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Clinical Investigations: CARDIOLOGY |

Carvedilol Reduces the Inappropriate Increase of Ventilation During Exercise in Heart Failure Patients* FREE TO VIEW

Piergiuseppe Agostoni, MD, PhD, FCCP; Marco Guazzi, MD, PhD; Maurizio Bussotti, MD; Stefano De Vita, MD; Pietro Palermo, MD
Author and Funding Information

*From the Centro Cardiologico, Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto di Cardiologia, Università di Milano, Milan, Italy.

Correspondence to: Piergiuseppe Agostoni, MD, PhD, FCCP, Centro Cardiologico, Monzino, Istituto di Cardiologia, Università di Milano, via Parea 4, 20138 Milan, Italy; e-mail: Piergiuseppe.Agostoni@cardiologicomonzino.it



Chest. 2002;122(6):2062-2067. doi:10.1378/chest.122.6.2062
Text Size: A A A
Published online

Study objective: To evaluate the effects of β-blockers on ventilation in heart failure patients. Indeed, β-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 β-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 (V̇e)/carbon dioxide output (V̇co2) ratio (from 36.4 ± 8.9 to 31.7 ± 3.8; p < 0.01) and reduced ventilation at the following times: at peak exercise (from 60 ± 14 to 48 ± 15 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 42 ± 14 to 34 ± 13 L/min; p < 0.05, at third min). The end-expiratory pressure for carbon dioxide increased as ventilation decreased. The reduction in the V̇e/V̇co2 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.

Figures in this Article

Long-term treatment with β-blockers ameliorates the clinical condition and cardiac function of patients with heart failure.13 However, this does not translate into an improvement in exercise capacity during both maximal and submaximal effort.46 A lack of appropriate chronotropic response has been suggested as the possible cause of the incapacity of β-blockers to improve exercise performance.7However, the difference between heart rates at rest and at peak exercise is not affected by β-blocker therapy reducing both the resting and peak exercise heart rates.8Ventilation 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.911 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 β-blockers in heart failure patients.5,8 Recently, Ponikowski et al12 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 driven through sympathetic pathways. This conclusion proposes a new rationale for the use of β-blocker therapy in heart failure patients and suggests why β-blocker therapy does not improve exercise capacity and ventilation.

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 self-administered 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 (V̇e)/carbon dioxide output (V̇co2) 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 follows: stable clinical condition with heart failure known for at least 6 months; the absence of previous or current β-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 76 ± 11 kg, 171 ± 6 cm, and 1.87 ± 0.16 m2, 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 234 ). 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 V̇e/V̇co2 slope with treatment was analyzed by linear regression analysis. A p value < 0.05 was considered to be statistically significant.

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 42.5 ± 9.2 mg, with no differences between the two groups. The Minnesota Living with Heart Failure Quality-of-Life Questionnaire scored a mean of 19 ± 12 with placebo and 15 ± 15 with carvedilol (p < 0.05). Resting pulmonary function is reported in Table 1 .

Constant-workload exercise was performed at 76 ± 31 W, which is above the anaerobic threshold (which was measured at 53 ± 15 and 55 ± 17 W, respectively, with placebo and carvedilol) but below the respiratory compensation point (86 ± 24 and 81 ± 28 W [p < 0.05], respectively, with placebo and carvedilol). The difference in oxygen uptake (V̇o2) between the sixth and third minutes was 129 ± 50 mL/min ([p < 0.05]) [group A, 106 ± 52 mL/min; group B, 147 ± 60 mL/min) and 145 ± 52 mL min (group A, 135 ± 60 mL/min; group B, 153 ± 76 mL/min), respectively, with placebo and carvedilol. Values for ventilation, end-expiratory pressure for carbon dioxide (Petco2) and V̇co2 at the third and sixth minute of constant-workload exercise are reported in Table 2. With carvedilol therapy, ventilation was lower and Petco2 was higher, both at the third and sixth minute of constant-workload exercise, while V̇co2 was not significantly changed by treatment.

Carvedilol therapy did not affect exercise capacity. The peak V̇o2 and maximal work rate were unaffected by treatment (Tables 3and 4). At peak exercise, carvedilol reduced ventilation, tidal volume, and V̇co2(Table 3and 4). Carvedilol also reduced the V̇e/V̇co2 ratio slope from 36.4 ± 8.9 to 31.7 ± 3.8 (p < 0.01). Figure 2 reports the value of the V̇e/V̇co2 ratio slope in all subjects. The horizontal line indicates 2 SDs above the mean value for healthy subjects.15 The reduction of the V̇e/V̇co2 ratio slope by carvedilol therapy was greater in patients with high V̇e/V̇co2 ratio values. Finally, the V̇e/V̇co2 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 V̇co2 and the CO2 set point. The CO2 set point can be noninvasively estimated by the Petco2 during exercise before the metabolic compensation point is reached (Table 5 ). As shown in Figure 4 , carvedilol therapy increased the CO2 set point, particularly in patients with the poorest exercise capacity.

This study shows, as do several previous reports,17,13 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,1719 and carvedilol has been shown to improve both.14,13

We advance the hypothesis that the sensation of well-being that has been observed in many patients who have been treated with β-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 V̇e/V̇co2 ratio slope, respiratory compensation point, ventilatory data at the maximal Petco2 and at peak exercise on the ramp exercise test were made for this purpose. During constant-workload exercise, carvedilol significantly reduced ventilation and increased Petco2 to a normal value despite minor changes in V̇co2. 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.12,2022 The positive effects of carvedilol on ventilation are not paralleled by effects on V̇o2. Indeed, the peak V̇o2 was unaffected by carvedilol administration, and the difference in V̇o2 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 O2 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 Petco2 as the highest value of Petco2 recorded during a ramp exercise test. This measurement was observed between the anaerobic threshold and the respiratory compensation point when Petco2 remains constant.15 The observation that with carvedilol the recorded maximal Petco2 was higher and ventilation was lower with an unchanged V̇co2(Table 5) strongly favors a reduction of V̇co2-independent regulation of ventilation. It is of note that carvedilol-induced changes in maximal Petco2 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 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 V̇o2 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 1and 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 Petco2 exercise), a reduction in reflex-increased ventilation takes place. Second, the lower V̇co2 values observed at peak exercise during carvedilol treatment imply a reduced metabolic production of CO2.

The slope of the V̇e/V̇co2 ratio is probably the best indicator of an inappropriate increase of ventilation.2526 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 V̇e/V̇co2 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 V̇e/V̇co2 ratio slope is a prognostic indicator that is even stronger than peak V̇o2.28 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.

Abbreviations: Petco2 = end-expiratory pressure for carbon dioxide; V̇co2 = carbon dioxide output; V̇e = minute ventilation; V̇o2 = oxygen uptake

This research has been supported by a research grant of the Centro Cardiologico Monzino, IRCCS.

Table Graphic Jump Location
Table 2. Ventilation, Petco2, and V̇co2 at the Third and Sixth Minutes of Constant-Workload Exercise Values While on Placebo and Carvedilol*
* 

Values given as mean ± SD.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 3. Cardiopulmonary Measurements at Peak Exercise (Ramp Protocol)*
* 

Values given as mean ± SD. Vt = tidal volume; RR = respiratory rate.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 4. Cardiopulmonary Measurements at Peak Exercise in Both Groups Combined (Ramp Protocol)*
* 

Values given as mean ± SD. See Table 3 for abbreviations not used in the text.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 1. Resting Pulmonary Function and Diffusion of Both Groups Combined*
* 

Values given as mean ± SD. MVV = maximal voluntary ventilation; Dlco = diffusing capacity of the lung for carbon monoxide.

Figure Jump LinkFigure 2. The ramp exercise protocol. V̇e/V̇co2 slope in placebo and carvedilol is shown in all subjects (group A, •; and group B, ○). Triangles indicate the mean ± SD of both groups combined. The horizontal dotted line indicates 2 SDs above the mean of healthy subjects. * = p < 0.01.Grahic Jump Location
Figure Jump LinkFigure 3. Correlation between differences (Δ) in the Minnesota Living with Heart Failure Quality-of-Life Questionnaire (QLT) and the V̇e/V̇co2 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.Grahic Jump Location
Table Graphic Jump Location
Table 5. Ventilation, V̇co2, and Work Rate at Maximal Petco2 (Ramp Protocol)*
* 

Values given as mean ± SD.

 

p < 0.05 vs carvedilol.

Figure Jump LinkFigure 4. Differences in the maximal Petco2 (ΔPetco2) between placebo and carvedilol treatment vs peak V̇o2 with placebo. Carvedilol increased the maximal Petco2, 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.Grahic Jump Location
Krum, H, Sackner-Bernstein, JD, Goldsmith, RL, et al (1995) Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure.Circulation92,1499-1506. [PubMed] [CrossRef]
 
Colucci, WS, Packer, M, Bristow, MR, et al Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure.Circulation1996;94,2800-2806. [PubMed]
 
Packer, M, Colucci, WS, Sackner-Bernstein, JD, et al Double-blind, 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.Circulation1996;94,2793-2799. [PubMed]
 
Bristow, MR, Gilbert, EM, Abraham, WT, et al Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure.Circulation1996;94,2807-2816. [PubMed]
 
Guazzi, M, Agostoni, P, Matturri, M, et al Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol.Am Heart J1999;138,460-467. [PubMed]
 
Australia/New Zealand Heart Failure Research Collaborative Group.. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet1997;349,375-380. [PubMed]
 
Metra, M, Nodari, S, D’Aloia, A, et al Effects of neurohormonal antagonism on symptoms and quality-of-life in heart failure.Eur Heart J1998;19,B25-B35. [PubMed]
 
Guazzi, M, Agostoni, PG Monitoring gas exchange during a constant work rate exercise in patients with left ventricular dysfunction treated with carvedilol.Am J Cardiol2000;85,660-664. [PubMed]
 
Sullivan, MJ, Higginbotham, MB, Cobb, FR Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities.Circulation1988;77,552-559. [PubMed]
 
Metra, M, Dei Cas, L, Panina, G, et al Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics.Am J Cardiol1992;70,622-628. [PubMed]
 
Wasserman, K, Zhang, YY, Gitt, A, et al Lung function and exercise gas exchange in chronic heart failure.Circulation1997;96,2221-2227. [PubMed]
 
Ponikowski, P, Francis, DP, Piepoli, MF, et al Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis.Circulation2001;103,967-972. [PubMed]
 
Bristow, MR, Gilbert, EM, Abraham, WT, et al Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure: MOCHA Investigators.Circulation1996;94,2807-2816. [PubMed]
 
Rector, TS, Kubo, SH, Cohn, JN Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo.Am J Cardiol1993;71,1106-1107. [PubMed]
 
Wasserman, K, Hansen, JE, Sue, DY, et al Principles of exercise testing and interpretation 3rd ed.1999,10-61 Lippincott Williams & Wilkins. Baltimore, MD:
 
Chua, TP, Ponikowski, P, Harrington, D, et al Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure.J Am Coll Cardiol1997;29,1585-1590. [PubMed]
 
Mancini, DM, Eisen, H, Kussmaul, W, et al Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure.Circulation1991;83,778-786. [PubMed]
 
Weber, KT, Janicki, JS Cardiopulmonary exercise testing for evaluation of chronic cardiac failure.Am J Cardiol1985;55,22A-31A. [PubMed]
 
Szlachcic, J, Massie, BM, Kramer, BL, et al Correlates and prognostic implication of exercise capacity in chronic congestive heart failure.Am J Cardiol1985;55,1037-1042. [PubMed]
 
Chua, TP, Clark, AL, Amadi, AA, et al Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure.J Am Coll Cardiol1996;27,650-657. [PubMed]
 
Ponikowski, P, Chua, TP, Piepoli, M, et al Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure.Circulation1997;96,2586-2594. [PubMed]
 
Piepoli, M, Clark, AL, Volterrani, M, et al Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training.Circulation1996;93,940-952. [PubMed]
 
Zhang, YY, Wasserman, K, Sietsema, KE, et al O2uptake kinetics in response to exercise: a measure of tissue anaerobiosis in heart failure.Chest1993;103,735-741. [PubMed]
 
Agostoni, PG, Butler, J Cardiac evaluation. Murray, J Nadel, A eds.Textbook of respiratory medicine 2nd ed.1994,943-960 WB Saunders. Philadelphia, PA:
 
Clark, AL, Volterrani, M, Swan, JW, et al The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology.Heart1997;77,138-146. [PubMed]
 
Reindl, I, Wernecke, KD, Opitz, C, et al Impaired ventilatory efficiency in chronic heart failure: possible role of pulmonary vasoconstriction.Am Heart J1998;136,778-785. [PubMed]
 
Kleber, FX, Vietzke, G, Wernecke, KD, et al Impairment of ventilatory efficiency in heart failure: prognostic impact.Circulation2000;101,2803-2809. [PubMed]
 
Robbins, M, Francis, G, Pashkow, FJ, et al Ventilatory and heart rate responses to exercise: better predictors of heart failure mortality than peak oxygen consumption.Circulation1999;100,2411-2417. [PubMed]
 

Figures

Figure Jump LinkFigure 2. The ramp exercise protocol. V̇e/V̇co2 slope in placebo and carvedilol is shown in all subjects (group A, •; and group B, ○). Triangles indicate the mean ± SD of both groups combined. The horizontal dotted line indicates 2 SDs above the mean of healthy subjects. * = p < 0.01.Grahic Jump Location
Figure Jump LinkFigure 3. Correlation between differences (Δ) in the Minnesota Living with Heart Failure Quality-of-Life Questionnaire (QLT) and the V̇e/V̇co2 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.Grahic Jump Location
Figure Jump LinkFigure 4. Differences in the maximal Petco2 (ΔPetco2) between placebo and carvedilol treatment vs peak V̇o2 with placebo. Carvedilol increased the maximal Petco2, 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.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 2. Ventilation, Petco2, and V̇co2 at the Third and Sixth Minutes of Constant-Workload Exercise Values While on Placebo and Carvedilol*
* 

Values given as mean ± SD.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 3. Cardiopulmonary Measurements at Peak Exercise (Ramp Protocol)*
* 

Values given as mean ± SD. Vt = tidal volume; RR = respiratory rate.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 4. Cardiopulmonary Measurements at Peak Exercise in Both Groups Combined (Ramp Protocol)*
* 

Values given as mean ± SD. See Table 3 for abbreviations not used in the text.

 

p < 0.05 vs carvedilol.

Table Graphic Jump Location
Table 1. Resting Pulmonary Function and Diffusion of Both Groups Combined*
* 

Values given as mean ± SD. MVV = maximal voluntary ventilation; Dlco = diffusing capacity of the lung for carbon monoxide.

Table Graphic Jump Location
Table 5. Ventilation, V̇co2, and Work Rate at Maximal Petco2 (Ramp Protocol)*
* 

Values given as mean ± SD.

 

p < 0.05 vs carvedilol.

References

Krum, H, Sackner-Bernstein, JD, Goldsmith, RL, et al (1995) Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure.Circulation92,1499-1506. [PubMed] [CrossRef]
 
Colucci, WS, Packer, M, Bristow, MR, et al Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure.Circulation1996;94,2800-2806. [PubMed]
 
Packer, M, Colucci, WS, Sackner-Bernstein, JD, et al Double-blind, 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.Circulation1996;94,2793-2799. [PubMed]
 
Bristow, MR, Gilbert, EM, Abraham, WT, et al Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure.Circulation1996;94,2807-2816. [PubMed]
 
Guazzi, M, Agostoni, P, Matturri, M, et al Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol.Am Heart J1999;138,460-467. [PubMed]
 
Australia/New Zealand Heart Failure Research Collaborative Group.. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet1997;349,375-380. [PubMed]
 
Metra, M, Nodari, S, D’Aloia, A, et al Effects of neurohormonal antagonism on symptoms and quality-of-life in heart failure.Eur Heart J1998;19,B25-B35. [PubMed]
 
Guazzi, M, Agostoni, PG Monitoring gas exchange during a constant work rate exercise in patients with left ventricular dysfunction treated with carvedilol.Am J Cardiol2000;85,660-664. [PubMed]
 
Sullivan, MJ, Higginbotham, MB, Cobb, FR Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities.Circulation1988;77,552-559. [PubMed]
 
Metra, M, Dei Cas, L, Panina, G, et al Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics.Am J Cardiol1992;70,622-628. [PubMed]
 
Wasserman, K, Zhang, YY, Gitt, A, et al Lung function and exercise gas exchange in chronic heart failure.Circulation1997;96,2221-2227. [PubMed]
 
Ponikowski, P, Francis, DP, Piepoli, MF, et al Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis.Circulation2001;103,967-972. [PubMed]
 
Bristow, MR, Gilbert, EM, Abraham, WT, et al Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure: MOCHA Investigators.Circulation1996;94,2807-2816. [PubMed]
 
Rector, TS, Kubo, SH, Cohn, JN Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo.Am J Cardiol1993;71,1106-1107. [PubMed]
 
Wasserman, K, Hansen, JE, Sue, DY, et al Principles of exercise testing and interpretation 3rd ed.1999,10-61 Lippincott Williams & Wilkins. Baltimore, MD:
 
Chua, TP, Ponikowski, P, Harrington, D, et al Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure.J Am Coll Cardiol1997;29,1585-1590. [PubMed]
 
Mancini, DM, Eisen, H, Kussmaul, W, et al Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure.Circulation1991;83,778-786. [PubMed]
 
Weber, KT, Janicki, JS Cardiopulmonary exercise testing for evaluation of chronic cardiac failure.Am J Cardiol1985;55,22A-31A. [PubMed]
 
Szlachcic, J, Massie, BM, Kramer, BL, et al Correlates and prognostic implication of exercise capacity in chronic congestive heart failure.Am J Cardiol1985;55,1037-1042. [PubMed]
 
Chua, TP, Clark, AL, Amadi, AA, et al Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure.J Am Coll Cardiol1996;27,650-657. [PubMed]
 
Ponikowski, P, Chua, TP, Piepoli, M, et al Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure.Circulation1997;96,2586-2594. [PubMed]
 
Piepoli, M, Clark, AL, Volterrani, M, et al Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training.Circulation1996;93,940-952. [PubMed]
 
Zhang, YY, Wasserman, K, Sietsema, KE, et al O2uptake kinetics in response to exercise: a measure of tissue anaerobiosis in heart failure.Chest1993;103,735-741. [PubMed]
 
Agostoni, PG, Butler, J Cardiac evaluation. Murray, J Nadel, A eds.Textbook of respiratory medicine 2nd ed.1994,943-960 WB Saunders. Philadelphia, PA:
 
Clark, AL, Volterrani, M, Swan, JW, et al The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology.Heart1997;77,138-146. [PubMed]
 
Reindl, I, Wernecke, KD, Opitz, C, et al Impaired ventilatory efficiency in chronic heart failure: possible role of pulmonary vasoconstriction.Am Heart J1998;136,778-785. [PubMed]
 
Kleber, FX, Vietzke, G, Wernecke, KD, et al Impairment of ventilatory efficiency in heart failure: prognostic impact.Circulation2000;101,2803-2809. [PubMed]
 
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