From the Departments of Nuclear Medicine a, and Pulmonology, c University of Munich, Munich, and Department of Cardiology,

Transcription

1 Relationship between right ventricular ejection fraction and maximum exercise oxygen consumption: A methodological study in chronic heart failure patients Marcus Hacker, MD, a Stefan Störk, MD, MSc, b Diana Stratakis, MD, c Christiane E. Angermann, MD, b Rudolf Huber, MD, c Klaus Hahn, MD, a and Andreas Tausig, MD a Background. Peak oxygen consumption at maximum exercise (peak VO 2 ) predicts survival in chronic heart failure (CHF) patients. Right ventricular ejection fraction (RVEF) at rest has been reported to correlate with peak VO 2. We evaluated the strength and consistency of the association between peak VO 2 and RVEF measured by different radionuclide ventriculography (RNV) techniques in a prospective cohort study. Methods and Results. In 58 consecutive CHF patients (mean age, 53 years; 39 patients with dilated cardiomyopathy; 48 men), upright symptom-limited bicycle ergometry was performed. During exercise, ventilatory and gas exchange data were recorded and peak VO 2 was calculated. RVEF was calculated by use of first-pass (FP) RNV with single and dual region of interest (ROI) acquisition and planar multigated acquisition (MUGA). Irrespective of the method used, RVEF showed no relevant correlation with the corresponding peak VO 2 value (r 0.11 for FP single ROI, r 0.06 for FP dual ROI, r 0.16 for MUGA). Peak VO 2 or changes in peak VO 2 after 6 and 12 months of follow-up were not determined by RVEF measurements. Conclusion. In CHF patients no association was found between peak VO 2 at maximum exercise and RVEF at rest with different RNV techniques. Changes in exercise capacity are not reliably reflected by changes in RVEF measurements at rest. (J Nucl Cardiol 2003;10:644-9.) Key Words: Chronic heart failure right ventricular ejection fraction peak oxygen consumption radionuclide ventriculography Chronic heart failure (CHF) remains a leading cause of morbidity and mortality, despite improved pharmacologic and surgical treatment options. 1 Peak oxygen consumption at maximum exercise (peak VO 2 ) or achieved percentage of predicted peak VO 2 (%VO 2 ) is an established tool for monitoring and guiding CHF therapy. 2-9 Hemodynamic parameters at rest have also been shown to predict outcome in CHF patients. Besides left ventricular (LV) ejection fraction (EF), right ventricular (RV) EF seems to play an important role as a prognostic determinant and has been described as an independent From the Departments of Nuclear Medicine a, and Pulmonology, c University of Munich, Munich, and Department of Cardiology, b University of Würzburg, Würzburg, Germany Drs Hacker and Störk share the authorship of this article equally. Received for publication Sept 17, 2002; final revision accepted May 28, Reprint requests: Marcus Hacker, MD, Klinik und Poliklinik für Nuklearmedizin der LMU, Ziemssenstrasse 1, München, Germany; marcus.hacker@nuk.med.uni-muenchen.de. Copyright 2003 by the American Society of Nuclear Cardiology /2003/$ doi: /s (03) predictor of survival in 205 patients with moderate CHF. 10 In a small group of patients with advanced CHF, a close correlation between RVEF and peak VO 2 has been reported, 11 suggesting good agreement between RV function assessed at rest and a combined (RV and LV) measurement of functional exercise capacity. Radionuclide ventriculography (RNV) measures RVEF independently of RV geometry and is most commonly used for serial RVEF assessment in CHF patients. RNV acquisition in CHF patients is not standardized, mainly because it is unknown whether RVEF values measured with more sophisticated techniques will allow better patient management or whether standard techniques will suffice. The majority of studies calculated RVEF by multigated acquisition (MUGA). However, planar MUGA in the left anterior oblique projection tends to underestimate RVEF if there is major overlap of the right atrium and right ventricle, which is common in CHF. First-pass (FP) techniques in the 30 right anterior oblique projection avoid this limitation and are therefore assumed superior to planar MUGA in terms of calculating true RVEF. 12,13 Moreover, FP RNV can be easily acquired without exposing the patient to additional radi- 644

2 Journal of Nuclear Cardiology Hacker et al 645 Volume 10, Number 6;644-9 Lack of correlation of right ventricular function and peak oxygen consumption in CHF ation if MUGA or technetium 99m based myocardial scintigraphy is planned. 14 This study aimed to evaluate, in cross-sectional and longitudinal analyses, the strength and consistency of the association between different techniques of radionuclide RVEF measurement at rest and peak VO 2 at maximum exercise in a nonselected group of CHF patients. METHODS CHF Patients Consecutive CHF patients from our heart failure outpatient clinic who were hospitalized to optimize medical treatment and/or to assess the need for heart transplantation were eligible. Between January 1998 and November 2000, in 89 patients cardiopulmonary exercise testing and RNV (FP and MUGA) were performed on the same day. This report is restricted to 58 patients (65%) in whom baseline data were complete regarding three different RNV acquisition techniques and cardiopulmonary exercise testing. Follow-up was scheduled at 6 and 12 months. Cardiopulmonary Exercise Testing Spiroergometry was performed on an electronically braked ergometer in an air-conditioned room at 11:30 AM. Patients had taken their regular medication with a light breakfast at 8:00 AM. Patients started cycling at a workload of 10 W or 30 W depending on their clinical status, followed by a 10 W increase after each minute up to maximum physical exertion. Respiratory gas exchange and electrocardiographic changes were monitored continuously. Peak VO 2 was defined as the highest VO 2 during any stage that could be sustained for more than 1 minute. Respiratory threshold was documented but not used in the evaluation of exercise capacity and was reached in 96% of examinations. None of the 58 patients developed exercise-induced ischemia (ie, horizontal or downsloping STsegment depression 1 mm) before reaching the point of maximum exertion or respiratory threshold. Blood pressure was recorded automatically every minute. RNV RVEF studies were performed at rest by in vivo red blood cell labeling. Sn-pyrophosphate was injected intravenously. After 20 minutes, patients were placed upright in front of a Picker SIM 400 multicrystal camera, equipped with a lowenergy, high-sensitivity, parallel-hole collimator in approximately 30 right anterior oblique projection. Then, 740 MBq Tc-99m pertechnetate was injected. The camera acquired a total of 1500 frames at 25 milliseconds per frame. An initial RV region of interest (ROI) was drawn and the time-activity curve generated. The start and stop of the RV phase and the first identifiable RV beat were defined and the ROI modified through iterative steps by the computer software. Borders of the RV end-diastolic region were determined from the phase image Table 1. Baseline characteristics of study cohort (n 58) and the end-systolic difference image. The phase image was used to identify the pulmonic valve and tricuspid valve planes. The end-systolic region was drawn from the end-systolic image as described previously. 13 FP RVEF was calculated by use of a single end-diastolic frame (single ROI) and both end-diastolic and end-systolic frames (dual ROI). LVEF was calculated by the dual ROI method. After the FP acquisition, patients were positioned supine for planar MUGA. A Picker Prism 2000 gamma camera (Philips, Cleveland, Ohio) equipped with a low-energy high-resolution collimator was positioned at the 40 left anterior oblique projection ( best septal view ). LVEF and RVEF were calculated by the dual ROI method. The background ROI was placed adjacent to the free wall of the ventricle. Data Analysis Characteristic Data Age (y) 52.9 (28 76) Body mass index (kg/m 2 ) 26.7 (17 35) Female gender 10 (17) NYHA class II 21 (36) III 28 (48) IV 9 (16) Cardiac diagnosis Ischemic heart disease 17 (29) Dilated cardiomyopathy 39 (67) Other (hypertrophic/valvular 2 (4) cardiomyopathy) ACE inhibitor 52 (90) Diuretic 53 (91) -blocking agent 40 (69) Digoxin 31 (53) Nitrate 8 (14) Values are mean (range) or No. (%). ACE, Angiotensin-converting enzyme. Results are presented as mean SD and range, unless stated otherwise. Differences between groups at baseline and differences between follow-up examinations were assessed by use of the Wilcoxon test for unpaired and paired data as appropriate. The Spearman coefficient (r) is given when correlations are reported. Univariate determinants of peak VO 2 were selected by means of linear regression analysis from baseline characteristics (Table 1), blood pressure variables, and heart rate, with a liberal of.15. In multivariate models statistical significance was accepted at an of.05. The identical approach was followed in building models with change in peak VO 2, percent of predicted VO 2, and O 2 uptake per heart rate as dependent variables. All P values are reported 2-sided.

3 646 Hacker et al Journal of Nuclear Cardiology Lack of correlation of right ventricular function and peak oxygen consumption in CHF November/December 2003 Table 2. Descriptors of symptom-limited exercise test in baseline cohort (n 58) Descriptors Mean SD (range) Before exercise test Systolic blood pressure (70 170) Diastolic blood pressure (46 120) Heart rate (beats/min) (50 120) O 2 per heart rate (ml) ( ) At maximum exercise Systolic blood pressure (80 256) Diastolic blood pressure (62 109) Heart rate (beats/min) (69 197) O 2 per heart rate (ml) ( ) Peak VO 2 (ml/min) ( ) Peak VO 2 (ml min ( ) kg 1 ) % Predicted VO (27 102) Respiratory quotient ( ) Radionuclide measurements RVEF: MUGA (%) (10 76) RVEF: FP single ROI (%) 43 9 (16 66) RVEF: FP dual ROI (%) (15 68) LVEF: FP dual ROI (%) 32 9 (18 50) LVEF: MUGA (%) (13 57) RESULTS Cross-Sectional Analysis at Baseline In this study 58 patients, 48 men and 10 women, met the requirements for analysis (as described in the Methods section). The characteristics of the study cohort are given in Table 1. All patients received at least 2 medications for CHF, predominantly a combination therapy of angiotensin-converting enzyme inhibitors, diuretics, and -blocking agents. No cardiac events were registered during exercise. The detailed descriptors of cardiopulmonary exercise tests and radionuclide assessments are given in Table 2. Mean peak VO 2 and LVEF were severely compromised, and RVEF was moderately compromised, which is consistent with advanced CHF. Peak VO 2 was 10 ml kg 1 min 1 or lower in 6 tests, and was between 10 and 14 ml kg 1 min 1 in 22 tests. FP RVEF (dual ROI) recorded the highest RVEF values, followed by FP RVEF (single ROI) and MUGA RVEF. The correlation in RVEF between the two FP methods was moderate (r 0.75) but was worse between FP methods and MUGA (r 0.61 for single ROI and r Figure 1. Correlation between peak VO 2 and RV function measured by 3 different radionuclide techniques at baseline (n 58) for dual ROI, respectively). No correlation was found between MUGA LVEF and MUGA RVEF (r 0.03). In addition, no correlation was found between any RVEF method and peak VO 2 (Figure 1). In univariate linear regression analysis, age, body mass index, New York Heart Association (NYHA) class, and therapy with -blocking agents showed inverse associations with peak VO 2. In multivariate analysis only age and body mass index remained as independent determinants of peak VO 2 (P.001). RV measurements were not associated with peak VO 2 in regression analysis, either univariately or after adjustment for age and body mass index (Table 3). LV measurements showed no association with peak VO 2 in univariate analysis but showed a trend after adjustment for age and body mass index (Table 3).

4 Journal of Nuclear Cardiology Hacker et al 647 Volume 10, Number 6;644-9 Lack of correlation of right ventricular function and peak oxygen consumption in CHF Table 3. Multivariate linear regression analyses for peak VO 2 at baseline coefficient (95% confidence interval)* Serial Examinations at 6 and 12 Months Complete follow-up data (3 different RNV acquisitions and cardiopulmonary exercise testing) were available for 36 patients at 6 months and 25 patients at 12 months. Reasons for incomplete data at 6 and 12 months, respectively, were death (n 6 and n 9), inability to perform the exercise test because of the severity of CHF (n 3 and n 4), no follow-up visit (n 2 and n 5), invalid exercise test (n 0 and n 1), and incomplete RNV data (n 11 and n 14). Mean peak VO 2, RV and LV measurements, and NYHA class were unchanged after 12 months of follow-up (Table 4). Multivariate regression coefficients at 6 and 12 months were unchanged compared with baseline (data not shown). We repeated all analyses using change in peak VO 2, percent of predicted VO 2,orO 2 per heart rate, respectively, as the dependent variable. Finally, all analyses were repeated after excluding patients with an anaerobic threshold lower than 1.05, because this subgroup might be characterized by other unmeasured coexisting conditions. In none of these analyses were associations observed between measurements at rest and at maximum exercise. DISCUSSION P value RVEF: MUGA (%) 0.07 ( 0.07 to 0.15).29 RVEF: FP single ROI (%) 0.16 ( 0.08 to 0.16).31 RVEF: FP dual ROI (%) 0.03 ( 0.10 to 0.14).59 LVEF: MUGA (%) 0.10 ( 0.01 to 0.22).08 LVEF: FP dual ROI (%) 0.08 ( 0.01 to 0.18).09 *Each coefficient refers to a separate analysis, adjusted for age and body mass index. The main finding of this investigation in CHF patients was that RVEF assessment at rest, independent of the radionuclide technique used, showed no correlation with peak VO 2 measured at maximum exercise. Our findings support the view that changes in hemodynamics at rest and at maximum exercise occur independently of each other in CHF patients. It is therefore not possible to infer reliably the state of exercise capacity based on resting RNV in the same patient. Parallel monitoring of the resting and exercise state may be desirable in high-risk groups. The potential limitations of this investigation need to be considered. Radionuclide assessment and ergospirometry are affected by age, hormonal changes, level of medication, conditioning status, and biologic variability, as well as by patient motivation in the case of exercise testing. In this investigation care was taken to minimize these influencing factors. RNV and ergospirometry were performed in a standardized fashion after recompensation and stabilization of decompensated CHF. Maximum exertion during ergospirometry was enforced, and peak VO 2 at maximum exercise level rather than at the level of anaerobic threshold was used as our primary parameter of interest. Medication was found to be relatively homogeneously distributed among patients. Thus, although we cannot exclude that these effects distorted existent correlations, we consider it unlikely. This view is strengthened by the consistency of our null findings in all cross-sectional and serial analyses. We found a moderate correlation between single and dual ROI FP RVEF. However, the correlation between MUGA RVEF and the FP methods was only fair. This is in accordance with a study comparing different radionuclide methods with cine magnetic resonance imaging as the reference standard. 13 In this study cine magnetic resonance imaging correlated well with FP methods but only weakly with MUGA. RVEF values and RVEF changes over time did not correlate with peak VO 2 or changes in peak VO 2 in any of the univariate or multivariate regression analyses. Our findings strongly suggest that hemodynamics at rest and at maximum exercise do not change simultaneously. Results from other studies are inconsistent. Baker et al 15 found a correlation between FP RVEF (single ROI) and peak VO 2 in 25 patients with severe heart failure. In a group of 24 patients with severe heart failure, Ben-Gal et al 16 showed that RVEF values lower than 30% measured with FP and MUGA RVEF were associated with significantly lower VO 2 values, suggesting a pathophysiologic relationship between RVEF and peak VO 2. Conversely, Clark et al 17 could not find such a correlation between MUGA RVEF and peak VO 2 in 42 CHF patients. Similarly, Szlachcic et al 18 were unable to detect a correlation between MUGA RVEF and VO 2 in 27 patients. The comparability of all these studies is limited, however, because they were based on low patient numbers, major differences in the severity of CHF, and different RVEF calculation methods. Moreover, CHF may predominantly be due to RV or LV dysfunction or a combination of both, may respond differently to treatment over time, and may affect exercise capacity very differently despite uniformly lowered LVEF. In general, cardiomyopathy induces LV remodeling as an adaptive mechanism, leading to LV enlargement, hypertrophy, and distortion of regional and global geometry. 19 However, compromised cardiac output is not

5 648 Hacker et al Journal of Nuclear Cardiology Lack of correlation of right ventricular function and peak oxygen consumption in CHF November/December 2003 Table 4. Paired differences of follow-up examinations after 6 and 12 months Paired differences between baseline and 6 mo follow-up, (n 36) Paired differences between baseline and 12 mo followup, (n 25) Mean SD P value Mean SD P value NYHA class NS NS Body mass index (kg/m 2 ) NS Peak VO 2 (ml min 1 Kg 1 ) NS NS RVEF: MUGA (%) NS RVEF: FP single ROI (%) NS NS RVEF: FP dual ROI (%) NS NS LVEF: MUGA (%) NS LVEF: FP dual ROI (%) NS NS NS, Not significant. paralleled by compromised exercise capacity and NYHA functional class in all patients. Conversely, other reasons for a reduced exercise capacity include a diminished nutritive blood flow to skeletal muscles and abnormalities of skeletal muscle metabolism. 20,21 These factors were not measured in this study but may, in part, explain our null findings. Moreover, deteriorating RV function is not solely a consequence of pulmonary hypertension due to LV dysfunction but may also be observed with normal pulmonary artery pressure. 22 Inclusion of patients with primary RV dysfunction in our study may be another reason for the lack of correlation of RVEF and exercise capacity. To our knowledge, there are no studies that have systematically in cross-sectional and longitudinal analyses compared peak VO 2 at maximum exercise with the different radionuclide modalities to calculate RVEF, and the FP (dual ROI) approach has not yet been used for this problem. For the clinical feasibility of serial RVEF measurements, the accuracy, precision, and practicalities of the methodology need to be considered. In patients with atypical heart-axis orientation, FP RVEF can hardly be obtained because it cuts off parts of the ventricle. In addition, using the dual ROI method delineation of end-diastolic and end-systolic expansion of the right ventricle, particularly at the valve plane area, can be difficult. From our analysis of serial measurements, we conclude that a decrease in peak VO 2 values does not necessarily indicate a deterioration in RVEF. For serial measurements, it seems advisable to monitor CHF patients with the same method of RVEF calculation over time. This might be especially important in patients who are unable to perform exercise testing. Whether RVEF measurements in general and MUGA in particular represent independent predictors of clinical outcome in patients with advanced CHF is within the scope of an ongoing study at our institution. In conclusion, RVEF calculated by planar MUGA correlated moderately with FP RNV (single ROI) values. Regardless of the RNV technique applied, no association was found between RVEF at rest and peak VO 2 at maximum exercise, and the change in peak VO 2 was not reflected by the change in RV function. Peak VO 2 and RVEF at rest may reflect different pathophysiologic aspects in moderate and severe CHF, thus justifying assessment of both parameters for optimal monitoring and risk evaluation in this group of patients. Acknowledgment The authors have indicated they have no financial conflicts of interest. References 1. Cowie MR, Mosterd A, Wood DA, et al. The epidemiology of heart failure. Eur Heart J 1997;18: Pardaens K, Van Cleemput J, Vanhaecke J, Fagard RH. Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates. Circulation 2000;101: Florea VG, Henein MY, Anker SD, et al. Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure. Eur Heart J 2000;21: Stelken AM, Younis LT, Jennison SH, et al. Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy. J Am Coll Cardiol 1996;27:

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