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β-blockers in heart failure—Much more than heart rate reduction
Journal of Cardiac Failure Vol. 8 No. 6 2002
Editorial Comment
-Blockers in Heart Failure—Much More Than Heart Rate Reduction STEPHAN VON HAEHLING, MD, STEFAN D. ANKER, MD, PhD London, United Kingdom; Berlin, Germany
Similarly, the glucose oxidation rate was increased only in the carvedilol group (P < .05). Thus only carvedilol may shift body substrate utilization from predominant lipid to glucose oxidation. Protein oxidation was not affected by either -blocker. It is well known that -blocker treatment interferes with basal metabolic rate; this has been confirmed by recent studies.5,6 In children suffering from severe burns, propranolol has been reported to decrease REE, thus attenuating the catecholamine-mediated hypermetabolic response.7 It has recently been demonstrated that metoprolol reduces oxidative metabolism in patients with left ventricular dysfunction.8 Thus far no study has examined the effect of -blocker treatment on substrate utilization in CHF. Although Podbregar and Voga suggest that the -blocker–induced shift of metabolism observed in their work might be able to attenuate the development of cardiac cachexia, this assertion is weakened by the lack of cachectic patients in their study. Another criticism may be that the methodology employed by the authors to assess substrate metabolism and body composition is indirect and relies on assumptions that are not necessarily valid in CHF patients. Bioimpedance, for instance, estimates total body resistance; however, the latter depends on the body’s water content, which is well-known to be variable even in nonedematous stable CHF patients.9 Dual-energy x-ray absorptiometry certainly is also not perfect but it is superior to bioimpedance for assessing body composition in CHF.10 An interesting subfinding is that serum uric acid levels decreased in the carvedilol group while remaining unchanged in the bisoprolol group. Some studies suggest that uric acid is a marker of peripheral blood flow,11 anaerobic threshold,12 and impaired oxidative metabolism.13 A causal relationship between insulin resistance and serum uric acid levels has also been proposed.13 Moreover, cachectic patients were found to have the highest levels of uric acid
In the past few years a wealth of data has accumulated underscoring that altered metabolism is a key feature of chronic heart failure (CHF). These metabolic changes are thought to be involved in the development of skeletal muscle wasting, leading to body wasting and eventually culminating in cardiac cachexia. Previous studies on resting energy expenditure (REE) and total daily energy expenditure have shown that these parameters are abnormal in CHF.1 Uric acid is a simple humoral marker indicating metabolic status in CHF. Hyperuricemia occurs in conditions of purine accumulation (resulting from insulin resistance or cell death) and when xanthine oxidase activity is raised (resulting from tissue hypoxia or ischemia).1 In this issue of the Journal of Cardiac Failure, Podbregar and Voga report on the impact of -blocker treatment on REE, substrate metabolism, and uric acid levels.2 Both drugs used in this randomized, open-label trial—the 1-selective -blocker bisoprolol and the nonselective -blocker carvedilol—are known to improve survival in CHF.3,4 Although the two treatment groups consisted of only 13 patients, the authors provide interesting insight into basic mechanisms underlying -blocker efficacy. After a treatment period of 6 months, the REE decreased in both treatment groups (mean changes: carvedilol ⫺ 9.34%, bisoprolol ⫺ 4.82%, both P < .05, P ⫽ NS between groups). The lipid oxidation rate (adjusted for body mass index) was decreased in the carvedilol, but not in the bisoprolol group (P < .05). From the National Heart and Lung Institute, Imperial College School of Medicine, Department of Clinical Cardiology, London, UK, and Franz-Volhard Klinik, Charite´ Medical School, Campus BerlinBuch, Berlin, Germany. Reprint Requests: Dr. Stefan Anker, MD, PhD, Department of Clinical Cardiology, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, United Kingdom. Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0004$35.00/0 doi:10.1054/jcaf.2002.130310
379
380 Journal of Cardiac Failure Vol. 8 No. 6 December 2002 among CHF patients.14 Whether some of the beneficial effects of carvedilol are mediated through its effects on uric acid is a matter of speculation. That carvedilol’s beneficial effects cause uric acid levels to fall (mean change < 10%) seems more likely. Theoretically, a uricosuric effect of carvedilol (that is not known to exist) also could explain the findings. Uricosuric effects have, for instance, been reported for the angiotensin II receptor antagonist losartan.15 Targeting uric acid may be of benefit in CHF patients. It has recently been shown that the xanthine oxidase inhibitor allopurinol (which can reduce uric acid levels by >20% in 1 week) improves peripheral blood flow in arms and legs of CHF patients with hyperuricemia.16 This effect seems to be attributable to an improvement in endothelial dysfunction. Allantoin, a marker of oxygen free radical generation was also decreased after allopurinol treatment.16 Interestingly, a recent study suggests that long-term high-dose allopurinol treatment (ⱖ 300 mg/day) in CHF is associated with a lower mortality than is long-standing low-dose allopurinol treatment.17 Effectively improving the metabolic status of CHF patients is likely to contribute to prevention of cardiac cachexia. This may, in itself, be a therapeutic goal of the future.
References 1. Obisesan TO, Toth MJ, Donaldson K, Gottlieb SS, Fisher ML, Vaitekevicius P, Poehlman ET: Energy expenditure and symptom severity in men with heart failure. Am J Cardiol 1996;77:1250–1252 2. Podbregar M, Voga G: Effect of selective and nonselective -blockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Card Fail 2002;8:369–378 3. CIBIS-II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13 4. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658 5. Kunz I, Schorr U, Klaus S, Sharma AM: Resting metabolic rate and substrate use in obesity hypertension. Hypertension 2000;36:26–32 6. Hyltander A, Daneryd P, Sandstrom R, Korner U, Lundholm K: Beta-adrenoceptor activity and resting energy metabolism in weight losing cancer patients. Eur J Cancer 2000;36:330–334
7. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223–1229 8. Beanlands RS, Nahmias C, Gordon E, Coates G, deKemp R, Firnau G, Fallen E: The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, positron-emission tomography study. Circulation 2000;102:2070–2075 9. Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD: The regulation and measurement of plasma volume in heart failure. J Am Coll Cardiol 2002;39:1901– 1908 10. Anker SD, Ponikowski PP, Clark AL, Leyva F, Rauchhaus M, Kemp M, Teixeira MM, Hellewell PG, Hooper J, Poole-Wilson PA, Coats AJ: Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J 1999;20:683–693 11. Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ: Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart 1997;78:39–43 12. Leyva F, Chua TP, Anker SD, Coats AJ: Uric acid in chronic heart failure: a measure of the anaerobic threshold. Metabolism 1998;47:1156–1159 13. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ: Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997;18:858–865 14. Doehner W, Rauchhaus M, Florea VG, Sharma R, Bolger AP, Davos CH, Coats AJ, Anker SD: Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance. Am Heart J 2001;141:792–799 15. Wurzner G, Gerster JC, Chiolero A, Maillard M, FallabStubi CL, Brunner HR, Burnier M: Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. J Hypertens 2001;19:1855–1860 16. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R: Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002;105:2619–2624 17. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM: Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study. Heart 2002;87:229–234
Editorial Comment
-Blockers in Heart Failure—Much More Than Heart Rate Reduction STEPHAN VON HAEHLING, MD, STEFAN D. ANKER, MD, PhD London, United Kingdom; Berlin, Germany
Similarly, the glucose oxidation rate was increased only in the carvedilol group (P < .05). Thus only carvedilol may shift body substrate utilization from predominant lipid to glucose oxidation. Protein oxidation was not affected by either -blocker. It is well known that -blocker treatment interferes with basal metabolic rate; this has been confirmed by recent studies.5,6 In children suffering from severe burns, propranolol has been reported to decrease REE, thus attenuating the catecholamine-mediated hypermetabolic response.7 It has recently been demonstrated that metoprolol reduces oxidative metabolism in patients with left ventricular dysfunction.8 Thus far no study has examined the effect of -blocker treatment on substrate utilization in CHF. Although Podbregar and Voga suggest that the -blocker–induced shift of metabolism observed in their work might be able to attenuate the development of cardiac cachexia, this assertion is weakened by the lack of cachectic patients in their study. Another criticism may be that the methodology employed by the authors to assess substrate metabolism and body composition is indirect and relies on assumptions that are not necessarily valid in CHF patients. Bioimpedance, for instance, estimates total body resistance; however, the latter depends on the body’s water content, which is well-known to be variable even in nonedematous stable CHF patients.9 Dual-energy x-ray absorptiometry certainly is also not perfect but it is superior to bioimpedance for assessing body composition in CHF.10 An interesting subfinding is that serum uric acid levels decreased in the carvedilol group while remaining unchanged in the bisoprolol group. Some studies suggest that uric acid is a marker of peripheral blood flow,11 anaerobic threshold,12 and impaired oxidative metabolism.13 A causal relationship between insulin resistance and serum uric acid levels has also been proposed.13 Moreover, cachectic patients were found to have the highest levels of uric acid
In the past few years a wealth of data has accumulated underscoring that altered metabolism is a key feature of chronic heart failure (CHF). These metabolic changes are thought to be involved in the development of skeletal muscle wasting, leading to body wasting and eventually culminating in cardiac cachexia. Previous studies on resting energy expenditure (REE) and total daily energy expenditure have shown that these parameters are abnormal in CHF.1 Uric acid is a simple humoral marker indicating metabolic status in CHF. Hyperuricemia occurs in conditions of purine accumulation (resulting from insulin resistance or cell death) and when xanthine oxidase activity is raised (resulting from tissue hypoxia or ischemia).1 In this issue of the Journal of Cardiac Failure, Podbregar and Voga report on the impact of -blocker treatment on REE, substrate metabolism, and uric acid levels.2 Both drugs used in this randomized, open-label trial—the 1-selective -blocker bisoprolol and the nonselective -blocker carvedilol—are known to improve survival in CHF.3,4 Although the two treatment groups consisted of only 13 patients, the authors provide interesting insight into basic mechanisms underlying -blocker efficacy. After a treatment period of 6 months, the REE decreased in both treatment groups (mean changes: carvedilol ⫺ 9.34%, bisoprolol ⫺ 4.82%, both P < .05, P ⫽ NS between groups). The lipid oxidation rate (adjusted for body mass index) was decreased in the carvedilol, but not in the bisoprolol group (P < .05). From the National Heart and Lung Institute, Imperial College School of Medicine, Department of Clinical Cardiology, London, UK, and Franz-Volhard Klinik, Charite´ Medical School, Campus BerlinBuch, Berlin, Germany. Reprint Requests: Dr. Stefan Anker, MD, PhD, Department of Clinical Cardiology, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, United Kingdom. Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0004$35.00/0 doi:10.1054/jcaf.2002.130310
379
380 Journal of Cardiac Failure Vol. 8 No. 6 December 2002 among CHF patients.14 Whether some of the beneficial effects of carvedilol are mediated through its effects on uric acid is a matter of speculation. That carvedilol’s beneficial effects cause uric acid levels to fall (mean change < 10%) seems more likely. Theoretically, a uricosuric effect of carvedilol (that is not known to exist) also could explain the findings. Uricosuric effects have, for instance, been reported for the angiotensin II receptor antagonist losartan.15 Targeting uric acid may be of benefit in CHF patients. It has recently been shown that the xanthine oxidase inhibitor allopurinol (which can reduce uric acid levels by >20% in 1 week) improves peripheral blood flow in arms and legs of CHF patients with hyperuricemia.16 This effect seems to be attributable to an improvement in endothelial dysfunction. Allantoin, a marker of oxygen free radical generation was also decreased after allopurinol treatment.16 Interestingly, a recent study suggests that long-term high-dose allopurinol treatment (ⱖ 300 mg/day) in CHF is associated with a lower mortality than is long-standing low-dose allopurinol treatment.17 Effectively improving the metabolic status of CHF patients is likely to contribute to prevention of cardiac cachexia. This may, in itself, be a therapeutic goal of the future.
References 1. Obisesan TO, Toth MJ, Donaldson K, Gottlieb SS, Fisher ML, Vaitekevicius P, Poehlman ET: Energy expenditure and symptom severity in men with heart failure. Am J Cardiol 1996;77:1250–1252 2. Podbregar M, Voga G: Effect of selective and nonselective -blockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Card Fail 2002;8:369–378 3. CIBIS-II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13 4. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658 5. Kunz I, Schorr U, Klaus S, Sharma AM: Resting metabolic rate and substrate use in obesity hypertension. Hypertension 2000;36:26–32 6. Hyltander A, Daneryd P, Sandstrom R, Korner U, Lundholm K: Beta-adrenoceptor activity and resting energy metabolism in weight losing cancer patients. Eur J Cancer 2000;36:330–334
7. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223–1229 8. Beanlands RS, Nahmias C, Gordon E, Coates G, deKemp R, Firnau G, Fallen E: The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, positron-emission tomography study. Circulation 2000;102:2070–2075 9. Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD: The regulation and measurement of plasma volume in heart failure. J Am Coll Cardiol 2002;39:1901– 1908 10. Anker SD, Ponikowski PP, Clark AL, Leyva F, Rauchhaus M, Kemp M, Teixeira MM, Hellewell PG, Hooper J, Poole-Wilson PA, Coats AJ: Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J 1999;20:683–693 11. Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ: Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart 1997;78:39–43 12. Leyva F, Chua TP, Anker SD, Coats AJ: Uric acid in chronic heart failure: a measure of the anaerobic threshold. Metabolism 1998;47:1156–1159 13. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ: Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997;18:858–865 14. Doehner W, Rauchhaus M, Florea VG, Sharma R, Bolger AP, Davos CH, Coats AJ, Anker SD: Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance. Am Heart J 2001;141:792–799 15. Wurzner G, Gerster JC, Chiolero A, Maillard M, FallabStubi CL, Brunner HR, Burnier M: Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. J Hypertens 2001;19:1855–1860 16. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R: Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002;105:2619–2624 17. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM: Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study. Heart 2002;87:229–234