Effects of β-blockers on ventilation efficiency in heart failure Piergiuseppe Agostoni, MD, PhD, a,b Anna Apostolo, MD, a Gaia Cattadori, MD, a Elisabetta Salvioni, PhD, a Giovanni Berna, MD, a Laura Antonioli, MD, a Carlo Vignati, MD, a Mauro Schina, MD, c Susanna Sciomer, MD, c Maurizio Bussotti, MD, a,d Pietro Palermo, MD, a Cesare Fiorentini, MD, a and Mauro Contini, MD a Milan, Milano, and Roma, Italy; and Seattle, WA Background Hyperventilation and consequent reduction of ventilation (VE) efficiency are frequently observed during exercise in heart failure (HF) patients, resulting in an increased slope of VE/carbon dioxide (VE/VCO 2 ) relationship. The latter is an independent predictor of HF prognosis. β-Blockers improve the prognosis of HF patients. We evaluated the effect on the efficiency of VE of a β 1 -β 2 unselective (carvedilol) versus a β 1 selective (bisoprolol) β-blocker. Methods We analyzed consecutive maximal cardiopulmonary exercise tests performed on 572 clinically stable HF patients (New York Heart Association class I-III, left ventricle ejection fraction ≤50%) categorized in 3 groups: 81 were not treated with β-blocker, 304 were treated with carvedilol, and 187 were treated with bisoprolol. Clinical conditions were similar. Results The VE/VCO 2 slope was lower in carvedilol- compared with bisoprolol-treated patients (29.7 ± 0.4 vs 31.6 ± 0.5, P = .023, peak oxygen consumption adjusted) and with patients not receiving β-blockers (31.6 ± 0.7, P = .036). Maximum end-tidal CO 2 pressure during the isocapnic buffering period was higher in patients treated with carvedilol (39.0 ± 0.3 mm Hg) than with bisoprolol (37.2 ± 0.4 mm Hg, P b .001) and in patients not receiving β-blockers (37.2 ± 0.5 mm Hg, P = .001). Conclusions Reduction of hyperventilation, with improvement of VE efficiency during exercise (reduction of VE/VCO 2 slope and increase of maximum end-tidal CO 2 pressure), is specific to carvedilol (β 1 -β 2 unselective blocker) and not to bisoprolol (β 1 -selective blocker). (Am Heart J 2010;159:1067-73.) A reduced efficiency of ventilation is a peculiar characteristic of heart failure (HF). 1-5 Ventilation efficien- cy is assessed during exercise by the slope of the relationship between ventilation and carbon dioxide production (VE/VCO 2 ). 1,3,4,6-8 An increase in VE/VCO 2 slope is an indicator of poor prognosis in HF patients. 4,8 Hyperventilation, which can be considered either as the cause or the effect of a reduced efficiency of ventilation, is associated to an increase of waste ventilation. 2,9,10 An improvement of the efficiency of ventilation—and therefore a reduction of hyperventilation—is among the therapeutic goals of HF treatment. β-Blockers, which are among the most efficacious drugs for HF treatment in terms of both prognosis and patients' quality of life, 11-14 reduce exercise-induced hyperventilation. 15,16 Indeed, several reports showed that increased sympathetic tone enhances the ventilatory response in healthy individual, 17-19 in diabetic subjects, 20 and in chronic HF patients. 21-25 Lower ventilation response to VCO 2 is paralleled by an amelioration of patients' quality of life. 15,16 Ventilation depends on VCO 2 , dead space to tidal volume (VT) ratio, and PaCO 2 . 2,9,10 All are possible targets of β-blocker therapy so that several are the possible sites of action of β-blockers on the regulation of ventilation in HF patients. Indeed, VCO 2 depends on muscle activity; dead space to VT ratio depends on the ventilation/perfusion mismatch in the lung, part of which is also related to a derangement of gas diffusion across the alveolar-capillary membrane; and PaCO 2 is the set point of CO 2 . The latter, in HF, is reduced by an increased sympathetic mediated reflex activity of both metabo- and chemoreflexes. 21-25 The overwhelming majority of studies on β-blockers and hyperventilation in HF have been done using carvedilol as the tested drug or the drug more frequently From the a Centro Cardiologico Monzino, IRCCS, Department of Cardiovascular Sciences, University of Milan, Milan, Italy, b Division of Respiratory and Critical Care, University of Washington, Seattle, WA, c Department of Cardiovascular and Respiratory Sciences, University “Sapienza,” Roma, Italy, and d Cardiac Rehabilitation Unit, Fondazione Maugeri, Milano, Italy. Submitted December 22, 2009; accepted March 31, 2010. Reprint requests: Piergiuseppe Agostoni, MD, PhD, Via C. Parea 4, 20138 Milan, Italy. E-mail: piergiuseppe.agostoni@unimi.it 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.03.034