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(Chest. 2003;124:954-961.)
© 2003 American College of Chest Physicians

A New Method Using Pulmonary Gas-Exchange Kinetics To Evaluate Efficacy of ß-Blocking Agents in Patients With Dilated Cardiomyopathy*

Yasuyo Taniguchi, MD, PhD; Kenji Ueshima, MD; Ikuo Chiba, MD; Ikuo Segawa, MD; Noboru Kobayashi, MD; Masahiko Saito and Katsuhiko Hiramori, MD

* From the Second Department of Internal Medicine, Iwate Medical University, Iwate, Japan.

Correspondence to: Yasuyo Taniguchi, MD, PhD, Second Department of Internal Medicine, Iwate Medical University, Uchimaru 19-1, Morioka City, Iwate, Japan; e-mail: y_taniguchi{at}imu.ncvc.go.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background and objectives: The effects of ß-blocking agents on exercise tolerance in cardiopulmonary exercise testing (CPX) have not been fully identified. Because the negative chronotropic effects of these agents produce a sluggish increase in heart rate (HR) during CPX, exercise capacity is actually underestimated by methods that depend on HR-related variables such as peak oxygen uptake (O2) and anaerobic threshold (AT). The aim of this study was to clarify the efficacy of ß-blocking agents by means of O2 kinetics, a parameter independent of HR, in patients with dilated cardiomyopathy (DCM).

Design and patients: The exercise capacity of 12 patients (9 men and 3 women; mean ± SD age, 54 ± 12 years; New York Heart Association class I [n = 1], NYHA class 2 [n = 4], and NYHA class III [n = 6]) with DCM, who were treated with ß-blocking agents, was evaluated by CPX. O2 was calculated from respiratory gas analysis on a breath-by-breath basis. Nine patients were treated with metoprolol (30 mg or 60 mg), two with carteolol (10 mg or 20 mg), and one patient with atenolol (25 mg).

Results: All patients showed a significantly favorable results (ie, improvement in symptoms of congestive heart failure). Peak O2 (20.4 ± 5.1 to 18.8 ± 5.8 mL/min/kg), AT (12.7 ± 3.5 to 12.1 ± 2.1 mL/min/kg), and exercise time (4.8 ± 2.2 to 4.5 ± 2.1 s) were unchanged. The time constant of O2 kinetics ({tau}) on response to constant low-dose work loading (warm up) decreased significantly (64 ± 30 to 44 ± 24 s; p < 0.01) and ejection fraction increased (30 ± 14 to 44 ± 15%, p < 0.01) significantly following treatment with ß-blocking agents. In spite of excluding two NYHA I patients, these changes were also statistically correlated.

Conclusion: In the low level of exercise, {tau} was prolonged in patients with DCM. Although indexes of total exercise time and AT were not useful markers for clinical improvement in cardiac performance as assessed by echocardiography, measuring can validly assess the beneficial effects in heart failure treated with ß-blocking agents.

Key Words: anaerobic threshold • ß-blocking agents • cardiopulmonary exercise testing • dilated cardiomyopathy • time constant of oxygen uptake kinetics


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Dilated cardiomyopathy (DCM) is a heart disease of unknown etiology associated with impairment of myocardial contractility and dilatation of the left ventricle. It is associated with poor prognosis and frequently results in sudden death or death due to congestive heart failure (CHF).1 2 Waagstein et al3 first described the efficacy of ß-blocking agents for treatment of advanced DCM and an improvement in prognosis in these patients. Controlled clinical trials4 5 6 7 showed a beneficial effect of ß-blocking agents on symptoms, exercise tolerance, and left ventricular function in idiopathic DCM. ß-blocking agents reduce mortality, improve symptoms, and increase exercise tolerance in patients with DCM.

Cardiopulmonary exercise testing (CPX) is widely used to evaluate exercise tolerance.8 In patients with CHF, peak oxygen uptake (O2) and exercise time are good markers of prognosis and provide a useful guide for timing of cardiac transplantation surgery.9 10 Percentage of achieved predicted peak O2 and aerobic threshold (AT) also have value for prognosis of CHF11 12 13 ; however, in patients treated with negative chronotropic drugs such as ß-blocking agents, the rate of increase in heart rate (HR) is slowed with the onset of exercise. The end point of CPX is usually determined by symptoms such as dyspnea or leg fatigue. Furthermore, with very low exercise capacity, exercise time (because it is also influenced by muscle atrophy and poor exercise motivation) does not precisely reflect the exercise capacity. In this study, we examined whether the time constant for O2 kinetics ({tau}) during constant low-level exercise is a valid reflection of improvement in exercise capacity after treatment with ß-blocking agents.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We studied 12 consecutive patients (9 men and 3 women; mean ± SD age, 54 ± 12 years) who were admitted to our hospital and received a diagnosis of DCM. Prior to enrollment in this study, patients had CHF for at least 6 months and were in clinically stable condition for at least 3 months. DCM was defined by a left ventricular end-diastolic diameter of >= 58 mm and left ventricular ejection fraction (LVEF) [determined with Teichholtz method14 ] of <= 40% on echocardiography. Endomyocardial biopsy of the right ventricle from all patients was examined histologically. Nonspecific fibrosis and atrophic myocytes were observed. Patients with history of hypertension, significant pulmonary disease, and myocardial infarction were excluded. The mean LVEF was 30 ± 14%, and all patients except one had a reduced peak O2 (20.4 ± 5.1 mL/min/kg). Two patients had New York Heart Association (NYHA) functional class I symptoms, four patients had NYHA functional class II, and six patients had NYHA functional class III. These findings were obtained after the standard treatment for acute exacerbation of CHF (digitalis, diuretics, and vasodilators, not ß-blocking agents). ß-blocking agents metoprolol [Seroken; AstraZeneca PLC; London, UK] at 30 mg or 60 mg for nine patients, carvedilol (Artist; Daiichi Pharmaceutical; Tokyo, Japan) at 10 mg or 20 mg for two patients, and atenolol (Tenormin; AstraZeneca Japan; Osaka, Japan) at 25 mg for one patient were then continuously administered for the next 14.4 ± 0.9 months. Patient characteristics are summarized in Table 1 .


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  		Table 1.. Patient Characteristics*

 
Exercise Testing
Symptom-limited CPX using a ramp protocol with a bicycle ergometer (Lode-I Ergometer; Lode; Groningen, The Netherlands) was performed before and after 6 months of continuous administration of ß-blocking agents. After a 2-min rest (sitting position) on the cycle ergometer, exercise began with a 3-min warm up at 10 W followed by the ramp protocol (15 W/min). Heart rate (HR), ST-T changes, and arrhythmias were monitored by a 12-lead ECG using a model Case 16 exercise testing system (Marquette Electronics; Milwaukee, WI). BP was also measured at 1-min intervals by the cuff method using an automatic manometer (STBP-780B; Colin Denshi; Aichi, Japan).

Ventilatory Gas Analysis
Ventilatory gas exchange (O2), carbon dioxide output (CO2) and minute ventilation (E) was measured on a breath-by-breath basis with a gas analyzer (Aerometer AE-280s, Minato Medical Science Co, Osaka, Japan). The system was carefully calibrated before each test. From these measurements, the ventilatory equivalent for O2 was calculated as E/O2 and for carbon dioxide was E/CO2, and the gas exchange ratio as CO2/O2. These parameters were simultaneously displayed on the monitor using an NEC personal computer (PC-9821; NEC; Tokyo, Japan). The AT was determined using two methods; the V-slope method and ventilatory equivalent method, in which the ratio of the E/O2 curve inflects systematically upward. Peak O2 was defined as the average of values obtained during the last 30 s of exercise.

{tau}
The {tau} has been used to assess O2 kinetics during constant-load exercise protocols of light-to-moderate intensity.15 16 17 Resting (or baseline) O2 was determined as the average of 2 min with the subject sitting on the bicycle ergometer before starting exercise. The {tau} during 3-min warm up at 10 W of exercise was determined (Fig 1 ). According to the report by Koike et al,18 O2 time, the time taken to reach 80% of steady-rate O2, is solved through nonlinear regression analysis. Independent of protocol selection, efficiency of the oxygen delivery-utilization system profoundly influences {Delta}O2/{Delta}workload slope.19



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  		Figure 1.. O2 curve during CPX; loaded work is showed over the O2 curve. Resting O2 was determined as the average of 2 min with the subject sitting on the bicycle ergometer before starting exercise. The {tau} during 10 W of exercise (warming-up period) was determined. The kinetics of O2 at the beginning of exercise had single exponential kinetics and was calculated using least-square nonlinear regression analysis. The {tau} is determined as the time it took to reach the steady state of O2 during 10 W of exercise. Actual data from the patient (patient B.S.) are shown. Longitudinal line shows O2, and transverse line shows examination time.

 
Echocardiographic Measurement
Two-dimensional echocardiography was performed in all patients using a Hewlett Packard Sonos 2500 equipped with 2.5-MHz transducer (Philips; Eindhoven, The Netherlands). The following conventional variables were measured according to the criteria of the American Society of Echocardiography: left ventricular end-diastolic and end-systolic volumes, dimensions, and LVEF (calculated with the Teichholtz method).14

Statistical Analysis
Group data are expressed as the means ± SD. The mean values of parameters between before and after ß-blocking agent treatments were compared by the paired Student t test. The correlation between the changes of parameters were analyzed by a simple linear regression test. Differences were statistically significant at the p < 0.05 level.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
During the follow-up period (14.4 ± 0.9 months), none of the patients had any major complications, such as worsening of heart failure, sudden cardiac death, or any other cardiac event.

Changes in HR, BP, and NYHA Functional Class
HR and systolic BP at rest decreased from 96 ± 16 to 75 ± 11 beats/min and from 131 ± 19 to 111 ± 19 mm Hg, respectively (p < 0.01). Individual data were shown in Table 1 . The indexes of cardiac performance such as NYHA functional class improved, and mean functional class changed from 2.3 ± 0.8 to 1.5 ± 0.5 (p < 0.05; serial changes are shown in Fig 2 ). Other indexes such as cardiothoracic ratio (CTR) and LVEF improved from 59 ± 7 to 53 ± 7% and from 30 ± 14 to 44.0 ± 15%, respectively (p < 0.01) after administration of ß-blocking agents (Table 2 ). After excluding data from the patients who were NYHA class I before treatment, significant improvement remained (Table 2 ; Fig 3 ,4 ). No apparent worsening was seen on these indexes.



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  		Figure 2.. Changes in NYHA functional class before and after administration of ß-blocking agents.

 

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  		Table 2.. Study Findings*

 


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  		Figure 3.. Changes of CTR on chest radiography with echocardiography before and after administration of ß-blocking agents. The data of the patients with NYHA I were excluded.

 


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  		Figure 4.. Changes of LVEF with echocardiography before and after administration of ß-blocking agents. The data of the patients with NYHA I were excluded. EF = ejection fraction.

 
Changes in Exercise Capacity
The AT and peak O2 of one patient could not be determined before treatment because she gave up exercise during the warm-up period. Before and after treatment, O2 at AT was 12.7 ± 3.5 mL/min/kg and 12.1 ± 2.1 mL/min/kg, and peak O2 was 20.4 ± 5.1 mL/min/kg and 18.8 ± 5.8 mL/min/kg, respectively. There was no significant change after treatment with ß-blocking agents. Exercise times were 4.8 ± 2.2 s and 4.5 ± 2.1 s before and after treatment, respectively (Table 2) . After treatment with ß-blocking agents, {tau} (in all studied patients) was significantly shortened (from 64 ± 30 to 44 ± 24 s, p < 0.01; Table 2 ). After excluding data from two patients who were NYHA I, {tau} remained to be shortened (from 61 ± 32 to 43 ± 26 s, p < 0.05; Table 2 ; Fig 5 ). Although the posttreatment changes in {tau} ({Delta}{tau}) did not have any correlation with those in CTR ({Delta}CTR; Fig 6 , bottom), {Delta}{tau} negatively correlated with the posttreatment changes in LVEF ({Delta}LVEF; Fig 6 , top).



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  		Figure 5.. The {tau} before and after administration of ß-blocking agents. The data of the patients with NYHA I were excluded.

 


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  		Figure 6.. Scatterplots show the relation of the changes in {tau} and those in ejection fraction (top) and the changes in {tau} and those in CTR (bottom). The data of the patients with NYHA I were excluded. See Figure 4 legend for expansion of abbreviation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study demonstrated in 12 patients with stable DCM that O2 kinetics can be used during warm-up (low-dose) exercise to detect ß-blocking agent-mediated symptom improvement. In all 12 treated patients, the indexes of cardiac performance (CTR and LVEF) improved and {tau} was significantly shortened. Shortening {tau} only correlated with change in LVEF. Peak O2, AT, and exercise time were unchanged.

In previous studies, {tau} describes the rate change in O2s measurements at the initiation of exercise.15 16 17 {tau} is prolonged in patients with CHF compared with individuals who have normal cardiopulmonary function.18 19 20 Prolonged {tau} with CHF has a prognostic implication.21 Koike et al19 reported that longer O2 dynamics at exercise onset reflects an insufficient increase in stroke volume. The ability to rapidly increase oxygen delivery at the onset of exercise also depends on the rate of increase in cardiac output. The contribution that pulmonary, vascular, and skeletal muscle function makes to delayed {tau} in CHF has yet to be determined.18 19 20 Our data also showed that the patients with lower cardiac performance had longer {tau}, and shortening of {tau} after treatment reflected improvement of cardiac performance.

In CPX testing, peak O2 is a good prognostic marker to risk-stratify patients and a useful help to determine the timing of cardiac transplantation in patients with CHF.8 9 Stelken et al8 reported that the percentage of predicted peak O2 and the cutoff point (< 50% predicted peak O2) were more sensitive than peak O2 in detecting cardiac events. Apart from these indexes, symptomatic status is frequently estimated by NYHA functional class status. According to multicenter randomized trials3 4 5 6 7 using ß-blocking agents (metoprolol, bisoprolol, and carvedilol), NYHA functional class of patients with CHF and their hospitalization rate were significantly improved. In the patients treated with ß-blocking agents, the parameters determined by O2 are not able to show exact exercise capacity, because the HR increment slows the O2 increase during exercise. Improvement in peak exercise capacity (peak O2 and exercise time) has been shown in only one multicenter trial (metoprolol in dilated cardiomyopathy) in a subgroup of patients receiving metoprolol for 1 year.22 23 Other ß-blocking agents failed to demonstrate an improvement of exercise capacity in peak or submaximal exercise tests in the multicenter trials.24 25 26 Negative chronotropic effects of ß-blocking agents produce a sluggish increase in HR during exercise testing and result in a large HR reserve.27 These data suggest that ß-blocking agents significantly reduce maximal attained HR, and thus myocardial performance makes it difficult to use peak O2 to assess the effect of treatment in a valid fashion. {tau} was also prolonged by ß-blocking agents due to slow adaptation of O2 to steady state.28 29 The principal benefits of ß-blocking agents in heart failure appeared to be related to their favorable influence on disease progression.22 30 31 In spite of the improvement in LVEF and left ventricular diameter at rest, the lack of significant relationship between LVEF at rest and peak O2 has been noted. In our study, NYHA functional class status and LVEF as well as {tau} were improved, but peak O2 and AT were unchanged. This findings support the previous report that improved cardiac function undoubtedly impacted {tau}.32 33

Limitations of this study are that this is a small sample size, three different ß-blocking agents were used for treatment, and not all patients obtained the AT during the exercise testing. We believe that {tau} is a sensitive marker and useful index of evaluation for cardiac function in patients treated with ß-blocking agents. The {tau} would be useful in assessing "cardiac reserve" in heart failure patients who are unable to exercise (even mild exercise) because of muscle weakness. Valid assessment of clinical improvement in patients with heart failure due to DCM and treated with ß-blocking agents is possible with measurement of {tau}. The {tau} can assess the exercise tolerance of cardiac patients during submaximal and safe levels of exercise.


   Footnotes
 
Abbreviations: AT = anaerobic threshold; CHF = congestive heart failure; CPX = cardiopulmonary exercise testing; CTR = cardiothoracic ratio; DCM = dilated cardiomyopathy; HR = heart rate; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; {tau} = time constant of oxygen uptake kinetics; CO2 = carbon dioxide output; E = minute ventilation; O2 = oxygen uptake

Received for publication July 12, 2002. Accepted for publication January 6, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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