Carvedilol

Study objective: To evaluate the effects of [beta]-blockers on ventilation in heart failure patients. Indeed, [beta]-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 [bet]a-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 ([+ or -] SD) slope of the minute ventilation (VE)/carbon dioxide output (VC[O.sub.2]) ratio (from 36.4 [+ or -] 8.9 to 31.7 [+ or -] 3.8; p < 0.01) and reduced ventilation at the following times: at peak exercise (from 60 [+ or -] 14 to 48 [+ or -] 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 [+ or -] 14 to 34 [+ or -] 13 L/min; p < 0.05, at third min). The end-expiratory pressure for carbon dioxide increased as ventilation decreased. The reduction in the VE/VC[O.sub.2] 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.

Key words: carvedilol; exercise; heart failure; oxygen uptake; ventilation

Abbreviations: PETC[O.sub.2] = end-expiratory pressure for carbon dioxide; VC[O.sub.2] = carbon dioxide output; VE = minute ventilation; V[O.sub.2] = oxygen uptake

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Long-term treatment with [beta]-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 [beta]-blockers to improve exercise performance. (7) However, the difference between heart rates at rest and at peak exercise is not affected by [beta]-blocker therapy reducing both the resting and peak exercise heart rates,s 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. (9-11) 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 [beta]-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 driven through sympathetic pathways. This conclusion proposes a new rationale for the use of [beta]-blocker therapy in heart failure patients and suggests why [beta]-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.

[FIGURE 1 OMITTED]

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 (VE)/ carbon dioxide output (VC[O.sub.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 follows: stable clinical condition with heart failure known for at least 6 months; the absence of previous or current [beta]-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 ([+ or -] SD) age of 56 [+ or -] 8 years. The mean weight, height, and body surface area were 76 [+ or -] 11 kg, 171 [+ or -] 6 cm, and 1.87 [+ or -] 0.16 [m.sup.2], respectively. The mean left ventricle ejection fraction was 32 [+ or -] 10%, with a mean left ventricle end-diastolic diameter of 68 [+ or -] 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 [+ or -] 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 VE/VC[O.sub.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 42.5 [+ or -] 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 [+ or -] 12 with placebo and 15 [+ or -] 15 with carvedilol (p < 0.05). Resting pulmonary function is reported in Table 1.

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

Carvedilol therapy did not affect exercise capacity. The peak V[O.sub.2] and maximal work rate were unaffected by treatment (Tables 3 and 4). At peak exercise, carvedilol reduced ventilation, tidal volume, and VC[O.sub.2] (Table 3 and 4). Carvedilol also reduced the VE/VC[O.sub.2] ratio slope from 36.4 [+ or -] 8.9 to 31.7 [+ or -] 3.8 (p < 0.01). Figure 2 reports the value of the VE/VC[O.sub.2] ratio slope in all subjects. The horizontal line indicates 2 SDs above the mean value for healthy subjects. (15) The reduction of the VE/VC[O.sub.2] ratio slope by carvedilol therapy was greater in patients with high VE/VC[O.sub.2] ratio values. Finally, the VE/VC[O.sub.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].

[FIGURES 2-3 OMITTED]

The major regulatory mechanisms of ventilation are VC[O.sub.2] and the C[O.sub.2] set point. The C[O.sub.2] set point can be noninvasively estimated by the PETC[O.sub.2] during exercise before the metabolic compensation point is reached (Table 5). As shown in Figure 4, carvedilol therapy increased the C[O.sub.2] set point, particularly in patients with the poorest exercise capacity.

[FIGURE 4 OMITTED]

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, (17-19) 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 [beta]-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 VE/VC[O.sub.2] ratio slope, respiratory compensation point, ventilatory data at the maximal PETC[O.sub.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 PETC[O.sub.2] to a normal value despite minor changes in VC[O.sub.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.sub.2]. Indeed, the peak V[O.sub.2] was unaffected by carvedilol administration, and the difference in V[O.sub.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.sub.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 PETC[O.sub.2] as the highest value of PETC[O.sub.2] recorded during a ramp exercise test. This measurement was observed between the anaerobic threshold and the respiratory compensation point when PETC[O.sub.2] remains constant. (15) The observation that with carvedilol the recorded maximal PETC[O.sub.2] was higher and ventilation was lower with an unchanged VC[O.sub.2] (Table 5) strongly favors a reduction of VC[O.sub.2]-independent regulation of ventilation. It is of note that carvedilol-induced changes in maximal PETC[O.sub.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 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.sub.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 PETC[O.sub.2] exercise), a reduction in reflex-increased ventilation takes place. Second, the lower VC[O.sub.2] values observed at peak exercise during carvedilol treatment imply a reduced metabolic production of C[O.sub.2].

The slope of the VE/VC[O.sub.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 VE/VC[O.sub.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 VE/VC[O.sub.2] ratio slope is a prognostic indicator that is even stronger than peak V[O.sub.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; 92:1499-1506

(2) Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996; 94:2800-2806

(3) 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. Circulation 1996; 94:2793-2799

(4) 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. Circulation 1996; 94:2807-2816

(5) 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 J 1999; 138:460-467

(6) 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. Lancet 1997; 349:375-380

(7) Metra M, Nodari S, D'Aloia A, et al. Effects of neurohormonal antagonism on symptoms and quality-of-life in heart failure. Eur Heart J 1998; 19:B25-B35

(8) Guazzi M, Agostoni PG. Monitoring gas exchange during a constant work rate exercise in patients with left ventricular dysfunction treated with carvedilol. Am J Cardiol 2000; 85:660-664

(9) Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988; 77:552-559

(10) 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 Cardiol 1992; 70:622-628

(11) Wasserman K, Zhang YY, Gitt A, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation 1997; 96:2221-2227

(12) 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. Circulation 2001; 103:967-972

(13) 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. Circulation 1996; 94:2807-2816

(14) 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 Cardiol 1993; 71:1106-1107

(15) Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins 1999; 10-61

(16) 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 Cardiol 1997; 29:1585-1590

(17) 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. Circulation 1991; 83:778-786

(18) Weber KT, Janicki JS. Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 1985; 55:22A-31A

(19) Szlachcic J, Massie BM, Kramer BL, et al. Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985; 55:1037-1042

(20) Chua TP, Clark AL, Amadi AA, et al. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1996; 27:650-657

(21) 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. Circulation 1997; 96:2586-2594

(22) 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. Circulation 1996; 93:940-952

(23) Zhang YY, Wasserman K, Sietsema KE, et al. [O.sub.2] uptake kinetics in response to exercise: a measure of tissue anaerobiosis in heart failure. Chest 1993; 103:735-741

(24) Agostoni PG, Butler J. Cardiac evaluation. In: Murray J, Nadel A. eds. Textbook of respiratory medicine. 2nd ed. Philadelphia, PA: WB Saunders, 1994; 943-960

(25) Clark AL, Volterrani M, Swan JW, et al. The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology. Heart 1997; 77:138-146

(26) Reindl I, Wernecke KD, Opitz C, et al. Impaired ventilatory efficiency in chronic heart failure: possible role of pulmonary vasoconstriction. Am Heart J 1998; 136:778-785

(27) Kleber FX, Vietzke G, Wernecke KD, et al. Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation 2000; 101:2803-2809

(28) 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. Circulation 1999; 100:2411-2417

* From the Centro Cardiologico, Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto di Cardiologia, Universita 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, 2002.

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

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