Download Relationship between right ventricular ejection fraction and

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, MDa
Background. Peak oxygen consumption at maximum exercise (peak VO2) predicts survival
in chronic heart failure (CHF) patients. Right ventricular ejection fraction (RVEF) at rest has
been reported to correlate with peak VO2. We evaluated the strength and consistency of the
association between peak VO2 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 VO2 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 VO2 value (r ⴝ 0.11 for FP single
ROI, r ⴝ 0.06 for FP dual ROI, r ⴝ 0.16 for MUGA). Peak VO2 or changes in peak VO2 after
6 and 12 months of follow-up were not determined by RVEF measurements.
Conclusion. In CHF patients no association was found between peak VO2 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 VO2) or achieved
percentage of predicted peak VO2 (%VO2) 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 Medicinea, 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,
2003.
Reprint requests: Marcus Hacker, MD, Klinik und Poliklinik für
Nuklearmedizin der LMU, Ziemssenstrasse 1, 80336 München,
Germany; [email protected].
Copyright © 2003 by the American Society of Nuclear Cardiology.
1071-3581/2003/$30.00 ⫹ 0
doi:10.1016/S1071-3581(03)00659-7
644
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 VO2 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-
Journal of Nuclear Cardiology
Volume 10, Number 6;644-9
Hacker et al
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 VO2 at maximum
exercise in a nonselected group of CHF patients.
645
Table 1. Baseline characteristics of study cohort (n
⫽ 58)
Characteristic
Data
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.
Age (y)
Body mass index (kg/m2)
Female gender
NYHA class
II
III
IV
Cardiac diagnosis
Ischemic heart disease
Dilated cardiomyopathy
Other (hypertrophic/valvular
cardiomyopathy)
ACE inhibitor
Diuretic
␤-blocking agent
Digoxin
Nitrate
Cardiopulmonary Exercise Testing
Values are mean (range) or No. (%).
ACE, Angiotensin-converting enzyme.
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 VO2 was defined as the
highest VO2 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.
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.
METHODS
CHF Patients
52.9 (28–76)
26.7 (17–35)
10 (17)
21 (36)
28 (48)
9 (16)
17 (29)
39 (67)
2 (4)
52 (90)
53 (91)
40 (69)
31 (53)
8 (14)
Data Analysis
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
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 VO2
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 VO2, percent of predicted VO2, and O2 uptake
per heart rate as dependent variables. All P values are reported
2-sided.
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Hacker et al
Lack of correlation of right ventricular function and peak oxygen consumption in CHF
Journal of Nuclear Cardiology
November/December 2003
Table 2. Descriptors of symptom-limited exercise
test in baseline cohort (n ⫽ 58)
Mean ⴞ SD (range)
Descriptors
Before exercise test
Systolic blood pressure
(mm Hg)
Diastolic blood pressure
(mm Hg)
Heart rate (beats/min)
O2 per heart rate (mL)
At maximum exercise
Systolic blood pressure
(mm Hg)
Diastolic blood pressure
(mm Hg)
Heart rate (beats/min)
O2 per heart rate (mL)
Peak VO2 (mL/min)
Peak VO2 (mL · min–1 ·
kg–1)
% Predicted VO2
Respiratory quotient
Radionuclide measurements
RVEF: MUGA (%)
RVEF: FP single ROI (%)
RVEF: FP dual ROI (%)
LVEF: FP dual ROI (%)
LVEF: MUGA (%)
116 ⫾ 20 (70–170)
79 ⫾ 14 (46–120)
77 ⫾ 15 (50–120)
3.89 ⫾ 0.90 (2.05–6.12)
150 ⫾ 37 (80–256)
84 ⫾ 11 (62–109)
130 ⫾ 29 (69–197)
9.92 ⫾ 2.61 (6.13–16.20)
1206 ⫾ 442 (542–2420)
15.2 ⫾ 5.1 (7.4–28.0)
56 ⫾ 15 (27–102)
1.05 ⫾ 0.09 (0.77–1.41)
39 ⫾ 13 (10–76)
43 ⫾ 9 (16–66)
48 ⫾ 11 (15–68)
32 ⫾ 9 (18–50)
29 ⫾ 11 (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 VO2 and LVEF were
severely compromised, and RVEF was moderately compromised, which is consistent with advanced CHF. Peak
VO2 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 VO2 and RV function
measured by 3 different radionuclide techniques at baseline (n
⫽ 58).
0.47 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 VO2 (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 VO2. In multivariate analysis only
age and body mass index remained as independent
determinants of peak VO2 (P ⬍ .001). RV measurements
were not associated with peak VO2 in regression analysis, either univariately or after adjustment for age and
body mass index (Table 3). LV measurements showed no
association with peak VO2 in univariate analysis but
showed a trend after adjustment for age and body mass
index (Table 3).
Journal of Nuclear Cardiology
Volume 10, Number 6;644-9
Hacker et al
Lack of correlation of right ventricular function and peak oxygen consumption in CHF
Table 3. Multivariate linear regression analyses for
peak VO2 at baseline
␤ coefficient
(95% confidence
P
interval)*
value
RVEF:
RVEF:
RVEF:
LVEF:
LVEF:
MUGA (%)
FP single ROI (%)
FP dual ROI (%)
MUGA (%)
FP dual ROI (%)
0.07
0.16
0.03
0.10
0.08
(–0.07
(–0.08
(–0.10
(–0.01
(–0.01
to
to
to
to
to
0.15)
0.16)
0.14)
0.22)
0.18)
.29
.31
.59
.08
.09
*Each ␤ coefficient refers to a separate analysis, adjusted for age
and body mass index.
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 VO2, 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 VO2, percent
of predicted VO2, or O2 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
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 VO2 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
647
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
VO2 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 VO2 or changes in peak VO2 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 al15
found a correlation between FP RVEF (single ROI) and
peak VO2 in 25 patients with severe heart failure. In a
group of 24 patients with severe heart failure, Ben-Gal et
al16 showed that RVEF values lower than 30% measured
with FP and MUGA RVEF were associated with significantly lower VO2 values, suggesting a pathophysiologic
relationship between RVEF and peak VO2. Conversely,
Clark et al17 could not find such a correlation between
MUGA RVEF and peak VO2 in 42 CHF patients.
Similarly, Szlachcic et al18 were unable to detect a
correlation between MUGA RVEF and VO2 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
648
Hacker et al
Lack of correlation of right ventricular function and peak oxygen consumption in CHF
Journal of Nuclear Cardiology
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 ⴝ 36)
NYHA class
Body mass index (kg/m2)
Peak VO2 (mL · min–1 · Kg–1)
RVEF: MUGA (%)
RVEF: FP single ROI (%)
RVEF: FP dual ROI (%)
LVEF: MUGA (%)
LVEF: FP dual ROI (%)
Paired differences between
baseline and 12 mo followup, (n ⴝ 25)
Mean
SD
P
value
Mean
SD
P
value
0.16
–0.62
–0.21
–3.20
–1.47
–3.73
–2.82
–1.84
0.64
2.88
3.80
8.59
10.61
12.62
6.81
9.03
NS
NS
NS
.043
NS
NS
.008
NS
0.27
–0.84
–0.88
–3.44
–0.65
–3.25
–4.00
–4.07
0.70
1.66
2.72
7.98
11.50
17.09
10.15
10.03
NS
.019
NS
NS
NS
NS
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 VO2 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 VO2 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 VO2 at
maximum exercise, and the change in peak VO2 was not
reflected by the change in RV function. Peak VO2 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.
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