Carvedilol Reduces the Inappropriate Increase of Ventilation During Exercise in Heart Failure Patients* Study objective: To evaluate the effects of

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1 Carvedilol Reduces the Inappropriate Increase of Ventilation During Exercise in Heart Failure Patients* Piergiuseppe Agostoni, MD, PhD, FCCP; Marco Guazzi, MD, PhD; Maurizio Bussotti, MD; Stefano De Vita, MD; and Pietro Palermo, MD; Study objective: To evaluate the effects of -blockers on ventilation in heart failure patients. Indeed, -blockers ameliorate the clinical condition and cardiac function of heart failure patients, but not exercise capacity. Because ventilation is inappropriately elevated in heart failure patients due to overactive reflexes from ergoreceptors and chemoreceptors, we hypothesized that -blockers can elicit their positive clinical effects through a reduction of ventilation. Design: This was a double-blind, randomized, placebo-controlled study. Setting: University hospital heart failure unit. Patients and interventions: While receiving placebo (2 months) and a full dosage of carvedilol (4 months), 15 chronic heart failure patients were evaluated by quality-of-life questionnaire, pulmonary function tests, cardiopulmonary exercise tests with constant workload, and a ramp protocol. Results: Therapy with carvedilol did not affect resting pulmonary function and exercise capacity. However, carvedilol improved the results of the quality-of-life questionnaire, reduced the mean ( SD) slope of the minute ventilation (V E)/carbon dioxide output (V CO2 ) ratio (from to ; p < 0.01) and reduced ventilation at the following times: at peak exercise (from to L/min; p < 0.05); during the intermediate phases of a ramp-protocol exercise; and during the steady-state phase of a constant-workload exercise (from to L/min; p < 0.05, at third min). The end-expiratory pressure for carbon dioxide increased as ventilation decreased. The reduction in the V E/V CO2 ratio was correlated with improvement in quality of life (r 0.603; p < 0.02). Conclusions: Improvement in the clinical conditions of heart failure patients treated with carvedilol is associated with reductions in the inappropriately elevated ventilation levels observed during exercise. (CHEST 2002; 122: ) Key words: carvedilol; exercise; heart failure; oxygen uptake; ventilation Abbreviations: Petco 2 end-expiratory pressure for carbon dioxide; V co 2 carbon dioxide output; V e minute ventilation; V o 2 oxygen uptake Long-term treatment with -blockers ameliorates the clinical condition and cardiac function of patients with heart failure. 1 3 However, this does not translate into an improvement in exercise capacity during both maximal and submaximal effort. 4 6 A lack of appropriate chronotropic response has been suggested as the possible cause of the incapacity of *From the Centro Cardiologico, Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto di Cardiologia, Università di Milano, Milan, Italy. This research has been supported by a research grant of the Centro Cardiologico Monzino, IRCCS. Manuscript received September 6, 2001; revision accepted May 14, Correspondence to: Piergiuseppe Agostoni, MD, PhD, FCCP, Centro Cardiologico, Monzino, Istituto di Cardiologia, Università di Milano, via Parea 4, Milan, Italy; Piergiuseppe. Agostoni@cardiologicomonzino.it -blockers to improve exercise performance. 7 However, the difference between heart rates at rest and at peak exercise is not affected by -blocker therapy reducing both the resting and peak exercise heart rates. 8 Ventilation for a given work rate is inappropriately increased in heart failure patients, but ventilation at peak exercise is lower as the severity of the disease becomes greater We have suggested previously that the lack of increase in ventilation at peak exercise could be the cause of the absence of improvement in exercise capacity during long-term treatment with -blockers in heart failure patients. 5,8 Recently, Ponikowski et al 12 showed that the inappropriate increase of ventilation for a given work rate in heart failure patients was due to the widespread derangement of cardiovascular reflexes, which are 2062 Clinical Investigations

2 driven through sympathetic pathways. This conclusion proposes a new rationale for the use of -blocker therapy in heart failure patients and suggests why -blocker therapy does not improve exercise capacity and ventilation. Materials and Methods Study Design and Data Acquisition This was a double-blind, randomized, placebo-controlled study. All patients who participated in the study underwent a study run-in period of 2 weeks, during which clinical stability was assessed and patients performed at least two cardiopulmonary exercise tests (ramp protocol) to become familiarized with the exercise procedure. Patients were randomized to two groups (A and B), composed of eight and seven subjects, respectively. The study protocol is summarized in Figure 1. It was 8 months long and contained a carvedilol titration period of 2 months, during which the carvedilol dose was increased by 12.5 mg every 2 weeks under clinical and ECG surveillance. 13 The titration period was guided by an investigator who used labeled carvedilol pills and did not participate in any other part of the investigation. The full carvedilol dosage was defined as the highest carvedilol dose that could be tolerated by the patients during the carvedilol titration period. The full carvedilol dosage was administered for 4 months, while the placebo treatment lasted for 2 months. In group A, placebo titration preceded carvedilol titration and treatment. In group B, placebo titration followed carvedilol titration. During the study, patients were clinically evaluated every 15 days, or more often if required or desired by the patients. At the end of each treatment period, patients underwent the following evaluations. (1) Quality of life was evaluated utilizing the Minnesota quality-of-life questionnaire, which is a standard and selfadministered questionnaire. It consists of 21 brief questions, each of which is answered on a scale of 0 to 5, with 0 indicating no effect of heart failure and 5 indicating a very large effect. 14 (2) Standard pulmonary function tests and a lung diffusion evaluation for carbon monoxide (2200; SensorMedics; Yorba Linda, CA) were administered. (3) Two cardiopulmonary exercise tests were given. One was a constant-workload exercise test of 6 min duration with a workload equal to the 60% of the maximal workload measured in the second familiarization exercise test performed in the run-in period. The other was a maximal exercise test with a personalized ramp protocol that was aimed at achieving peak exercise in 10 min, as evaluated in the study run-in period. Thereafter, the workload of both the constant and ramp protocol was kept the same in each patient. Both of the exercise tests were performed on the cycle ergometer, with breath-by-breath respiratory gas and volume measurements (V Max; SensorMedics). The anaerobic threshold was calculated using the V-slope analysis and the respiratory compensation point as the point where the slope of the minute ventilation (V e)/ carbon dioxide output (V co 2 ) relationship started to increase. 15 For evaluation, the data were averaged over the 30 s during which the examined event occurred. Patient Population Patients were enrolled consecutively in the study and were heart failure patients who had been referred to the Heart Failure Unit of the Centro Cardiologico Monzino, Department of Cardiology, University of Milan, who met the study inclusion/ exclusion criteria. Patients were classified as being in New York Heart Association functional classes II (six patients) and III (nine patients). The etiology of heart failure was idiopathic dilated cardiomyopathy in all cases. All patients were receiving optimized and personally tailored anti-heart failure treatment, which was kept constant throughout the study. Treatment included therapy with diuretics in all patients, antialdosterone therapy in 7 patients, digoxin in 7 patients, angiotensin-converting enzyme inhibitors in 13 patients, angiotensin II type 1 blockers in 3 patients, and amiodarone in 4 patients. Inclusion criteria were as Figure 1. Design of the study protocol. CHEST / 122 / 6/ DECEMBER,

3 Table 1 Resting Pulmonary Function and Diffusion of Both Groups Combined* Variables Placebo Carvedilol FEV 1, L/s Vital capacity, L MVV, L/min Dlco, ml/min/mm Hg *Values given as mean SD. MVV maximal voluntary ventilation; Dlco diffusing capacity of the lung for carbon monoxide. follows: stable clinical condition with heart failure known for at least 6 months; the absence of previous or current -blocker treatment; an echocardiographic ejection fraction of 40%; and normal findings from coronary angiography. Exclusion criteria included a history of and/or clinical evidence of myocardial infarction, uncontrolled diabetes, COPD, peripheral vascular disease, primary pulmonary hypertension, effort-induced cardiac ischemia, angina, or arrhythmia. We enrolled 15 patients (13 men and 2 women) with a mean ( SD) age of 56 8 years. The mean weight, height, and body surface area were kg, cm, and m 2, respectively. The mean left ventricle ejection fraction was 32 10%, with a mean left ventricle end-diastolic diameter of 68 9 mm. Our Human Research Committee approved the study. The protocol was explained to the patients in detail, and afterward they provided written consent to be enrolled in the research trial. Data Analysis The data are reported as the mean SD. Differences within groups were evaluated by two-way repeated measures analysis of variance (see Tables 2 4). Differences between the two groups combined were analyzed by paired t test. The relationship between differences in the Minnesota Living with Heart Failure Quality-of-Life Questionnaire vs V e/v co 2 slope with treatment was analyzed by linear regression analysis. A p value 0.05 was considered to be statistically significant. Results All patients completed the trial. No difference was observed between the two groups regarding patients characteristics, treatment, or heart failure severity. The mean carvedilol-tolerated dosage was mg, with no differences between the two groups. The Minnesota Living with Heart Failure Qualityof-Life Questionnaire scored a mean of with placebo and with carvedilol (p 0.05). Resting pulmonary function is reported in Table 1. Constant-workload exercise was performed at W, which is above the anaerobic threshold (which was measured at and W, respectively, with placebo and carvedilol) but below the respiratory compensation point (86 24 and W [p 0.05], respectively, with placebo and carvedilol). The difference in oxygen uptake (V o 2 ) between the sixth and third minutes was ml/min ([p 0.05]) [group A, ml/min; group B, ml/min) and ml min (group A, ml/min; group B, ml/min), respectively, with placebo and carvedilol. Values for ventilation, endexpiratory pressure for carbon dioxide (Petco 2 ) and V co 2 at the third and sixth minute of constantworkload exercise are reported in Table 2. With carvedilol therapy, ventilation was lower and Petco 2 was higher, both at the third and sixth minute of constant-workload exercise, while V co 2 was not significantly changed by treatment. Carvedilol therapy did not affect exercise capacity. The peak V o 2 and maximal work rate were unaffected by treatment (Tables 3 and 4). At peak exercise, carvedilol reduced ventilation, tidal volume, and V co 2 (Table 3 and 4). Carvedilol also reduced the V e/v co 2 ratio slope from to (p 0.01). Figure 2 reports the value of the V e/v co 2 ratio slope in all subjects. The horizontal line indicates 2 SDs above the mean value for healthy subjects. 15 The reduction of the V e/v co 2 ratio slope by carvedilol therapy was greater in patients with high V e/v co 2 ratio values. Finally, Table 2 Ventilation, PETCO 2, and V CO2 at the Third and Sixth Minutes of Constant-Workload Exercise Values While on Placebo and Carvedilol* Ventilation, L/min Petco 2,mmHg V co 2, ml/min Groups Third minute Sixth minute Third minute Sixth minute Third minute Sixth minute Group A Placebo , , Carvedilol , , Group B Placebo , , Carvedilol , , Both groups combined Placebo , , Carvedilol , , *Values given as mean SD Clinical Investigations

4 Table 3 Cardiopulmonary Measurements at Peak Exercise (Ramp Protocol)* Group A Group B Variables Placebo Carvedilol Placebo Carvedilol V o 2 ml/min 1, , , , ml/kg/min V co 2, ml/min 1, , , , Maximal work rate W % predicted V e, L/min Vt, ml RR, beats/min Petco 2,mmHg *Values given as mean SD. Vt tidal volume; RR respiratory rate. the V e/v co 2 ratio slope changes were correlated with the Minnesota Living with Heart Failure Quality-of-Life Questionnaire score improvement (r 0.603; p 0.02) [Fig 3]. The major regulatory mechanisms of ventilation are V co 2 and the CO 2 set point. The CO 2 set point can be noninvasively estimated by the Petco 2 during exercise before the metabolic compensation point is reached (Table 5). As shown in Figure 4, carvedilol therapy increased the CO 2 set point, particularly in patients with the poorest exercise capacity. Discussion This study shows, as do several previous reports, 1 7,13 that clinical condition, but not exercise capacity, improves in patients with heart failure that has been treated with carvedilol. This well-known discrepancy is relevant because exercise capacity correlates with the clinical condition of and prognosis for heart failure patients, and carvedilol has been shown to improve both. 1 4,13 We advance the hypothesis that the sensation of well-being that has been observed in many patients who have been treated with -blockers is related to a reduction of the inappropriate increase of ventilation, which is frequently observed in heart failure patients. Measurements of ventilatory parameters during constant-workload exercise and measurements of V e/v co 2 ratio slope, respiratory compensation point, ventilatory data at the maximal Petco 2 and at peak exercise on the ramp exercise test were made for this purpose. During constant-workload exercise, carvedilol significantly reduced ventilation and increased Petco 2 to a normal value despite minor changes in V co 2. This means that the inappropriate increase of ventilation is reduced by carvedilol therapy. This might be due to a reduction in the increased excitatory inputs on ventilation from overactive ergoreflexes and chemoreflexes. 12,20 22 The positive effects of carvedilol on ventilation are not paralleled by effects on V o 2. Indeed, the peak V o 2 was unaffected by carvedilol administration, and the difference in V o 2 between the sixth and the third minutes of a constant-workload exercise, which is an index of exercise performance, 23 increased with carvedilol therapy, showing, if anything, a deterioration of exercise performance. This could be due to a lack of proper cardiac output increase or inappropriate O 2 availability/utilization at the muscular level during exercise. Accordingly, the respiratory compensation point, which takes place when isocapnic buffering for metabolic acidosis ends, 15 occurs at a lower workload with carvedilol treatment. We defined the maximal Petco 2 as the highest Table 4 Cardiopulmonary Measurements at Peak Exercise in Both Groups Combined (Ramp Protocol)* Variables Placebo Carvedilol V o 2 ml/min 1, , ml/kg/min V co 2, ml/min 1, , Maximal work rate W % predicted V e, L/min Vt, ml RR, beats/min Petco 2,mmHg *Values given as mean SD. See Table 3 for abbreviations not used in the text. CHEST / 122 / 6/ DECEMBER,

5 Table 5 Ventilation, V CO2, and Work Rate at Maximal PETCO 2 (Ramp Protocol)* Groups Placebo Carvedilol Figure 2. The ramp exercise protocol. V e/v co 2 slope in placebo and carvedilol is shown in all subjects (group A, F; and group B, E). Triangles indicate the mean SD of both groups combined. The horizontal dotted line indicates 2 SDs above the mean of healthy subjects. * p value of Petco 2 recorded during a ramp exercise test. This measurement was observed between the anaerobic threshold and the respiratory compensation point when Petco 2 remains constant. 15 The observation that with carvedilol the recorded maximal Petco 2 was higher and ventilation was lower with an unchanged V co 2 (Table 5) strongly favors a reduction of V co 2 -independent regulation of ventilation. It is of note that carvedilol-induced changes in maximal Petco 2 are greater in those patients with the poorest exercise performance (ie, those patients who are more likely have inappropriately increased ventilation) [Fig 4]. The data at peak exercise show a lower ventilation Group A Maximal Petco 2,mmHg Ventilation, L/min V co 2 at maximal Petco 2, ml/min Group B Maximal Petco 2,mmHg Ventilation, L/min V co 2 at maximal Petco 2, ml/min Both groups combined Maximal Petco 2,mmHg Ventilation, L/min V co 2 at maximal Petco 2, ml/min *Values given as mean SD. with carvedilol due to the reduction of tidal volume. Therefore, at first glance it is possible to suggest that carvedilol reduces ventilation at peak exercise because of a negative mechanical action on the lungs. However, under such circumstances one would expect the following: (1) a reduced peak V o 2 and work rate, whereas both remained unchanged; or (2) ventilation at peak exercise to be near the maximal level of voluntary ventilation, whereas it was at 50% (Tables 1 and 3). 24 Two mechanisms might be responsible for the reduction in peak exercise ventilation. First, it is possible that at peak exercise, as happens during exercise (see the data for constant workload and maximal Petco 2 exercise), a reduction in reflex-increased ventilation takes place. Second, the lower V co 2 values observed at peak exercise during carvedilol treatment imply a reduced metabolic production of CO 2. Figure 3. Correlation between differences ( ) in the Minnesota Living with Heart Failure Quality-of-Life Questionnaire (QLT) and the V e/v co 2 ratio slope between placebo and carvedilol treatment (r 0.603; p 0.02). See the legend of Figure 2 for an explanation of the symbols used. Figure 4. Differences in the maximal Petco 2 ( Petco 2 ) between placebo and carvedilol treatment vs peak V o 2 with placebo. Carvedilol increased the maximal Petco 2, particularly in patients with the poorest exercise performance. See the text for details. See the legend of Figure 2 for an explanation of the symbols used Clinical Investigations

6 The slope of the V e/v co 2 ratio is probably the best indicator of an inappropriate increase of ventilation. 25,26 Its reduction shows that carvedilol reduces the inappropriate increase of ventilation in heart failure patients, which agrees with all the observations reported earlier. Carvedilol therapy reduces the V e/v co 2 ratio slope, and this reduction correlates with the changes in the Minnesota Living with Heart Failure Quality-of-Life Questionnaire results. This suggests that the sensation of well-being that is reported during carvedilol treatment is related to a reduction of ventilation that takes place not only at peak exercise but also at a workload comparable with normal life activities. Moreover, the V e/v co 2 ratio slope is a prognostic indicator that is even stronger than peak V o 2. 27,28 In conclusion, the improvement in the clinical conditions of patients treated with carvedilol seems to be related to a reduction in the inappropriate increase of ventilation characteristics of heart failure patients. References 1 Krum H, Sackner-Bernstein JD, Goldsmith RL, et al. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995; 92: Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996; 94: Packer M, Colucci WS, Sackner-Bernstein JD, et al. Doubleblind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial; Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. 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