- Email: [email protected]
Contribution of peak respiratory exchange ratio to peak VO2 prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity
Contribution of peak respiratory exchange ratio to peak VO2 prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity Alessandro Mezzani, MD,a Ugo Corra`, MD,a Enzo Bosimini, MD,a Andrea Giordano,b and Pantaleo Giannuzzi, MDa Veruno, Italy
Background We evaluated the influence of peak respiratory exchange ratio (pRER), as an index of effort adequacy, on peak VO2 prognostic reliability in patients with chronic heart failure (CHF) and reduced exercise capacity, whose peak VO2 may be underestimated because of poor patient motivation. Methods A cardiopulmonary exercise test was performed in 570 patients with CHF (age 60 ⫾ 10 years, ejection fraction 26% ⫾ 7%, New York Heart Association class 2.2 ⫾ 0.6), 193 of whom had a peak VO2 that was ⬎10 but ⱕ14 mL/kg/min (reduced exercise capacity) and 80 of whom had a peak VO2 ⱕ10 mL/kg/min (severely reduced exercise capacity). Results Seventy-eight events (72 cardiovascular deaths and 6 status I heart transplantations) occurred during follow-up (19.6 ⫾ 14 months). The 2-year survival rate was 69% in patients with a peak VO2 ⱕ10 and 83% in patients with a peak VO2 ⬎10 but ⱕ14 (P ⬍ .0001). However, in the group of patients with a peak VO2 ⱕ10, patients who had a pRER ⱖ1.15 had a 2-year survival rate of 52%, and this pRER value (but not ⱖ1, ⱖ1.05, or ⱖ1.10) was the only independent predictor of the composite end point (2 ⫽ 4.73, P ⫽ .03). Conversely, in the group of patients with a peak VO2 ⱕ10, patients who had a pRER value ⬍1.15 had a survival rate of 83%, which was comparable with that of the group of patients with a peak VO2 ⬎10 but ⱕ14. Conclusion
Patients with CHF and severely reduced exercise capacity should be encouraged to exercise to an RER as close as possible to 1.15, to ascertain their motivation and ensure their peak VO2 prognostic reliability. (Am Heart J 2003;145:1102-7.)
Peak exercise oxygen uptake plays an important role in risk stratification and selection of heart transplant candidates among patients with chronic heart failure (CHF). A reduced aerobic power is known to indicate a bad prognosis in this population,1-5 and patients with a peak VO2 ⱕ14 mL/kg/min are currently considered to be potential candidates for heart transplantation.6 However, patients with CHF are less used to accomplishing strenuous daily activities with clinical progression of the disease,7,8 and their motivation to reach maximal effort and experience symptoms during an
From the aDivision of Cardiology, and the bBioengineering Department, Salvatore Maugeri Foundation, IRCCS, Veruno Scientific Institute, Veruno, Italy. Submitted February 19, 2002; accepted October 18, 2002. Reprint requests: Alessandro Mezzani, MD, Fondazione Salvatore Maugeri Istituto Scientifico di Veruno, Via per Revislate, 13, 28010, Veruno (NO), Italy. E-mail: [email protected]. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(03)00100-5
exercise test may be lacking.9,10 The identification of objective indices of maximal effort is therefore crucial in patients with CHF and reduced exercise capacity, to ensure peak VO2 measurement reliability and avoid inappropriate prognostic stratification because of poor motivation on the part of the patient. A peak respiratory exchange ratio (pRER) between 1.10 and 1.20 is considered to be a good descriptor of maximal effort in healthy subjects,11-13 because an RER increment higher than the value of 1 is related to anaerobic metabolism activation and exercise-induced metabolic acidosis with consequent VCO2 increase.14 However, a pRER value equal to at least 1 is commonly used to describe adequate effort and motivation in the CHF population,15-17 and it is not clear to what extent such a pRER value may reflect effort adequacy and ensure peak VO2 prognostic reliability. Indeed, a pRER value of at least 1.1 has been recently proposed as subsidiary evidence of VO2 maxium attainment in the CHF population,18 and the anaerobic threshold
American Heart Journal Volume 145, Number 6
usually occurs at 50% to 70% of total exercise time in patients with CHF,19-21 which demonstrates their ability to exercise—and eventually increase oxygen consumption—long after the onset of anaerobic metabolism. We reasoned that peak VO2 prognostic validity would be mainly confirmed in patients with a significant anaerobic metabolism activation at peak effort (ie, a pRER significantly ⬎1). Thus, the aim of this study was to determine the influence of pRER value on peak VO2 prognostic power in a group of patients with CHF who have reduced exercise tolerance (ie, peak VO2 ⱕ14 mL/kg/ min).
Methods Study population A total of 647 patients who underwent a cardiopulmonary exercise test between January 1, 1996, and May 31, 2000, at our institution were considered for the study. Inclusion criteria were 1) history of ischemic or idiopathic dilated cardiomyopathy with unequivocal clinical episodes of heart failure for ⱖ6 months; 2) echocardiographic left ventricular ejection fraction ⱕ40%; 3) cardiopulmonary exercise test stopped for fatigue, dyspnea, or both; 4) absence of severe chronic obstructive pulmonary disease, symptomatic peripheral vascular disease, diabetes mellitus with severe end-organ damage, or orthopedic limitations; and 5) stable medication doses with no exacerbation of symptoms or need for intravenous inotropic support for a duration of 4 weeks before assessment. In accordance with these criteria, 570 patients were selected, 273 of whom had a peak VO2 ⱕ14 mL/kg/min. Of these 273 patients, 193 had a peak VO2 ⬎10 but ⱕ14 mL/kg/min and 80 had a peak VO2 ⱕ10 mL/kg/min. Of the 77 patients who were excluded from the study, 19 (24%) had a cardiomyopathy that was not of ischemic or idiopathic origin, 13 (17%) had a left ventricular ejection fraction ⬎40%, and 45 (59%) stopped their exercise test for reasons other than fatigue and dyspnea or had significant extracardiac diseases. All patients underwent an echocardiographic evaluation within 5 ⫾ 2 days of the cardiopulmonary exercise test, and an activity score defining the patients’ level of habitual physical activity was determined before the exercise test, as previously described.8 Patients were included in the study after giving informed written consent.
Cardiopulmonary exercise test The cardiopulmonary exercise test was performed on a bicycle ergometer (Ergo-metrics 800S, Sensormedics, Yorba Linda, Calif). After a 1-minute warm-up period at 0 watts (W) workload, a ramp protocol of 10 W/min was started, and patients were encouraged to exercise until exhaustion. A 12lead electrocardiogram was monitored continuously during the test (MAX-1, Marquette Electronics, Milwaukee, Wis), and cuff blood pressure was manually recorded every 2 minutes. Respiratory gas exchange measurements were obtained breath-by-breath with a computerized metabolic cart (Vmax29, Sensormedics) and displayed with a 30-second average. Peak VO2 and VCO2 were recorded as the mean value
Mezzani et al 1103
observed during the last 30 seconds of the test. RER at peak effort was defined as the peak VCO2/peak VO2 ratio, and values of 1.00, 1.05, 1.10, and ⱖ1.15 were considered to be different maximal effort indices. The ventilatory anaerobic threshold was estimated with the V-slope or respiratory equivalents method, or both.14 The slope of the ventilation (VE) versus the VCO2 relationship was measured excluding, when present, its final nonlinear portion because of acidotic ventilatory drive.
Follow-up and survival analysis Patients were followed up at the outpatient clinic of our hospital. The follow-up of patients who did not attend their scheduled appointments was obtained by telephone interview of the patient, patient’s family, or his/her primary care physician. The composite end point of the study was death due to cardiovascular causes (sudden death, progressive heart failure-related death, acute myocardial infarction, and pulmonary embolism) or need for urgent heart transplantation (status I patients). Data from patients who survived until the end of the follow-up period, who died of noncardiac-related causes, or who underwent nonurgent heart transplantation were evaluated as “censored” observations.
Statistical analysis The unpaired t test was used to compare the means of quantitative variables, whereas the 2 test with the Fisher exact test was used for qualitative data. Cumulative survival was estimated with the product-limit Kaplan-Meier method, and differences between survival curves were tested with the log-rank Mantel-Cox and Wilcoxon tests. The Cox proportional hazards regression model was used to determine the independent predictors of the evaluated composite end point. The level of statistical significance was set at a 2-tailed P value of ⱕ.05. Calculations were performed with the StatView version 5.0.1 and SAS version 6.12 statistical software packages (SAS Institute, Cary, NC).
Results Demographic and clinical characteristics The entire study population (n ⫽ 570) had a mean age value of 60 ⫾ 10 years, with a New York Heart Association (NYHA) class of 2.2 ⫾ 0.6, an activity score of 1.7 ⫾ 0.5, an ejection fraction of 26% ⫾ 7%, and a peak VO2 of 14.5 ⫾ 4 mL/kg/min. Patients with a peak VO2 ⱕ14 mL/kg/min were considered to have a reduced exercise capacity. Clinical and exercise test parameters for this group of patients and subgroups of patients with a peak VO2 ⱕ10 mL/ kg/min (ⱕ10 group, severely reduced exercise capacity) and patients with a peak VO2 ⬎10 but ⱕ14 mL/ kg/min (⬎10 –ⱕ14 group) are shown in Table I. Patients in the ⱕ10 group, when compared with patients in the ⬎10 –ⱕ14 group, had a lower functional capacity, as expressed with a reduced habitual activity score and a higher NYHA class, and a more impaired left ventricular systolic function. The cause of left ven-
American Heart Journal June 2003
1104 Mezzani et al
Table I. Clinical and exercise test characteristics of patients with reduced exercise capacity (peak VO2 ⱕ14 mL/kg/min)
No. of patients Age (y) Male (%) NYHA class Activity score LVEF DecT (ms) Ischemic LVD (%) Digoxin (%) Diuretics (%) ACE-inhibitors (%) -Blockers (%) Peak VO2 (mL/kg/min) Peak HR (beats/min) Peak SBP (mm Hg) VE/VCO2 slope Peak RER Peak RER ⱖ 1 (%) Peak RER ⱖ 1.05 (%) Peak RER ⱖ 1.10 (%) Peak RER ⱖ 1.15 (%) VAT identified (%)
Total
>10-<14 Group
<10 Group
P*
273 62 ⫾ 9 225 (82) 2.4 ⫾ 0.5 1.4 ⫾ 0.5 24% ⫾ 8% 157 ⫾ 42 202 (74) 169 (62) 241 (88) 254 (93) 114 (42) 11.1 ⫾ 2 118 ⫾ 21 149 ⫾ 26 34.9 ⫾ 8 1.17 ⫾ 0.1 262 (96) 243 (89) 202 (74) 155 (57) 143 (52)
193 61 ⫾ 10 166 (86) 2.3 ⫾ 0.5 1.5 ⫾ 0.5 24% ⫾ 5% 159 ⫾ 42 144 (74) 109 (56) 167 (86) 179 (93) 89 (46) 12.1 ⫾ 1 120 ⫾ 19 155 ⫾ 25 32.7 ⫾ 6 1.17 ⫾ 0.1 190 (98) 178 (92) 151 (78) 116 (60) 125 (64)
80 63 ⫾ 9 59 (73) 2.7 ⫾ 0.5 1.2 ⫾ 0.5 21% ⫾ 8% 151 ⫾ 42 58 (72) 61 (76) 74 (93) 74 (93) 25 (31) 8.6 ⫾ 1 114 ⫾ 23 135 ⫾ 23 40.6 ⫾ 11 1.16 ⫾ 0.1 72 (90) 65 (80) 51 (62) 39 (48) 18 (22)
– NS .022 ⬍.0001 ⬍.0001 ⬍.0001 NS NS NS NS NS .03 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 NS NS NS NS NS ⬍.0001
Values are presented as mean ⫾ SD or number (%). ACE, Angiotensin-converting enzyme; DecT, early deceleration time of transmitral flow; HR, heart rate; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; NS, not statistically significant; NYHA, New York Heart Association; PetCO2, end-tidal PCO2; RER, respiratory exchange ratio; SBP, systolic blood pressure; VAT, ventilatory anaerobic threshold; VE, ventilation. *ⱕ 10 Group vs ⬎10-ⱕ14 group.
Figure 1
-blocking therapy. Moreover, patients in the ⱕ10 group had lower peak heart rate and peak systolic blood pressure mean values and a less efficient ventilatory response to exercise, as indicated by a higher mean VE/VCO2 slope. Mean pRER and percentages of patients reaching a pRER of at least 1.00, 1.05, 1.10, and 1.15 did not differ in the 2 subgroups. The ventilatory anaerobic threshold was identified more frequently in the ⬎10 –ⱕ14 group than in the ⱕ10 group.
Survival
Kaplan-Meier plot of cumulative survival for patients grouped by peak VO2 ⬎14, ⬎10 but ⱕ14, and ⱕ10 mL/kg/min.
tricular dysfunction was predominantly ischemic in both groups, which did not differ with digoxin, diuretic, and angiotensin-converting enzyme inhibitor administration; however, significantly more patients in the ⬎10 –ⱕ14 group than in the ⱕ10 group received
Eleven patients were lost to follow-up, and the mean follow-up duration was 19.6 ⫾ 14 months. Seventytwo deaths from cardiovascular causes were observed, 35 of which (49%) were sudden, 27 of which (37%) were due to progressive heart failure, and 10 of which (14%) were due to other cardiac causes. Six patients underwent heart transplantation in clinical status I. Thus, the composite end point was reached in 78 of the patients in the whole study group (14%). The 2-year survival rate was 93% versus 75% in patients with a peak VO2 ⬎14 and ⱕ14 mL/kg/min, respectively (P ⬍ .0001), and 89% versus 69% in patients with a peak VO2 ⬎10 and ⱕ10 mL/kg/min, respectively (P ⬍ .0001). The 2-year survival rate also differed in patients with a peak VO2 ⬎14, patients with a peak VO2 ⬎10 –ⱕ14, and patients with a peak VO2
American Heart Journal Volume 145, Number 6
Mezzani et al 1105
Table II. Univariate significant comparisons between survivors and patients reaching the combined endpoint in the ⱕ10 group
No. of patients Activity score NYHA class LVEF DecT (ms) -Blockers (%) Peak SBP (mm Hg) VE/VCO2 slope Peak RER ⱖ1.15 (%)
Table IV. Clinical and exercise test characteristics of patients with severely reduced exercise capacity (peak VO2 ⱕ10 mL/ kg/min) according to peak RER ⬍ and ⱖ1.15
Survivors
Death/TX
P
54 1.3 ⫾ 0.5 2.5 ⫾ 0.5 23% ⫾ 8% 160 ⫾ 44 23 (41) 142 ⫾ 22 39 ⫾ 8 21 (39)
26 1.0 ⫾ 0.3 2.8 ⫾ 0.3 17% ⫾ 6% 133 ⫾ 33 3 (11) 119 ⫾ 19 45 ⫾ 13 17 (65)
– .02 .013 .003 .02 .009 ⬍.0001 .017 .031
Values are presented as mean ⫾ SD or number (%). TX, Heart transplantation.
Table III. Multivariate analysis for the ⱕ10 group
NYHA class Peak SBP BB, yes Activity score VE/VCO2 slope DecT LVEF Peak RER ⱖ1.15
2
RR
95% CI
P
.07 .19 .57 .70 .73 1.56 2.69 4.73
.69 .98 .45 .39 .95 .98 .88 1.65
.05-10.4 .92-1.04 .06-3.48 .04-3.46 .85-1.06 .96-1.01 .76-1.02 .07-25
.79 .66 .44 .40 .39 .21 .10 .03
BB, -Blocking therapy; RR, relative risk.
ⱕ10 mL/kg/min (93% vs 83% vs 69%, respectively, P ⬍ .0001) (Figure 1). In the ⱕ10 group, patients reaching the composite end point had a significantly lower activity score, NYHA class, and left ventricular ejection fraction, a shorter early deceleration time of transmitral flow, and a lower percentage of -blocker administration than survivors (Table II). They also had a lower peak systolic blood pressure and a higher VE/VCO2 slope and percentage of pRER ⱖ1.15 attainment than survivors, whereas the percentages of patients with a pRER of at least 1.00, 1.05, and 1.10 did not differ in the 2 groups (Table II). With multivariate analysis, the ability to attain a pRER ⱖ1.15 was the only independent predictor of the composite end point (2 ⫽ 4.73, P ⫽ .03), with a relative risk of 1.65 (Table III). Indeed, in the ⱕ10 group, patients unable to reach a pRER ⱖ1.15 (n ⫽ 41) had a 2-year survival rate of 83%, far higher than that of patients (n ⫽ 39) who were able to reach such a pRER value (52%, P ⬍ .0001), but similar to that observed in patients with a peak VO2 ⬎10 –ⱕ14 mL/kg/ min (Figure 2). When clinical and exercise test parameters of patients with a peak VO2 ⱕ10 mL/kg/min and a peak RER ⬍1.15 or ⱖ1.15 were compared, only the peak PetCO2 mean value differed in the 2 groups (Table IV), being significantly lower in the ⱖ1.15 group.
No. of patients Age (y) Male (%) NYHA class Activity score LVEF DecT (ms) Ischemic LVD (%) Digoxin (%) Diuretics (%) ACE-inhibitors (%) -Blockers (%) Peak VO2 (mL/kg/min) Peak HR (beats/min) Peak SBP (mm Hg) VE/VCO2 slope Peak PetCO2 (mm Hg) Peak RER VAT identified (%)
Peak RER <1.15 group
Peak RER >1.15 group
P
41 63 ⫾ 9 27 (66) 2.7 ⫾ 0.5 1.2 ⫾ 0.4 21% ⫾ 7% 154 ⫾ 40 28 (68) 30 (73) 36 (88) 35 (85) 17 (41) 8.5 ⫾ 1 113 ⫾ 24 134 ⫾ 22 38.6 ⫾ 7 31.4 ⫾ 4 1.05 ⫾ 0.6 16 (39)
39 63 ⫾ 9 31 (79) 2.6 ⫾ 0.4 1.2 ⫾ 0.4 20% ⫾ 8% 146 ⫾ 44 29 (74) 31 (79) 38 (97) 39 (100) 8 (21) 8.7 ⫾ 1 114 ⫾ 21 136 ⫾ 24 43.1 ⫾ 12 29 ⫾ 6 1.26 ⫾ 0.1 11 (29)
– NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS ⬍.03 ⬍.0001 NS
Values are presented as mean ⫾ SD or number (%).
Figure 2
Kaplan-Meier plot of cumulative survival for patients with a peak VO2 ⱕ10 mL/kg/min grouped by peak respiratory exchange ratio ⬍1.15 or ⱖ1.15. The survival rate of patients with a peak VO2 ⱕ10 mL/kg/min and a peak respiratory exchange ratio ⬍1.15 is not significantly different from that of patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/min, independent of their pRER.
In the ⬎10 –ⱕ14 group, patients reaching the combined end point had a significantly lower activity score (P ⫽ .021), NYHA class (P ⫽ .0006), left ventricular ejection fraction (P ⬍ .0001), and percentage of patients taking -blockers (P ⫽ .007) and a shorter early
1106 Mezzani et al
deceleration time of transmitral flow (P ⫽ .007) than survivors. Among peak effort parameters, peak VO2 was lower (P ⫽ .0002) and VE/VCO2 slope was higher (P ⫽ .002) in patients reaching the composite end point, but the percentages of patients attaining a pRER of at least 1.00, 1.05, 1.10, and 1.15 did not differ between survivors and nonsurvivors. Multivariate analysis indicated peak VO2 as the only independent predictor of the composite end point (2 ⫽ 3.85, P ⫽ .04) in this group.
Discussion Objective assessment of maximal effort in patients with CHF Objective indices of maximal effort are strongly needed for patients with CHF, because of the preeminent prognostic role played by peak VO21-6 and the frequently reduced level of habitual activities and consequent lack of motivation to exercise until exhaustion in this group.7-10 This is especially true for patients with CHF who have a reduced exercise capacity, whose treatment calls for a complex and costly therapeutic effort. Among traditional maximal exercise indices, a plateau of the VO2 versus work rate relationship is known to be very rare in the CHF population,16 and its occurrence has been questioned even in healthy subjects.22 The achievement of a fixed percentage of predicted maximal heart rate is also of little value for maximal exercise assessment in patients with CHF, because chronotropic incompetence is quite common in patients with symptomatic left ventricular dysfunction23,24 and the use of -blocking agents is increasing in the CHF population.25 A pRER between 1.10 and 1.20 has also been proposed as an index of achieved maximal effort.11-13 This approach seems reasonable because, beyond an RER of 1, buffering of exerciseinduced lactic acidosis results in excess production of CO2, more than that produced from aerobic metabolism, making both VCO2 and RER increase14 independently of the subject’s or patient’s absolute exercise tolerance. However, in patients with CHF, a clear-cut RER value for assessment of maximal effort has not yet been identified; different authors have suggested values ranging from ⱖ1.00 to ⱖ1.10.15-18 Moreover, anaerobic metabolism has been shown to activate at 50% to 70% of total exercise time19-21 in patients with CHF. Our hypothesis was that the confirmation of peak VO2 prognostic power would thus occur mainly in patients able to reach a pRER significantly higher than 1, that is, in the presence of a marked anaerobic metabolism activation caused by a maximal or near-maximal effort.
American Heart Journal June 2003
pRER and peak VO2 prognostic power Several authors have indicated that a peak aerobic power ⱕ10 mL/kg/min is a strong predictor of a poor prognosis in patients with CHF.1,2,4,5 In a study of 26 patients with CHF who had a peak VO2 ⱕ10 mL/kg/ min, Stevenson et al4 reported a 1-year survival rate of 77% and a 2-year survival rate of 48%. More recently, Opasich et al5 observed a 1-year survival rate of 64% and a 2-year survival rate of 54% in a group of 70 patients with CHF and similar peak aerobic power. Our results partially differ from these data, indicating a relatively better prognosis in patients with a peak VO2 ⱕ10 mL/kg/min (1- and 2-year survival rates of 75% and 69%, respectively). This is probably because of a different background therapy, with a high percentage of patients taking -blockers (31%) in our study. However, stratification of the ⱕ10 group by a pRER ratio ⱖ1.15 or ⬍1.15 showed that patients not reaching such a cutoff value (ie, patients with an apparently lower degree of anaerobic metabolism activation) had 1-year and 2-year survival rates of 90% and 83%, respectively, which is comparable with survival rates of patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/min (Figure 2); that is, better than expected according to peak VO2 value. However, in patients attaining a pRER ⱖ1.15, the unfavorable peak VO2 prognostic power was confirmed, with significantly lower 1- and 2-year survival rates (58% and 52%, respectively). These results seem to indicate a prognostic heterogeneity among CHF patients with a peak VO2 ⱕ10 mL/kg/min (ie, a group usually considered to have a very bad prognosis) and may be explained by considering patients who do not demonstrate a significant anaerobic metabolism activation as not adequately motivated to sustain maximal or near-maximal effort. This hypothesis is supported by the finding of a peak PetCO2 mean value significantly lower in patients with a peak VO2 ⱕ10 mL/kg/min and a pRER ⱖ1.15 than that in patients with a pRER ⬍1.15, which indicates a higher degree of hyperventilation (and thus a more strenuous effort) in patients with pRER values ⱖ1.15. In patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/ min, the pRER did not allow for the refinement of the peak VO2 prognostic power. This is not surprising, because a peak VO2 ⬎10 mL/kg/min is known to be per se a favorable prognostic indicator in patients with CHF,4,5 independently of maximal effort achievement, assuring a 2-year survival rate of 89% in our population. These findings are important from a clinical point of view, because they offer a means for defining peak VO2 prognostic reliability in patients with CHF who have severely reduced exercise tolerance, in whom peak oxygen consumption bears the highest prognostic and decisional impact. In this group, peak VO2 prognostic power should not be taken for granted, but
American Heart Journal Volume 145, Number 6
confirmed by the attainment of a pRER value as close as possible to 1.15 as an index of adequate motivation on the part of the patient.
Study limitations pRER values show a considerable interindividual variability,13,14,18 preventing the possibility of precise effort intensity comparisons; a cutoff RER value of 1.15 may thus not represent the same relative level of effort intensity in different patients. However, an RER of 1.15 has been demonstrated to be well related to VO2 maximum in healthy subjects, and an RER ⬎1.10 has been suggested as evidence that a true VO2 maximum has been attained.26 Because metabolic response to exercise higher than the anaerobic threshold does not seem to be qualitatively different in patients with CHF from that seen in healthy subjects, it is reasonable to assume that an RER value of 1.15 may well represent maximal or near-maximal effort also in the CHF population.
Conclusions A prognostic hetereogeneity seems to exist among patients with CHF and a severely reduced exercise capacity (ie, peak VO2 ⱕ10 mL/kg/min), because the expected negative peak VO2 prognostic power is confirmed only in patients reaching an RER of at least 1.15 at peak effort (ie, demonstrating a significant anaerobic metabolism exercise-induced activation as a result of adequate motivation). Conversely, patients unable to attain a pRER ⱖ1.15 have a prognosis comparable with that of patients with a better functional capacity, thus indicating the possibility that their measured peak VO2 is lower than their “true” peak aerobic power. These results suggest that patients with CHF and severely reduced exercise tolerance should be encouraged to exercise as close as possible to an RER of 1.15 to ascertain their motivation and ensure peak VO2 prognostic reliability; in the case of pRER values ⬍1.15, a cautious use of peak VO2 in clinical decision making may be recommended. Further studies will be needed to fully elucidate the link between pRER, motivation, and prognosis in patients with CHF and severely reduced exercise capacity.
References 1. Szlachcic J, Massie BM, Kramer BL, et al. Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985;55:1037-42. 2. 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;83:778-86. 3. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. Circulation 1995;92: 3593-612. 4. Stevenson LW, Couper G, Natterson B, et al. Target heart failure populations for newer therapies. Circulation 1995;92(2 Suppl):II174-81.
Mezzani et al 1107
5. Opasich C, Pinna GD, Bobbio M, et al. Peak oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol 1998;31:766-75. 6. Mudge GH, Goldstein S, Addonizio LJ, et al. Twenty-fourth Bethesda Conference: cardiac transplantation. Task Force 3: recipient guidelines/priorization. J Am Coll Cardiol 1993;22:21-31. 7. Oka RK, Gortner SR, Stotts NA, et al. Predictors of physical activity in patients with chronic heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996;77:159-63. 8. Mezzani A, Corra` U, Baroffio C, et al. Habitual activities and peak aerobic capacity in patients with asymptomatic and symptomatic left ventricular dysfunction: use of a new physical activity scoring system. Chest 2000;117:1291-9. 9. Clark AL, Poole-Wilson PA, Coats AJS. Effects of motivation of the patient on indices of exercise capacity in chronic heart failure. Br Heart J 1994;71:162-5. 10. Ramos-Barbon, Fitchett D, Gibbons WJ, et al. Maximal exercise testing for the selection of heart transplantation candidates: limitation of peak oxygen consumption. Chest 1995;115:410 –7. 11. Davies JA. Direct determination of aerobic power. In: Maud PJ, Foster C, editors. Physiological assessment of human fitness. Champaign (Ill): Human Kinetics; 1995. p. 9-17. 12. Exercise and the heart. Froelicher VF, Myers JN, editors. Philadelphia: W.B. Saunders Company; 2000. 13. Balady GJ, Berra KA, Golding LA, et al. Interpretation of clinical test data. In: Franklin BA, Whaley MH, Howley ET, editors. ACSM’s guidelines for exercise testing and prescription. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 115-33. 14. Wasserman K, Hansen J, Sue D, et al. Principles of exercise testing and interpretation. Philadelphia: Lippincott Williams & Wilkins; 1999. 15. ESC working group on exercise physiology, physiopathology, and electrocardiography. Guidelines for cardiac exercise testing. Eur Heart J 1993;14:969-88. 16. Cohen-Solal A. Cardiopulmonary exercise testing in chronic heart failure. In: Wasserman K, editor. Exercise gas exchange in heart disease. Armonk: Futura Publishing Company; 1996. p. 17-38. 17. Mancini D, LeJemtel T, Aaronson K. Peak VO2: a simple yet enduring standard. Circulation 2000;101:1080-2. 18. Fleg JL, Pina IL, Balady GJ, et al. Assessment of functional capacity in clinical and research applications. Circulation 2000;102:1591-7. 19. Weber KT, Kinasewitz GT, Janicki JS, et al. Oxygen utilization and ventilation during exercise in patients with chronic heart failure. Circulation 1982;65:1213-23. 20. Metra M, Raddino R, Dei Cas L, et al. Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure. Am J Cardiol 1990;65:1127-33. 21. Katz SD, Berkowitz R, LeJemtel TH. Anaerobic threshold detection in patients with congestive heart failure. Am J Cardiol 1992;69:1565-9. 22. Noakes TD. Implications of exercise testing for prediction of athletic performance: a contemporary perspective. Med Sci Sports Exerc 1988;20:319-30. 23. Clark AL, Coats AJS. Chronotropic incompetence in chronic heart failure. Int J Cardiol 1995;49:225-31. 24. Rundqvist B, Eisenhofer G, Elam M, et al. Attenuated cardiac sympathetic responsiveness during dynamic exercise in patients with heart failure. Circulation 1997;95:940-5. 25. Tavazzi L. Epidemiological burden of heart failure. Heart 1998; 79(2 Suppl):S6-9. 26. Issekutz B Jr, Birkhead NC, Rodahl K. Use of respiratory quotients in assessment of aerobic work capacity. J Appl Physiol 1962;17:47-50.
Background We evaluated the influence of peak respiratory exchange ratio (pRER), as an index of effort adequacy, on peak VO2 prognostic reliability in patients with chronic heart failure (CHF) and reduced exercise capacity, whose peak VO2 may be underestimated because of poor patient motivation. Methods A cardiopulmonary exercise test was performed in 570 patients with CHF (age 60 ⫾ 10 years, ejection fraction 26% ⫾ 7%, New York Heart Association class 2.2 ⫾ 0.6), 193 of whom had a peak VO2 that was ⬎10 but ⱕ14 mL/kg/min (reduced exercise capacity) and 80 of whom had a peak VO2 ⱕ10 mL/kg/min (severely reduced exercise capacity). Results Seventy-eight events (72 cardiovascular deaths and 6 status I heart transplantations) occurred during follow-up (19.6 ⫾ 14 months). The 2-year survival rate was 69% in patients with a peak VO2 ⱕ10 and 83% in patients with a peak VO2 ⬎10 but ⱕ14 (P ⬍ .0001). However, in the group of patients with a peak VO2 ⱕ10, patients who had a pRER ⱖ1.15 had a 2-year survival rate of 52%, and this pRER value (but not ⱖ1, ⱖ1.05, or ⱖ1.10) was the only independent predictor of the composite end point (2 ⫽ 4.73, P ⫽ .03). Conversely, in the group of patients with a peak VO2 ⱕ10, patients who had a pRER value ⬍1.15 had a survival rate of 83%, which was comparable with that of the group of patients with a peak VO2 ⬎10 but ⱕ14. Conclusion
Patients with CHF and severely reduced exercise capacity should be encouraged to exercise to an RER as close as possible to 1.15, to ascertain their motivation and ensure their peak VO2 prognostic reliability. (Am Heart J 2003;145:1102-7.)
Peak exercise oxygen uptake plays an important role in risk stratification and selection of heart transplant candidates among patients with chronic heart failure (CHF). A reduced aerobic power is known to indicate a bad prognosis in this population,1-5 and patients with a peak VO2 ⱕ14 mL/kg/min are currently considered to be potential candidates for heart transplantation.6 However, patients with CHF are less used to accomplishing strenuous daily activities with clinical progression of the disease,7,8 and their motivation to reach maximal effort and experience symptoms during an
From the aDivision of Cardiology, and the bBioengineering Department, Salvatore Maugeri Foundation, IRCCS, Veruno Scientific Institute, Veruno, Italy. Submitted February 19, 2002; accepted October 18, 2002. Reprint requests: Alessandro Mezzani, MD, Fondazione Salvatore Maugeri Istituto Scientifico di Veruno, Via per Revislate, 13, 28010, Veruno (NO), Italy. E-mail: [email protected]. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(03)00100-5
exercise test may be lacking.9,10 The identification of objective indices of maximal effort is therefore crucial in patients with CHF and reduced exercise capacity, to ensure peak VO2 measurement reliability and avoid inappropriate prognostic stratification because of poor motivation on the part of the patient. A peak respiratory exchange ratio (pRER) between 1.10 and 1.20 is considered to be a good descriptor of maximal effort in healthy subjects,11-13 because an RER increment higher than the value of 1 is related to anaerobic metabolism activation and exercise-induced metabolic acidosis with consequent VCO2 increase.14 However, a pRER value equal to at least 1 is commonly used to describe adequate effort and motivation in the CHF population,15-17 and it is not clear to what extent such a pRER value may reflect effort adequacy and ensure peak VO2 prognostic reliability. Indeed, a pRER value of at least 1.1 has been recently proposed as subsidiary evidence of VO2 maxium attainment in the CHF population,18 and the anaerobic threshold
American Heart Journal Volume 145, Number 6
usually occurs at 50% to 70% of total exercise time in patients with CHF,19-21 which demonstrates their ability to exercise—and eventually increase oxygen consumption—long after the onset of anaerobic metabolism. We reasoned that peak VO2 prognostic validity would be mainly confirmed in patients with a significant anaerobic metabolism activation at peak effort (ie, a pRER significantly ⬎1). Thus, the aim of this study was to determine the influence of pRER value on peak VO2 prognostic power in a group of patients with CHF who have reduced exercise tolerance (ie, peak VO2 ⱕ14 mL/kg/ min).
Methods Study population A total of 647 patients who underwent a cardiopulmonary exercise test between January 1, 1996, and May 31, 2000, at our institution were considered for the study. Inclusion criteria were 1) history of ischemic or idiopathic dilated cardiomyopathy with unequivocal clinical episodes of heart failure for ⱖ6 months; 2) echocardiographic left ventricular ejection fraction ⱕ40%; 3) cardiopulmonary exercise test stopped for fatigue, dyspnea, or both; 4) absence of severe chronic obstructive pulmonary disease, symptomatic peripheral vascular disease, diabetes mellitus with severe end-organ damage, or orthopedic limitations; and 5) stable medication doses with no exacerbation of symptoms or need for intravenous inotropic support for a duration of 4 weeks before assessment. In accordance with these criteria, 570 patients were selected, 273 of whom had a peak VO2 ⱕ14 mL/kg/min. Of these 273 patients, 193 had a peak VO2 ⬎10 but ⱕ14 mL/kg/min and 80 had a peak VO2 ⱕ10 mL/kg/min. Of the 77 patients who were excluded from the study, 19 (24%) had a cardiomyopathy that was not of ischemic or idiopathic origin, 13 (17%) had a left ventricular ejection fraction ⬎40%, and 45 (59%) stopped their exercise test for reasons other than fatigue and dyspnea or had significant extracardiac diseases. All patients underwent an echocardiographic evaluation within 5 ⫾ 2 days of the cardiopulmonary exercise test, and an activity score defining the patients’ level of habitual physical activity was determined before the exercise test, as previously described.8 Patients were included in the study after giving informed written consent.
Cardiopulmonary exercise test The cardiopulmonary exercise test was performed on a bicycle ergometer (Ergo-metrics 800S, Sensormedics, Yorba Linda, Calif). After a 1-minute warm-up period at 0 watts (W) workload, a ramp protocol of 10 W/min was started, and patients were encouraged to exercise until exhaustion. A 12lead electrocardiogram was monitored continuously during the test (MAX-1, Marquette Electronics, Milwaukee, Wis), and cuff blood pressure was manually recorded every 2 minutes. Respiratory gas exchange measurements were obtained breath-by-breath with a computerized metabolic cart (Vmax29, Sensormedics) and displayed with a 30-second average. Peak VO2 and VCO2 were recorded as the mean value
Mezzani et al 1103
observed during the last 30 seconds of the test. RER at peak effort was defined as the peak VCO2/peak VO2 ratio, and values of 1.00, 1.05, 1.10, and ⱖ1.15 were considered to be different maximal effort indices. The ventilatory anaerobic threshold was estimated with the V-slope or respiratory equivalents method, or both.14 The slope of the ventilation (VE) versus the VCO2 relationship was measured excluding, when present, its final nonlinear portion because of acidotic ventilatory drive.
Follow-up and survival analysis Patients were followed up at the outpatient clinic of our hospital. The follow-up of patients who did not attend their scheduled appointments was obtained by telephone interview of the patient, patient’s family, or his/her primary care physician. The composite end point of the study was death due to cardiovascular causes (sudden death, progressive heart failure-related death, acute myocardial infarction, and pulmonary embolism) or need for urgent heart transplantation (status I patients). Data from patients who survived until the end of the follow-up period, who died of noncardiac-related causes, or who underwent nonurgent heart transplantation were evaluated as “censored” observations.
Statistical analysis The unpaired t test was used to compare the means of quantitative variables, whereas the 2 test with the Fisher exact test was used for qualitative data. Cumulative survival was estimated with the product-limit Kaplan-Meier method, and differences between survival curves were tested with the log-rank Mantel-Cox and Wilcoxon tests. The Cox proportional hazards regression model was used to determine the independent predictors of the evaluated composite end point. The level of statistical significance was set at a 2-tailed P value of ⱕ.05. Calculations were performed with the StatView version 5.0.1 and SAS version 6.12 statistical software packages (SAS Institute, Cary, NC).
Results Demographic and clinical characteristics The entire study population (n ⫽ 570) had a mean age value of 60 ⫾ 10 years, with a New York Heart Association (NYHA) class of 2.2 ⫾ 0.6, an activity score of 1.7 ⫾ 0.5, an ejection fraction of 26% ⫾ 7%, and a peak VO2 of 14.5 ⫾ 4 mL/kg/min. Patients with a peak VO2 ⱕ14 mL/kg/min were considered to have a reduced exercise capacity. Clinical and exercise test parameters for this group of patients and subgroups of patients with a peak VO2 ⱕ10 mL/ kg/min (ⱕ10 group, severely reduced exercise capacity) and patients with a peak VO2 ⬎10 but ⱕ14 mL/ kg/min (⬎10 –ⱕ14 group) are shown in Table I. Patients in the ⱕ10 group, when compared with patients in the ⬎10 –ⱕ14 group, had a lower functional capacity, as expressed with a reduced habitual activity score and a higher NYHA class, and a more impaired left ventricular systolic function. The cause of left ven-
American Heart Journal June 2003
1104 Mezzani et al
Table I. Clinical and exercise test characteristics of patients with reduced exercise capacity (peak VO2 ⱕ14 mL/kg/min)
No. of patients Age (y) Male (%) NYHA class Activity score LVEF DecT (ms) Ischemic LVD (%) Digoxin (%) Diuretics (%) ACE-inhibitors (%) -Blockers (%) Peak VO2 (mL/kg/min) Peak HR (beats/min) Peak SBP (mm Hg) VE/VCO2 slope Peak RER Peak RER ⱖ 1 (%) Peak RER ⱖ 1.05 (%) Peak RER ⱖ 1.10 (%) Peak RER ⱖ 1.15 (%) VAT identified (%)
Total
>10-<14 Group
<10 Group
P*
273 62 ⫾ 9 225 (82) 2.4 ⫾ 0.5 1.4 ⫾ 0.5 24% ⫾ 8% 157 ⫾ 42 202 (74) 169 (62) 241 (88) 254 (93) 114 (42) 11.1 ⫾ 2 118 ⫾ 21 149 ⫾ 26 34.9 ⫾ 8 1.17 ⫾ 0.1 262 (96) 243 (89) 202 (74) 155 (57) 143 (52)
193 61 ⫾ 10 166 (86) 2.3 ⫾ 0.5 1.5 ⫾ 0.5 24% ⫾ 5% 159 ⫾ 42 144 (74) 109 (56) 167 (86) 179 (93) 89 (46) 12.1 ⫾ 1 120 ⫾ 19 155 ⫾ 25 32.7 ⫾ 6 1.17 ⫾ 0.1 190 (98) 178 (92) 151 (78) 116 (60) 125 (64)
80 63 ⫾ 9 59 (73) 2.7 ⫾ 0.5 1.2 ⫾ 0.5 21% ⫾ 8% 151 ⫾ 42 58 (72) 61 (76) 74 (93) 74 (93) 25 (31) 8.6 ⫾ 1 114 ⫾ 23 135 ⫾ 23 40.6 ⫾ 11 1.16 ⫾ 0.1 72 (90) 65 (80) 51 (62) 39 (48) 18 (22)
– NS .022 ⬍.0001 ⬍.0001 ⬍.0001 NS NS NS NS NS .03 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 NS NS NS NS NS ⬍.0001
Values are presented as mean ⫾ SD or number (%). ACE, Angiotensin-converting enzyme; DecT, early deceleration time of transmitral flow; HR, heart rate; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; NS, not statistically significant; NYHA, New York Heart Association; PetCO2, end-tidal PCO2; RER, respiratory exchange ratio; SBP, systolic blood pressure; VAT, ventilatory anaerobic threshold; VE, ventilation. *ⱕ 10 Group vs ⬎10-ⱕ14 group.
Figure 1
-blocking therapy. Moreover, patients in the ⱕ10 group had lower peak heart rate and peak systolic blood pressure mean values and a less efficient ventilatory response to exercise, as indicated by a higher mean VE/VCO2 slope. Mean pRER and percentages of patients reaching a pRER of at least 1.00, 1.05, 1.10, and 1.15 did not differ in the 2 subgroups. The ventilatory anaerobic threshold was identified more frequently in the ⬎10 –ⱕ14 group than in the ⱕ10 group.
Survival
Kaplan-Meier plot of cumulative survival for patients grouped by peak VO2 ⬎14, ⬎10 but ⱕ14, and ⱕ10 mL/kg/min.
tricular dysfunction was predominantly ischemic in both groups, which did not differ with digoxin, diuretic, and angiotensin-converting enzyme inhibitor administration; however, significantly more patients in the ⬎10 –ⱕ14 group than in the ⱕ10 group received
Eleven patients were lost to follow-up, and the mean follow-up duration was 19.6 ⫾ 14 months. Seventytwo deaths from cardiovascular causes were observed, 35 of which (49%) were sudden, 27 of which (37%) were due to progressive heart failure, and 10 of which (14%) were due to other cardiac causes. Six patients underwent heart transplantation in clinical status I. Thus, the composite end point was reached in 78 of the patients in the whole study group (14%). The 2-year survival rate was 93% versus 75% in patients with a peak VO2 ⬎14 and ⱕ14 mL/kg/min, respectively (P ⬍ .0001), and 89% versus 69% in patients with a peak VO2 ⬎10 and ⱕ10 mL/kg/min, respectively (P ⬍ .0001). The 2-year survival rate also differed in patients with a peak VO2 ⬎14, patients with a peak VO2 ⬎10 –ⱕ14, and patients with a peak VO2
American Heart Journal Volume 145, Number 6
Mezzani et al 1105
Table II. Univariate significant comparisons between survivors and patients reaching the combined endpoint in the ⱕ10 group
No. of patients Activity score NYHA class LVEF DecT (ms) -Blockers (%) Peak SBP (mm Hg) VE/VCO2 slope Peak RER ⱖ1.15 (%)
Table IV. Clinical and exercise test characteristics of patients with severely reduced exercise capacity (peak VO2 ⱕ10 mL/ kg/min) according to peak RER ⬍ and ⱖ1.15
Survivors
Death/TX
P
54 1.3 ⫾ 0.5 2.5 ⫾ 0.5 23% ⫾ 8% 160 ⫾ 44 23 (41) 142 ⫾ 22 39 ⫾ 8 21 (39)
26 1.0 ⫾ 0.3 2.8 ⫾ 0.3 17% ⫾ 6% 133 ⫾ 33 3 (11) 119 ⫾ 19 45 ⫾ 13 17 (65)
– .02 .013 .003 .02 .009 ⬍.0001 .017 .031
Values are presented as mean ⫾ SD or number (%). TX, Heart transplantation.
Table III. Multivariate analysis for the ⱕ10 group
NYHA class Peak SBP BB, yes Activity score VE/VCO2 slope DecT LVEF Peak RER ⱖ1.15
2
RR
95% CI
P
.07 .19 .57 .70 .73 1.56 2.69 4.73
.69 .98 .45 .39 .95 .98 .88 1.65
.05-10.4 .92-1.04 .06-3.48 .04-3.46 .85-1.06 .96-1.01 .76-1.02 .07-25
.79 .66 .44 .40 .39 .21 .10 .03
BB, -Blocking therapy; RR, relative risk.
ⱕ10 mL/kg/min (93% vs 83% vs 69%, respectively, P ⬍ .0001) (Figure 1). In the ⱕ10 group, patients reaching the composite end point had a significantly lower activity score, NYHA class, and left ventricular ejection fraction, a shorter early deceleration time of transmitral flow, and a lower percentage of -blocker administration than survivors (Table II). They also had a lower peak systolic blood pressure and a higher VE/VCO2 slope and percentage of pRER ⱖ1.15 attainment than survivors, whereas the percentages of patients with a pRER of at least 1.00, 1.05, and 1.10 did not differ in the 2 groups (Table II). With multivariate analysis, the ability to attain a pRER ⱖ1.15 was the only independent predictor of the composite end point (2 ⫽ 4.73, P ⫽ .03), with a relative risk of 1.65 (Table III). Indeed, in the ⱕ10 group, patients unable to reach a pRER ⱖ1.15 (n ⫽ 41) had a 2-year survival rate of 83%, far higher than that of patients (n ⫽ 39) who were able to reach such a pRER value (52%, P ⬍ .0001), but similar to that observed in patients with a peak VO2 ⬎10 –ⱕ14 mL/kg/ min (Figure 2). When clinical and exercise test parameters of patients with a peak VO2 ⱕ10 mL/kg/min and a peak RER ⬍1.15 or ⱖ1.15 were compared, only the peak PetCO2 mean value differed in the 2 groups (Table IV), being significantly lower in the ⱖ1.15 group.
No. of patients Age (y) Male (%) NYHA class Activity score LVEF DecT (ms) Ischemic LVD (%) Digoxin (%) Diuretics (%) ACE-inhibitors (%) -Blockers (%) Peak VO2 (mL/kg/min) Peak HR (beats/min) Peak SBP (mm Hg) VE/VCO2 slope Peak PetCO2 (mm Hg) Peak RER VAT identified (%)
Peak RER <1.15 group
Peak RER >1.15 group
P
41 63 ⫾ 9 27 (66) 2.7 ⫾ 0.5 1.2 ⫾ 0.4 21% ⫾ 7% 154 ⫾ 40 28 (68) 30 (73) 36 (88) 35 (85) 17 (41) 8.5 ⫾ 1 113 ⫾ 24 134 ⫾ 22 38.6 ⫾ 7 31.4 ⫾ 4 1.05 ⫾ 0.6 16 (39)
39 63 ⫾ 9 31 (79) 2.6 ⫾ 0.4 1.2 ⫾ 0.4 20% ⫾ 8% 146 ⫾ 44 29 (74) 31 (79) 38 (97) 39 (100) 8 (21) 8.7 ⫾ 1 114 ⫾ 21 136 ⫾ 24 43.1 ⫾ 12 29 ⫾ 6 1.26 ⫾ 0.1 11 (29)
– NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS ⬍.03 ⬍.0001 NS
Values are presented as mean ⫾ SD or number (%).
Figure 2
Kaplan-Meier plot of cumulative survival for patients with a peak VO2 ⱕ10 mL/kg/min grouped by peak respiratory exchange ratio ⬍1.15 or ⱖ1.15. The survival rate of patients with a peak VO2 ⱕ10 mL/kg/min and a peak respiratory exchange ratio ⬍1.15 is not significantly different from that of patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/min, independent of their pRER.
In the ⬎10 –ⱕ14 group, patients reaching the combined end point had a significantly lower activity score (P ⫽ .021), NYHA class (P ⫽ .0006), left ventricular ejection fraction (P ⬍ .0001), and percentage of patients taking -blockers (P ⫽ .007) and a shorter early
1106 Mezzani et al
deceleration time of transmitral flow (P ⫽ .007) than survivors. Among peak effort parameters, peak VO2 was lower (P ⫽ .0002) and VE/VCO2 slope was higher (P ⫽ .002) in patients reaching the composite end point, but the percentages of patients attaining a pRER of at least 1.00, 1.05, 1.10, and 1.15 did not differ between survivors and nonsurvivors. Multivariate analysis indicated peak VO2 as the only independent predictor of the composite end point (2 ⫽ 3.85, P ⫽ .04) in this group.
Discussion Objective assessment of maximal effort in patients with CHF Objective indices of maximal effort are strongly needed for patients with CHF, because of the preeminent prognostic role played by peak VO21-6 and the frequently reduced level of habitual activities and consequent lack of motivation to exercise until exhaustion in this group.7-10 This is especially true for patients with CHF who have a reduced exercise capacity, whose treatment calls for a complex and costly therapeutic effort. Among traditional maximal exercise indices, a plateau of the VO2 versus work rate relationship is known to be very rare in the CHF population,16 and its occurrence has been questioned even in healthy subjects.22 The achievement of a fixed percentage of predicted maximal heart rate is also of little value for maximal exercise assessment in patients with CHF, because chronotropic incompetence is quite common in patients with symptomatic left ventricular dysfunction23,24 and the use of -blocking agents is increasing in the CHF population.25 A pRER between 1.10 and 1.20 has also been proposed as an index of achieved maximal effort.11-13 This approach seems reasonable because, beyond an RER of 1, buffering of exerciseinduced lactic acidosis results in excess production of CO2, more than that produced from aerobic metabolism, making both VCO2 and RER increase14 independently of the subject’s or patient’s absolute exercise tolerance. However, in patients with CHF, a clear-cut RER value for assessment of maximal effort has not yet been identified; different authors have suggested values ranging from ⱖ1.00 to ⱖ1.10.15-18 Moreover, anaerobic metabolism has been shown to activate at 50% to 70% of total exercise time19-21 in patients with CHF. Our hypothesis was that the confirmation of peak VO2 prognostic power would thus occur mainly in patients able to reach a pRER significantly higher than 1, that is, in the presence of a marked anaerobic metabolism activation caused by a maximal or near-maximal effort.
American Heart Journal June 2003
pRER and peak VO2 prognostic power Several authors have indicated that a peak aerobic power ⱕ10 mL/kg/min is a strong predictor of a poor prognosis in patients with CHF.1,2,4,5 In a study of 26 patients with CHF who had a peak VO2 ⱕ10 mL/kg/ min, Stevenson et al4 reported a 1-year survival rate of 77% and a 2-year survival rate of 48%. More recently, Opasich et al5 observed a 1-year survival rate of 64% and a 2-year survival rate of 54% in a group of 70 patients with CHF and similar peak aerobic power. Our results partially differ from these data, indicating a relatively better prognosis in patients with a peak VO2 ⱕ10 mL/kg/min (1- and 2-year survival rates of 75% and 69%, respectively). This is probably because of a different background therapy, with a high percentage of patients taking -blockers (31%) in our study. However, stratification of the ⱕ10 group by a pRER ratio ⱖ1.15 or ⬍1.15 showed that patients not reaching such a cutoff value (ie, patients with an apparently lower degree of anaerobic metabolism activation) had 1-year and 2-year survival rates of 90% and 83%, respectively, which is comparable with survival rates of patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/min (Figure 2); that is, better than expected according to peak VO2 value. However, in patients attaining a pRER ⱖ1.15, the unfavorable peak VO2 prognostic power was confirmed, with significantly lower 1- and 2-year survival rates (58% and 52%, respectively). These results seem to indicate a prognostic heterogeneity among CHF patients with a peak VO2 ⱕ10 mL/kg/min (ie, a group usually considered to have a very bad prognosis) and may be explained by considering patients who do not demonstrate a significant anaerobic metabolism activation as not adequately motivated to sustain maximal or near-maximal effort. This hypothesis is supported by the finding of a peak PetCO2 mean value significantly lower in patients with a peak VO2 ⱕ10 mL/kg/min and a pRER ⱖ1.15 than that in patients with a pRER ⬍1.15, which indicates a higher degree of hyperventilation (and thus a more strenuous effort) in patients with pRER values ⱖ1.15. In patients with a peak VO2 ⬎10 but ⱕ14 mL/kg/ min, the pRER did not allow for the refinement of the peak VO2 prognostic power. This is not surprising, because a peak VO2 ⬎10 mL/kg/min is known to be per se a favorable prognostic indicator in patients with CHF,4,5 independently of maximal effort achievement, assuring a 2-year survival rate of 89% in our population. These findings are important from a clinical point of view, because they offer a means for defining peak VO2 prognostic reliability in patients with CHF who have severely reduced exercise tolerance, in whom peak oxygen consumption bears the highest prognostic and decisional impact. In this group, peak VO2 prognostic power should not be taken for granted, but
American Heart Journal Volume 145, Number 6
confirmed by the attainment of a pRER value as close as possible to 1.15 as an index of adequate motivation on the part of the patient.
Study limitations pRER values show a considerable interindividual variability,13,14,18 preventing the possibility of precise effort intensity comparisons; a cutoff RER value of 1.15 may thus not represent the same relative level of effort intensity in different patients. However, an RER of 1.15 has been demonstrated to be well related to VO2 maximum in healthy subjects, and an RER ⬎1.10 has been suggested as evidence that a true VO2 maximum has been attained.26 Because metabolic response to exercise higher than the anaerobic threshold does not seem to be qualitatively different in patients with CHF from that seen in healthy subjects, it is reasonable to assume that an RER value of 1.15 may well represent maximal or near-maximal effort also in the CHF population.
Conclusions A prognostic hetereogeneity seems to exist among patients with CHF and a severely reduced exercise capacity (ie, peak VO2 ⱕ10 mL/kg/min), because the expected negative peak VO2 prognostic power is confirmed only in patients reaching an RER of at least 1.15 at peak effort (ie, demonstrating a significant anaerobic metabolism exercise-induced activation as a result of adequate motivation). Conversely, patients unable to attain a pRER ⱖ1.15 have a prognosis comparable with that of patients with a better functional capacity, thus indicating the possibility that their measured peak VO2 is lower than their “true” peak aerobic power. These results suggest that patients with CHF and severely reduced exercise tolerance should be encouraged to exercise as close as possible to an RER of 1.15 to ascertain their motivation and ensure peak VO2 prognostic reliability; in the case of pRER values ⬍1.15, a cautious use of peak VO2 in clinical decision making may be recommended. Further studies will be needed to fully elucidate the link between pRER, motivation, and prognosis in patients with CHF and severely reduced exercise capacity.
References 1. Szlachcic J, Massie BM, Kramer BL, et al. Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985;55:1037-42. 2. 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;83:778-86. 3. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. Circulation 1995;92: 3593-612. 4. Stevenson LW, Couper G, Natterson B, et al. Target heart failure populations for newer therapies. Circulation 1995;92(2 Suppl):II174-81.
Mezzani et al 1107
5. Opasich C, Pinna GD, Bobbio M, et al. Peak oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol 1998;31:766-75. 6. Mudge GH, Goldstein S, Addonizio LJ, et al. Twenty-fourth Bethesda Conference: cardiac transplantation. Task Force 3: recipient guidelines/priorization. J Am Coll Cardiol 1993;22:21-31. 7. Oka RK, Gortner SR, Stotts NA, et al. Predictors of physical activity in patients with chronic heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996;77:159-63. 8. Mezzani A, Corra` U, Baroffio C, et al. Habitual activities and peak aerobic capacity in patients with asymptomatic and symptomatic left ventricular dysfunction: use of a new physical activity scoring system. Chest 2000;117:1291-9. 9. Clark AL, Poole-Wilson PA, Coats AJS. Effects of motivation of the patient on indices of exercise capacity in chronic heart failure. Br Heart J 1994;71:162-5. 10. Ramos-Barbon, Fitchett D, Gibbons WJ, et al. Maximal exercise testing for the selection of heart transplantation candidates: limitation of peak oxygen consumption. Chest 1995;115:410 –7. 11. Davies JA. Direct determination of aerobic power. In: Maud PJ, Foster C, editors. Physiological assessment of human fitness. Champaign (Ill): Human Kinetics; 1995. p. 9-17. 12. Exercise and the heart. Froelicher VF, Myers JN, editors. Philadelphia: W.B. Saunders Company; 2000. 13. Balady GJ, Berra KA, Golding LA, et al. Interpretation of clinical test data. In: Franklin BA, Whaley MH, Howley ET, editors. ACSM’s guidelines for exercise testing and prescription. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 115-33. 14. Wasserman K, Hansen J, Sue D, et al. Principles of exercise testing and interpretation. Philadelphia: Lippincott Williams & Wilkins; 1999. 15. ESC working group on exercise physiology, physiopathology, and electrocardiography. Guidelines for cardiac exercise testing. Eur Heart J 1993;14:969-88. 16. Cohen-Solal A. Cardiopulmonary exercise testing in chronic heart failure. In: Wasserman K, editor. Exercise gas exchange in heart disease. Armonk: Futura Publishing Company; 1996. p. 17-38. 17. Mancini D, LeJemtel T, Aaronson K. Peak VO2: a simple yet enduring standard. Circulation 2000;101:1080-2. 18. Fleg JL, Pina IL, Balady GJ, et al. Assessment of functional capacity in clinical and research applications. Circulation 2000;102:1591-7. 19. Weber KT, Kinasewitz GT, Janicki JS, et al. Oxygen utilization and ventilation during exercise in patients with chronic heart failure. Circulation 1982;65:1213-23. 20. Metra M, Raddino R, Dei Cas L, et al. Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure. Am J Cardiol 1990;65:1127-33. 21. Katz SD, Berkowitz R, LeJemtel TH. Anaerobic threshold detection in patients with congestive heart failure. Am J Cardiol 1992;69:1565-9. 22. Noakes TD. Implications of exercise testing for prediction of athletic performance: a contemporary perspective. Med Sci Sports Exerc 1988;20:319-30. 23. Clark AL, Coats AJS. Chronotropic incompetence in chronic heart failure. Int J Cardiol 1995;49:225-31. 24. Rundqvist B, Eisenhofer G, Elam M, et al. Attenuated cardiac sympathetic responsiveness during dynamic exercise in patients with heart failure. Circulation 1997;95:940-5. 25. Tavazzi L. Epidemiological burden of heart failure. Heart 1998; 79(2 Suppl):S6-9. 26. Issekutz B Jr, Birkhead NC, Rodahl K. Use of respiratory quotients in assessment of aerobic work capacity. J Appl Physiol 1962;17:47-50.