r) are presented.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
During the intervention period, no deaths occurred and none of the patients were lost from follow-up. Compliance to the study medication exceeded 90% in all but one subject who had non-insulin-dependent diabetes. No drug-related discontinuations occurred during the study, but one diabetic subject suffered acute myocardial infarction after completing the follow-up testing.

At baseline, there were no statistically significant differences in the lipid values, insulin sensitivity, maximal oxygen uptake and body mass index between (BMI) the β-adrenoceptor antagonist users and non-users. Determined by covariance analysis, metoprolol treatment instituted during the intervention did not have a significant confounding effect on the study results. The interaction P-values between the studied variables and the changes in β1-occupancy were all insignificant: P>0.2.

The patients’ compliance with the training program was estimated to be good or excellent in 26/31 (81%) of the patients. The results of the muscle repetition tests showed a statistically significant increase in all five muscle groups tested. The average number of repetitions increased from 20 to 23 in both groups (P<0.05, Table 2). However, we did not observe a statistically significant increase in maximal ergometric exercise capacity or oxygen uptake in this particular study. The maximal working capacity on ergometer was 137±7 W before and 136±6 W after the study, and the maximal oxygen uptakes 1.61±0.09 l/min and 1.62±0.07 l/min, respectively. However, the weight-corrected maximal oxygen uptake increased significantly in the celiprolol group (+13%, P<0.05, Table 2). Table 2 also shows that despite formal randomization, there was an imbalance between the groups at baseline regarding VO2max, ISI and HDL (although none of these were quite significant at P<0.05 level). As a consequence, the post-treatment maximal oxygen uptake was still higher in the control than in the celiprolol group.


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  		Table 2 Main metabolic changes and results of the spireogometry and skeletal muscle tests during 6-month physical conditioning and study therapya

 
3.1. Insulin sensitivity
During the study, increases in the primary variables describing carbohydrate metabolism (Table 3), the whole-body glucose uptake capacity (M) and insulin sensitivity (ISI), were observed in the whole study population (Fig. 1). ISI increased from 68.2±11.5 to 81.7±10.7 ml/min/kg (mU/l) (P=0.0128, paired t-test), and the M-value from 4.22±0.56 to 5.10±0.51 mg/min/kg body wt. (P=0.0127, paired t-test). Although the improvements in insulin sensitivity were greater in the celiprolol group as compared to the control group, the difference between groups was statistically only near-significant (Table 4, interaction P=0.072). In the within-group analysis, statistically significant improvements in insulin sensitivity were only seen in the celiprolol-treated group (Table 4), where the ISI increased by 33% (P<0.02), and the M-value by 35% (P<0.01). Notably, the improvement in insulin sensitivity occurred without any change in the BMI in the celiprolol group (from 28.7±0.8 to 28.5±0.8 kg/m2), whereas a slight but statistically significant decrease in the BMI was seen in the control group (from 27.4±1.0 to 26.6±0.9 kg/m2, P<0.03) (Table 2).


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  		Table 3 The effect of 6-month physical conditioning on metabolic variablesa

 


Figure 1
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  		Fig. 1 Insulin sensitivity index (ISI) determined using hyperinsulinemic euglycemic clamp before and after the study intervention. Celiprolol and control groups are presented both separately and combined. Mean±S.E.M. Per protocol analysis: number of the patients in the celiprolol group=11, control group n=8.

 


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  		Table 4 The results of the hyperinsulinemic euglycemic clamp tests during 6-month physical conditioning and study therapya

 
Although ISI at baseline correlated with the weight-corrected maximal oxygen uptake (Vo2max, r=0.65, P<0.0001), the change in ISI failed to associate either with VO2max at baseline (r=0.08, NS) or with the change in the VO2max (r=0.17, NS). Instead, the change in ISI correlated weakly with the change in the average result of the muscle repetition test (r=0.53, P<0.05, Fig. 2). In within-group analysis, this correlation was only seen in the control group (r=0.73, P<0.05), but not in the celiprolol-treated group (r=0.24, P=NS). As expected, insulin sensitivity was significantly associated with the BMI (all post-treatment data pooled together: r=–0.55, P<0.005).


Figure 2
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  		Fig. 2 Change of insulin sensitivity index (ISI) vs. change of skeletal muscle exercise capacity. ISI is expressed in ml/min/kg (U/l), and muscle exercise capacity as the mean repetition count of the five different muscle tests. Association was statistically significant; linear correlation coefficient r=0.533 (P=0.016). Triangles: celiprolol group, circles: control group.

 
3.2. Serum lipid levels
During the study period, there was a significant increase in the study group as a whole in serum HDL cholesterol (HDL), HDL/total cholesterol ratio, and the HDL/LDL ratio (P<0.005, Table 3). The decrease in the triglyceride levels was near-significant (P=0.07). No statistically significant changes were seen in serum total cholesterol or LDL cholesterol levels. In the between-groups analysis, the increase in the HDL cholesterol was significantly greater in the celiprolol than in the control group (interaction P<0.05, Table 2).

In the within-group analysis, a statistically significant increase in the serum HDL cholesterol level was seen in the celiprolol group (from 0.92±0.05 to 1.09±0.06 mmol/l, P<0.005) whereas the increase in the control group did not reach statistical significance (from 1.08±0.09 to 1.11±0.10 mmol/l, P=NS). These changes in serum HDL cholesterol level resulted in respective effects in the serum HDL/total cholesterol and HDL/LDL ratios in the celiprolol group (Table 2). Also, the decrease in serum triglyceride concentration in the celiprolol group was near-significant (from 2.04±0.29 to 1.71±0.19 mmol/l, P=0.058, Table 2).

3.3. β1-Adrenoreceptor antagonist activity
Samples for determination of β1-adrenoreceptor antagonist activity were drawn at baseline and after the completion of the study. No statistically significant increase was seen in the study group as a whole (RANOVA). The β1-adrenoreceptor antagonist activity tended to increase in the celiprolol group, but the increase was not statistically significant (from 52.3±77.0 to 97.5±90.9 metoprolol equivalents, P=0.094). No change was seen in the β1-antagonist activity in the control group (from 21.2±23.6 to 18.3±19.4 metoprolol equivalents, P=NS).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Exercise training has beneficial effects on exercise capacity and the quality of life in patients with chronic heart failure [13–15]. The use of β-adrenoceptor antagonists has been shown to improve ejection fraction, quality of life and even survival [16] in chronic heart failure due to both idiopathic dilated cardiomyopathy and ischemic heart disease [17]. However, only one report of the combined use of exercise training and β-adrenoceptor antagonist has been published previously [18], focusing on tolerability and effects on exercise capacity. The adverse effects of several β-adrenoceptor antagonists on serum lipid profile and insulin sensitivity are well known [19].

Insulin resistance has been linked to chronic heart failure [1], but its clinical relevance and role in the pathophysiology and progression of heart failure remain unsolved. Insulin resistance correlates with the severity of heart failure [20,21], but not with single hemodynamic measures, such as ejection fraction [21,22]. Interestingly, chronic heart failure predicts the development of clinical NIDDM [23].

Insulin resistance has been linked to the pathophysiology of peripheral muscle changes in heart failure [21]. The relationship between insulin resistance and skeletal muscle blood flow has been widely studied. Blood flow appears not to be a major determinant of whole body insulin sensitivity in healthy volunteers or in patients with chronic heart failure [22,24–27], although reports have been conflicting. The effect of exercise training on skeletal muscle blood flow in chronic heart failure is unclear, as both an increase and no change have been reported [28–30]. Measuring skeletal muscle blood flow was not included in our protocol. Whether the improvement in insulin sensitivity in our subjects was due to increased peripheral perfusion cannot therefore be directly answered by this study.

Exercise is known to improve insulin sensitivity in healthy subjects [2] and in athletes [3]. In our study, insulin sensitivity improved significantly in the study group as a whole. The change in ISI did not correlate statistically significantly with the change in either maximal ergometric exercise capacity or VO2max. Instead, the change in ISI correlated weakly (r=0.53) with the change in average performance of muscle repetition tests. This may suggest that the change in insulin sensitivity is at least partly due to improved skeletal muscle glucose uptake. Since ISI increased more in the celiprolol group but the correlation between impairment of ISI and skeletal muscle performance was more marked in the placebo group, it is likely that also other mechanisms contribute to the improvement of insulin sensitivity in the celiprolol-treated group. The difference in the relative increase of ISI between groups, however, can be partly explained by the imbalanced baseline levels (Table 4), which occurred despite formal randomization in this patient sample. This prevents us from drawing any definite conclusions on the nature of the interaction between exercise per se and exercise plus celiprolol treatment in improving insulin sensitivity during this study.

Celiprolol is a vasodilating, β1-receptor selective adrenoceptor antagonist with mild intrinsic sympathomimetic activity due to partial β2-agonism [31,32]. In long-term use celiprolol has been shown to improve insulin sensitivity in subjects with hypertension, and also to have beneficial effects on serum lipid levels [4]. However, in a study exploring the acute effects of intravenous celiprolol, no beneficial effects on insulin sensitivity in healthy volunteers were observed, despite a marked improvement in skeletal muscle blood flow [33]. Therefore, factors also other than vasodilatation and improved skeletal muscle blood flow probably play a role in the positive effects on insulin sensitivity with celiprolol. Whether this also is true during longer administration of celiprolol remains uncertain.

The effects of celiprolol on serum lipid levels are in agreement with those seen in dyslipidemic hypertensives [4]. The magnitude of these changes is also similar, although only the increase in HDL cholesterol and changes in HDL/total cholesterol and HDL/LDL ratios were statistically significant in the celiprolol group in our study.

Only minor changes in lipids were observed in the control patients, that is in the placebo- and exercise-treated group, and none of these changes were statistically significant in the within-group analysis. This was in line with previous observations showing that only minor effects on blood lipids occur after exercise training in patients with coronary artery disease [34].

The control but not the celiprolol-treated group lost weight statistically significantly during the study. Thus, weight loss did not explain the changes observed in either insulin sensitivity or serum lipid levels. Most of our patients were moderately overweight. However, since evaluation of body composition was not included in our study protocol, it remains possible that difference in changes in BMI reflect respective changes in fat-muscle ratios. These could have affected the measured metabolic variables.

Our study has limitations that must be taken into account when interpreting the results. Despite randomization the celiprolol-treated group had somewhat (although not statistically significantly on the P<0.05 level) lower baseline VO2max-value, insulin sensitivity index and HDL cholesterol at baseline. This may have influenced the results to the benefit of the celiprolol-treated group. The use of other β-adrenoceptor antagonists than celiprolol may have confounded the results. However, the use of other β-adrenoceptor antagonists than celiprolol was similar between the two groups (13/20 in celiprolol group and 8/11 in control group). This diminishes the possibility that the beneficial effect of celiprolol would merely have been a consequence of discontinuing potentially disadvantageous previous treatment. Also, in the analysis of β1-adrenoreceptor antagonist activity, no change was seen in the control group, whereas a near-significant increase was seen in the celiprolol-treated group. This suggests that the possible negative metabolic effects of β1-antagonism in this group were suppressed by other effects of celiprolol and exercise.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our results suggest that insulin sensitivity may be enhanced in patients with chronic heart failure by exercise training. Treatment with celiprolol, a vasodilating β1-selective adrenoceptor antagonist, potentiates this effect and causes favorable changes in serum lipid profile, especially by increasing HDL cholesterol.


   Acknowledgements
 
This study was supported by Leiras Pharmaceuticals Inc., Turku, Finland, Polar Electro, Oulu, Finland, and EVO funds of Turku University Central Hospital. The study drugs were donated by Leiras. The in-house training period was carried out in the Research and Development Centre of Social Insurance Institution, Turku, Finland.


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

  1. Swan J.W., Walton C., Godsland I.F., Clark A.L., Coats A.J.S., Oliver M.F. Insulin resistance in chronic heart failure. Eur Heart J (1994) 15:1528–1532.[Abstract/Free Full Text]
  2. Devlin J.T. Effects of exercise on insulin sensitivity in humans. Diabetes Care (1992) 15(suppl.4):1690–1693.[Abstract]
  3. Koivisto V.A., Yki-Järvinen H., DeFronzo D.A. Physical training and insulin sensitivity. Diabetes Metab Rev (1986) 1:445–481.[Medline]
  4. Malminiemi K., Lahtela J.T., Huupponen R. Effects of celiprolol on insulin sensitivity and glucose tolerance in dyslipidemic hypertension. Int J Clin Pharmacol Ther (1995) 33(3):156–163.[Web of Science][Medline]
  5. Dunn C.J., Spencer C.M. Celiprolol. An evaluation of its pharmacological properties and clinical efficacy in the management of hypertension and angina pectoris. Drugs Aging (1995) 7:394–411.[Web of Science][Medline]
  6. Alaranta H., Hurri H., Heliovaara M., Soukka A., Harju R. Non-dynamometric trunk performance tests: reliability and normative data. Scand J Rehabil Med (1994) 26(4):211–215.[Web of Science][Medline]
  7. DeFronzo R.A., Tobin J.A., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol (1979) 237:E214–E223.[Web of Science][Medline]
  8. Siedel J., Schlumberger H., Klose S., Ziegenhorn J., Wahlefeld A.W. Improved reagent for the enzymatic determination of serum cholesterol. J Clin Chem Clin Biochem (1981) 19:838–839.
  9. Wahlefeld A.W. Triglycerides — determination after enzymatic hydrolysis. In: Methods of enzymatic analysis. 2nd ed—Bergmeyer H.V., ed. (1974) New York: Verlag Chemie/Academic Press. 1831–1835.
  10. Izzo C., Grillo F., Murador E. Improved method for determination of high-density-lipoproteins by use of polyethylene glycol 6000. Clin Chem (1981) 27:371–374.[Abstract/Free Full Text]
  11. Friedewald W.T., Levy R.I., Fredrickson D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem (1972) 18(6):499–502.[Abstract]
  12. Wellstein A., Palm D., Pitchner H.F., Belz G.G. Receptor-binding of propranolol is the missing link between plasma concentration kinetics and the effect–time course in man. Eur J Clin Pharmacol (1985) 29:131–147.[CrossRef][Web of Science][Medline]
  13. Coats A.J.S., Adamopoulos S., Mayer T.E., Conway J., Sleight P. Effects of physical training in chronic heart failure. Lancet (1990) 335:63–66.[CrossRef][Web of Science][Medline]
  14. Coats A.J.S., Clark A.L., Piepoli M., Volterrani M., Poole-Wilson P.A. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J (1994) 72:S36–39.[Free Full Text]
  15. Tyni-Lenne R., Gordon A., Sylven C. Improved health-related quality of life in moderate chronic heart failure following submaximal exercising of leg muscle. J Card Failure (1996) 2:111–117.[CrossRef][Medline]
  16. Doughty R.N., Sharpe N., MacMahon S. Effects of beta-blocker therapy on mortality in patients with heart failure. Eur Heart J (1997) 18:560–565.[Abstract/Free Full Text]
  17. Australia-New Zealand Heart Failure Research Collaborative Group. Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Lancet (1997) 349:375–380.[CrossRef][Web of Science][Medline]
  18. Demopoulos L., Yeh M., Gentilucci M., et al. Nonselective beta-adrenergic blockade with carvedilol does not hinder the benefits of exercise training in patients with congestive heart failure. Circulation (1997) 95(7):1764–1767.[Abstract/Free Full Text]
  19. Lind L., Pollare T., Berne C., Lithell H. Long-term metabolic effects of antihypertensive drugs. Am Heart J (1994) 128:1177–1183.[CrossRef][Web of Science][Medline]
  20. Swan J.W., Walton C., Godsland I.F., Clark A.L. Relationship of insulin resistance to the severity and etiology of chronic heart failure. Circulation (1994) 90:I–74.
  21. Swan J.W., Anker S.D., Walton C., et al. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol (1997) 30(2):527–532.[Abstract]
  22. Paternostro G., Camici P., Lammertsma A., et al. Cardiac and skeletal muscle insulin resistance in patients with coronary artery disease. J Clin Invest (1996) 9:2094–2099.
  23. Amato L., Paolisso G., Cacciatore F., et al. Congestive heart failure predicts the development of non-insulin dependent diabetes mellitus in the elderly. Diabetes-Metab (1997) 23(3):213–218.
  24. Anker S.D., Leyva F., Poole-Wilson P.A., Kox W.J., Stevenson J.C., Coats A.J. Relation between serum uric acid concentration and lower limb blood flow in patients with chronic heart failure. Heart (1997) 78(1):39–43.[Abstract/Free Full Text]
  25. Houghton A.R., Harrison M., Perry A.J., Evans A.J., Cowley A.J. Endogenous insulin and insulin sensitivity. Eur Heart J (1998) 19:476–480.[Abstract/Free Full Text]
  26. Yki-Järvinen H., Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia (1998) 41:369–379.[CrossRef][Web of Science][Medline]
  27. Nuutila P., Raitakari M., Laine H., et al. Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O] water, and [18F] fluoro-deoxy-glucose and positron emission tomography. J Clin Invest (1996) 97:1741–1747.[Web of Science][Medline]
  28. Katz S.D., Yuen J., Bijou R., Le Jemtel T.H. Training improves endothelium-dependent vasodilatation in resistance vessels of patients with heart failure. J Appl Physiol (1997) 82(5):1488–1492.[Abstract/Free Full Text]
  29. Hambrecht R, Fiehn E, Jiangtao Y et al. Altered peripheral perfusion and skeletal muscle metabolic response to exercise in patients with chronic heart failure: chronic effect of endurance training. Circulation 1996;96(8) suppl.1:I 192 (Abstract).
  30. Ohtsubo M., Yonezawa K., Nishijima H., et al. Metabolic abnormality of calf skeletal muscle is improved by localized muscle training without changes in blood flow in chronic heart failure. Heart (1997) 78(5):437–443.[Abstract/Free Full Text]
  31. Tung L.H., Jackman G., Cambpell B., Louis S., Iakovidis D., Louis W.J. Partial agonist activity of celiprolol. J Cardiovasc Pharmacol (1993) 21:484–488.[Web of Science][Medline]
  32. Dhein S., Titzer S., Wallstein M., et al. Celiprolol exerts microvascular dilatation by activation of beta-2-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol (1992) 346:27–31.[CrossRef][Web of Science][Medline]
  33. Malminiemi K., Laine H., Knuuti M.J., et al. Acute effects of celiprolol on muscle blood flow and insulin sensitivity: studies using 15O-water, 18F- fluorodeoxyglucose and positron emission tomography. Eur J Clin Pharmacol (1997) 52(1):19–26.[CrossRef][Web of Science][Medline]
  34. Lavie C.J., Milani R.V. Effects of cardiac rehabilitation, exercise training, and weight reduction on exercise capacity, coronary risk factors, behavioral characteristics, and quality of life in obese coronary patients. Am J Cardiol (1997) 79(4):397–401.[CrossRef][Web of Science][Medline]

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