Download Relation Between Right Ventricular Function and Increased Right

Relation Between Right Ventricular Function and Increased
Right Ventricular [18F]Fluorodeoxyglucose Accumulation in
Patients With Heart Failure
Lisa M. Mielniczuk, MD, FRCPC; David Birnie, MB, ChB, MD; Maria C. Ziadi, MD;
Robert A. deKemp, PhD; Jean N. DaSilva, PhD; Ian Burwash, MD, FRCPC;
Anthony T. Tang, MD, FRCPC; Ross A. Davies, MD, FRCPC; Haissam Haddad, MD, FRCPC;
Ann Guo, MEng; May Aung, CNMT; Kathryn Williams, BSc, MS;
Heikki Ukkonen, MD; Rob S.B. Beanlands, MD, FRCPC
Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017
Background—Left heart failure is characterized by alterations in metabolic substrate utilization, and metabolic modulation
may be a future strategy in the management of heart failure. Little is known about cardiac metabolism in the right
ventricle and how it relates to other measures of right ventricular (RV) function. This study was designed to measure
glucose metabolism in the right ventricle, as estimated by [18F]fluorodeoxyglucose (FDG) positron emission
tomography imaging and to determine the relation between RV function and FDG uptake in patients with heart failure.
Methods and Results—A total of 68 patients underwent cardiac [18F]FDG positron emission tomography scanning with
measurement of RV FDG uptake as a standardized uptake value. Perfusion imaging was acquired at rest with
rubidium-82 or [13N]ammonia. RV function was determined by equilibrium radionuclide ventriculography. Relative RV
FDG uptake was determined as the ratio of RV to LV standardized uptake value. Fifty-five percent of these patients had
ischemic cardiomyopathy. The mean LV and RV ejection fractions were 21⫾7% and 35⫾10%, respectively. There was
a correlation between RV ejection fraction and the ratio of RV to LV FDG uptake whether the entire LV myocardium
(r⫽⫺0.40, P⬍0.001) or LV free wall (r⫽⫺0.43, P⬍0.001) was used. This relation persisted in the subgroup with
nonischemic cardiomyopathy (r⫽⫺0.37, P⫽0.04). RV FDG uptake was weakly related to increased RV systolic
pressure but not related to LV size, function, or FDG uptake. The correlation between RV ejection fraction and RV/LV
FDG was maintained after partial-volume correction (r⫽⫺0.68, P⬍0.001).
Conclusions—RV dysfunction is associated with an increase in RV FDG uptake, the magnitude of which may be correlated
with severity. (Circ Cardiovasc Imaging. 2011;4:59-66.)
Key Words: heart failure 䡲 right ventricle 䡲 FDG PET
R
ight ventricular (RV) dysfunction is associated with poor
prognosis in patients with preexisting coronary artery
disease, significant heart failure (HF), and pulmonary artery
hypertension.1–3 Alterations in myocardial substrate utilization
have been implicated in the pathogenesis of contractile dysfunction and HF.4 – 6 Studies of substrate utilization in left HF have
demonstrated that fatty acid utilization may be unchanged or
slightly increased in early HF7 but substantially decreased in
advanced HF, with a concomitant increase of glucose utilization
in early HF and a subsequent decline in advanced HF as insulin
resistance develops in the myocardium.8 –11 Whether the shift
toward glucose utilization represents an adaptive or a maladaptive response predisposing the heart to further myocardial
dysfunction also remains uncertain. Few have studied RV
metabolism in detail. Despite this, several lines of evidence
suggest that RV metabolism may be different.12–14
Clinical Perspective on p 66
It has been demonstrated that there are substantial differences among patients in their tendency to develop right HF.15
Recent literature suggests that the heterogeneity in clinical
course may be caused by a polymorphic variation in gene
expression and that the link between cardiac contractile
function and gene expression may be altered energy substrate
metabolism.16 An understanding of the metabolic changes
associated with RV failure and dysfunction may lead to a
potential target for the use of metabolic modulation in the
treatment and prevention of right HF. This study was de-
Received September 1, 2009; accepted October 12, 2010.
From the Division of Cardiology (L.M.M., D.BM.C.Z., R.A.d.K., J.N.D.S., I.B., R.A.D., H.H., A.G., M.A., K.W., R.S.B.B.), University of Ottawa
Heart Institute, Ottawa, and Division of Cardiology (A.T.T.), University of Victoria, Victoria, Canada; and Division of Cardiology (H.U.), Turku
University Hospital, Turku, Finland.
Correspondence to Dr Lisa M. Mielniczuk, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7 Canada. E-mail
[email protected]
© 2011 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
59
DOI: 10.1161/CIRCIMAGING.109.905984
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Circ Cardiovasc Imaging
January 2011
signed to measure glucose metabolism in the right ventricle
estimated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scans and to determine the relation
between RV function and FDG uptake in patients with HF.
Methods
Patient Population
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Sixty-eight patients were enrolled from 2 sources. First, 60 consecutive
adult patients (⬎18 years of age) with a history of congestive HF who
had a left ventricular (LV) ejection fraction (EF) ⱕ35% as documented
by equilibrium radionuclide ventriculography (ERVG), symptoms consistent with New York Heart Association functional class II-III despite
optimal medical therapy, and a QRS duration ⱖ130 ms based on
baseline ECG who had been recruited for the PREDICT study17 were
prospectively enrolled at the University of Ottawa Heart Institute. This
study evaluated the effect of lateral wall scar on reverse remodeling and
the clinical response to cardiac resynchronization therapy. For the most
part, these patients did not have severe pulmonary hypertension. To
include a patient population with a wider range of pulmonary hypertension, we also included a cohort of 8 consecutive patients with ischemic
cardiomyopathy and significant pulmonary hypertension who were
enrolled in the CADRE database, a regional registry study evaluating
cardiac PET use in Ontario.18 Ischemic etiology was defined as having
both a documented history of myocardial infarction and evidence of
significant coronary artery disease on coronary angiography (at least 1
stenosis ⱖ70% in ⱖ2 major arteries). Significant pulmonary hypertension was defined as a mean pulmonary artery pressure ⱖ40 mm Hg, or
an RV systolic pressure (RVSP) ⬎50 mm Hg on right heart catheterization or echocardiography done within 60 days of the PET study. All
patients enrolled provided informed consent for inclusion. The study
was approved by the human research ethics board of the University of
Ottawa Heart Institute.
Study Procedures
Echocardiographic Assessment of Wall Thickness
Transthoracic echocardiographic analysis was performed with a Phillips
Sonos 5500 ultrasound system. The pressure difference between the
right chambers was calculated from the modified Bernoulli equation:
gradient (⌬P), in mm Hg, ⫽4v2, where v2⫽accelerated velocity across
a stenosis, and the measured Doppler velocity of the regurgitant
tricuspid flow jet. The RVSP (in mm Hg) and right atrial pressure were
assessed by standard recommended techniques.
Wall thickness was measured from 2-dimensional echocardiographic
images. Each measurement was taken 3 times and then averaged. The
diastolic RV free wall was measured in a subcostal view, and parasternal
views were obtained to measure posterolateral LV wall thickness.19
ERVG Imaging and Analysis
Patients underwent ERVG planar imaging at baseline. The ERVGs
were acquired with a standard ECG-gated equilibrium technetium99m red blood cell blood pool imaging protocol.20,21 For quantitative
analysis of global RVEF and LVEF, data obtained from the left
anterior oblique view was used.
PET Rest Perfusion and Metabolic Imaging Protocol
Patients underwent a rest perfusion and a metabolism PET scan. All
patients were required to fast before the PET study and underwent
monitoring of blood glucose levels. Patients were positioned in a
Siemens/CTI (Siemens, Knoxville, Tenn) ECAT ART camera (n⫽52)
or a GE Discovery Rx/VCT camera (n⫽16). A 4-minute cesium-137
single-transmission scan22,23 was performed for attenuation correction in
the Siemens/CTI scanner. For the GE PET system, a scout scan and
low-dose computed tomography (15-cm field of view) were performed.
PET perfusion images were acquired at rest according to a
standard protocol with rubidium-82 or [13N]ammonia as described
previously. Immediately after the transmission scan, 8 to 10 MBq/kg
of rubidium-82 or 5 to 10 MBq/kg of [13N]ammonia was administered intravenously. Static perfusion images were acquired.24,25
For FDG imaging, nondiabetic patients were studied after an oral
glucose load; whereas an insulin-euglycemic clamp was used for
those with diabetes.25–27 A standard dose of 5 MBq/kg (⬍550 MBq)
of FDG was injected intravenously as a bolus 30 minutes after the
glucose load. For diabetic patients with insulin-euglycemic clamp,
plasma glucose levels were checked every 5 minutes. FDG injection
was performed after 3 stable plasma glucose levels were obtained
and stable glycemia was established (optimal glycemia⫽5 mmol/L).
FDG PET image acquisition was started 45 minutes after FDG
injection to ensure accurate myocardial tracer uptake.28
Image Processing
Transverse PET images were reconstructed by Fourier rebinning–
filtered back-projection with a 12-mm 3-dimensional Hann window of
the ramp filter. Photon attenuation and scatter corrections were applied
by ECAT v7.2 software. Automatic reorientation of the images into
short-axis sections was achieved with FlowQuant software.29
Determination of RV and LV Uptakes and Data Analyses
Areas of maximal LV and RV uptake were identified visually on the
static transaxial images. Once identified, 4 small regions of interest
(size ⬎2⫻2 pixels) were drawn on the whole RV free wall,
interventricular septum, whole LV, and LV lateral wall of the
end-diastolic transaxial image. The standardized uptake value
(SUV), a well-established index of tissue FDG uptake per unit
volume, was calculated as follows30: SUV⫽mean region of interest
count (counts per second per pixel)⫻body weight (kg)/injected dose
(mCi)⫻calibration factor (cps/mCi). All measures were performed
twice for both right and left ventricles.
In the subset of patients with RV and LV wall thickness measurements available, partial-volume recovery coefficients (RCs) were
calculated by convolution with a gaussian kernel representing the
reconstructed PET image resolution. Partial volume recovery– corrected FDG activity values were then calculated as SUV/RC.
Analyses
The primary objective of this study was to determine the relation
between RVEF and RV glucose uptake, estimated from RV FDG
SUV as well as the ratio of mean RV SUV to mean LV SUV. The
value of mean RV SUV/peak LV SUV (in regions confirmed to have
normal perfusion) was also determined to correct for any variability
in FDG uptake in the left ventricle owing to previous scar. Secondary
objectives included determination of the relation between RV FDG
uptake and RV size, LVEF and LV size, and RV FDG uptake and
estimates of pulmonary pressures.
Statistical Analysis
All values are expressed as mean⫾SD for normally distributed data and
medians with first and third quartiles for nonnormally distributed data.
Pearson correlation and simple linear regression analyses were used to
relate LVEF and markers of metabolism. Correlation coefficients were
compared by a Z-test after Fisher Z-transforms. Comparisons between
the tertiles of RV FDG groups were made with t tests for unequal
variances and ␹2 tests, where appropriate. All probability values were
2-sided, and a probability value ⬍0.05 was considered statistically
significant. All statistical analyses were performed with STATA software, version 9.2 (Stata Corp, College Station, Tex).
Results
Baseline Characteristics
Table 1 demonstrates the characteristics of the study population. All patients had advanced HF, with a mean LVEF of
21% and a mean RVEF of 35%. Seventy-five percent of patients
were in New York Heart Association class III. Forty-five percent
of the subjects had nonischemic cardiomyopathy. Moderate
pulmonary hypertension was common, with a median RVSP of
52 mm Hg (minimum, 25 mm Hg; maximum, 81 mm Hg). The
average RV wall thickness was 0.45⫾0.074 cm (median, 0.45
cm; interquartile range, 0.42 to 0.5 cm).
Mielniczuk et al
Table 1.
RV Metabolism in Heart Failure
61
Baseline Characteristics of Study Cohort
Total (N⫽68)
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Characteristic
Median age (interquartile range)
or mean⫾SD, y
Female sex
Ischemic cardiomyopathy
NYHA class III
Left bundle branch block
History of hypertension
Current smoker
Diabetes
History of revascularization
Therapies
␤-blockers
ACEI or ARB
Diuretics
Digoxin
Ventricular size/function, median
(interquartile range)
RVEF
LVEF
LVESV
LVEDV
RVSP
Metabolic parameters, median
(interquartile range) or mean⫾SD
RV SUV
LV SUV
RV SUV–LV SUV ratio
T1 or T2 (n⫽46)
69 (60–76)
65⫾12
T3 (n⫽22)
67⫾11
9 (13%)
37 (55%)
51 (75%)
48 (71%)
31 (46%)
13 (19%)
30 (45%)
37(55%)
16%
50%
72%
75%
50%
23%
40%
59%
5%
67%
80%
62%
38%
10%
62%
48%
64 (94%)
65 (95%)
62 (92)
29 (42%)
97%
95%
89%
38%
86%
99%
95%
50%
35% (23–43%)
21% (16–27%)
226 (170–276) mL
285 (242–340) mL
50 (42–62) mm Hg
36⫾11%
23⫾9%
237⫾109 mL
307⫾116 mL
49⫾11 mm Hg
25⫾11%*
19⫾6%
247⫾73 mL
310⫾82 mL
52⫾16 mm Hg
1.7 (1.2–2.4)
2.9 (2.1–3.6)
0.60 (0.51–0.75)
1.7⫾0.9
2.7⫾1.0
0.52⫾0.1
2.2⫾1.9*
2.5⫾1.0
0.87⫾0.23*
T indicates tertile; NYHA, New York Heart Association; ACEI, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; ESV, end-systolic volume; and EDV, end-diastolic volume.
*Denotes a significant difference between tertile 1/2 and tertile 3 (P⬍0.05).
RV Function and FDG Uptake
There was a statistically significant relation between increased
FDG uptake in the right ventricle and decreases in RVEF
(r⫽⫺0.32, P⫽0. 008; Figures 1 and 2). FDG uptake in the right
relative to the left ventricle was represented as (1) the ratio of
Figure 1. Examples of increased RV-LV FDG uptake in the right
ventricle in 2 patients with ischemic cardiomyopathy. Short-axis
images of myocardium demonstrate increased FDG uptake in
the RV free wall. Patient 1 is a 68-year-old male with a previous
anteroseptal myocardial infarction. His LVEF was 20% with an
RVEF of 30%. The RV SUV was 1.9, with a whole LV SUV of
2.55 and an RV-LV ratio of 0.75. Patient 2 is a 59-year-old male
with a previous coronary artery bypass graft, an LVEF of 18%,
and an RVEF of 37%. The RV SUV was 1.7, with a whole LV
SUV of 2.58 and an RV-LV ratio of 0.66.
RV SUV to LV SUV for the entire LV myocardium and (2) the
ratio of RV SUV to LV SUV when limited to uptake in the LV
free wall, given the high proportion of subjects with baseline left
bundle branch block. The ratio of normal RV to whole LV SUV
in healthy volunteers without cardiomyopathy ranged from 0.26
to 0.31, according to data obtained in our laboratory. The
relation between RVEF and relative RV:LV FDG uptake was
also significant, regardless of whether the whole LV was used
(r⫽⫺0.40, P⬍0.01) or the measurement was isolated to the LV
lateral wall FDG uptake alone (r⫽⫺0.43, P⬍0.001; Figure 3).
The significance of the RV-LV ratio was due to increased RV
FDG uptake, as there was no correlation between LV glucose
uptake and RV function or size.
Because FDG uptake may be variable, particularly in ischemic cardiomyopathy, we evaluated the ratio of RV uptake to LV
peak uptake (in segments confirmed to have normal perfusion).
Significant relations were observed similar to those for the ratio
of the mean SUVs. To further evaluate the effect of potential
variability in FDG uptake in the left ventricle of patients with
ischemic cardiomyopathy, the data were stratified by history of
ischemic versus nonischemic cardiomyopathy. Both groups
continued to display a relation between increased RV/LV FDG
uptake and decreases in RVEF (r⫽⫺0.37, P⫽0.04 for nonischemic cardiomyopathy, and r⫽⫺0.47, P⫽0.004 for those with
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Circ Cardiovasc Imaging
January 2011
Figure 2. Pearson correlation between RVEF and RV FDG SUV (A) (r⫽⫺0.32, P⫽0.008) and RV FDG SUV in those in the third tertile
only (r⫽⫺0.2, P⫽0.37) (B).
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ischemic cardiomyopathy). There was also no change between
absolute RV FDG uptake and RVEF in this stratified analysis
(r⫽⫺0.33, P⫽0.05 for nonischemic cardiomyopathy and
r⫽⫺0.33, P⫽0.04 for ischemic cardiomyopathy). In contrast,
LVEF was not related to RV FDG uptake (r⫽0.06, P⫽0.65) nor
the RV-LV FDG uptake ratio (r⫽⫺0.09, P⫽0.49). When
compared with subjects in the first and second tertiles of RV
SUV values, subjects in the third tertile had significantly lower
RVEFs (25⫾11% vs 36⫾25%, Pⱕ0.001) than in the other 2
tertiles (Table 1).
Partial-Volume Effect on RV FDG Uptake Versus
RV Function Relations
To consider the effect of partial volume on FDG measurements owing to differences in RV wall thickness, we evaluated the relations or RV SUV parameters to RVEF in 26
patients who underwent echocardiography within 60 days of
FDG PET. Table 2 shows the relations for the entire data set
and the subset of patients who underwent echocardiography
without and with partial-volume correction of their FDG data.
After correction for partial volume, the correlation coefficients for the relation between RV FDG SUV parameters and
RV function remained significant (Pⱕ0.03 for all 3 relations;
Figure 4) and were numerically greater than values from the
original data set (Table 2). Statistical comparisons between
correlation coefficients were not significantly different, although there was a trend for significant improvement in the
relation between RVEF and RV/whole LV FDG SUV data
when a partial-volume correction was applied (P⫽0.095).
Pulmonary Hypertension and RV Uptake
The majority of patients in this study had some degree of
pulmonary venous hypertension, with a median RVSP or (systolic pulmonary artery pressure, if available) at baseline of
52 mm Hg. Worsening pulmonary hypertension was weakly
related to increased RV FDG uptake (r⫽0.36, P⫽0.04) but not
LV FDG uptake (r⫽⫺0.02, P⫽0.91), nor was it related to the
ratio of whole RV to LV uptake (r⫽0.05, P⫽0.85; Figure 5).
When a partial-volume correction was considered in a smaller
cohort (n⫽16 for whom both RVSP and RV wall thickness
could be determined), the correlation coefficient was not significantly different because the relation was no longer statistically
significant. (r⫽0.19, P⫽0.43 for the subset without a partialvolume correction and r⫽0.05, P⫽0.85 for the subset with a
partial -volume correction; Table 2).
Figure 3. Pearson correlation between RVEF and the ratio of RV FDG SUV to whole LV SUV (r⫽⫺0.40, Pⱕ0.001) and RVEF and the
ratio of RV FDG SUV to LV lateral wall SUV (r⫽⫺0.43, Pⱕ0.001).
Mielniczuk et al
Table 2.
RV Metabolism in Heart Failure
63
Correlations for RVEF and RV SUV Parameters
Correlation
RVEF with
RV SUV uptake
RV/whole LV SUV
RV/LV lateral wall SUV
RVSP with
RV SUV uptake
Column 1
Entire Data Set⫺Original Data
(N⫽68)
Column 2
Echo Subset⫺Original Data
(N⫽26)*
Column 3
Echo Subset⫺Partial-Volume
Corrected Values (N⫽26)*
P Value
for Comparison
(Columns 1 and 3)
P Value
for Comparison
(Columns 2 and 3)
r⫽⫺0.32
P⫽0.008
r⫽⫺0.40,
P⬍0.01
r⫽⫺0.43
P⬍0.001
N⫽68
r⫽0.37
P⫽0.04
r⫽⫺0.22
P⫽0.3
r⫽⫺0.62
P⫽0.001
r⫽⫺0.44
P⫽0.03
N⫽16
r⫽0.19
P⫽0.43
r⫽⫺0.44
P⫽0.03
r⫽⫺0.68
P⫽0.002
r⫽⫺0.59
P⫽0.003
N⫽16
r⫽0.05
P⫽0.85
0.57
0.41
0.095
0.68
0.40
0.55
0.27
0.63
Reproducibility of RV FDG Image Analysis
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To evaluate intraobserver test reproducibility, a subset of
scans from 30% of the total population were reread by the
same image analyst (M.A.) ⬇6 months later. The intraclass
correlation for the whole LV uptake was 0.94 (interquartile
range, 0.84 to 0.98; P⬍0.0001) and 0.99 (interquartile range,
0.97 to 0.99; P⬍0.001) for the whole RV. To evaluate
interobserver test reproducibility, the same subset of scans was
read by 2 independent image analysts (M.A. and M.Z.). The
interclass correlation was 0.99 (interquartile range, 0.97 to 0.99;
P⬍0.0001) for the whole LV uptake and 0.95 (interquartile
range, 0.87 to 0.98; P⬍0.001) for the whole RV.
Discussion
This study demonstrates that RV glucose uptake increases
with decreasing RVEF. The ratio of uptake in the right versus
the left ventricle increased with progressive RV dysfunction,
independent of a history of ischemia and baseline LV glucose
Figure 4. Pearson correlation between RVEF and (A) RV FDG SUV/RC (r⫽⫺0.44, P⫽0.03), (B) the ratio of RV FDG SUV/RC to whole LV
SUV/RC (r⫽⫺0.68, P⫽0.0002), and (C) the ratio of RV FDG SUV/RC to LV lateral wall SUV/RC (r⫽⫺0.59, P⫽0.003).
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Circ Cardiovasc Imaging
January 2011
Figure 5. Pearson correlation between RVSP (or peak systolic
pulmonary pressure) and RV FDG SUV (r⫽0.36, P⫽0.04).
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metabolism. Finally, in a cohort of patients with known LV
failure, the severity of pulmonary hypertension was weakly
correlated to RV glucose metabolism. Importantly, RV FDG
SUV parameters and RVEF relations were not adversely
affected by a partial-volume recovery correction.
Alterations in myocardial substrate metabolism have been
implicated in the pathogenesis of HF and contractile dysfunction.4 – 6 Animal models of left HF have demonstrated that the
progression from cardiac hypertrophy to ventricular dysfunction
is associated with a decrease in the expression of genes coding
for fatty acid oxidation and a shift in metabolism, with glucose
becoming the primary energy substrate.6,31,32 A similar shift in
metabolism has been demonstrated in patients with idiopathic
dilated cardiomyopathy on PET imaging.33 However, it has also
been proposed that the reliance of the myocardium on glucose
may produce a relatively energy-deficient state that, in the long
term, could result in decreased contractile performance.4,5,34,35 It
is possible that although glucose metabolism may be beneficial
in early HF, in the long term this may lead to maladaptive
myocardial responses contributing to the development of worsening HF. An understanding of the alterations and clinical
significance of myocardial metabolism in HF is an important
initial step in developing strategies to target metabolic modulation as a potential therapy for patients with HF.
The evaluation of RV failure is an important goal in the
management of pulmonary artery hypertension, although few
studies have examined RV metabolism in detail. Increased
RV free-wall myocardial glucose utilization has been demonstrated in rat models of pulmonary artery hypertension.36
Oikawa and colleagues30 demonstrated that RV FDG accumulation increased in accordance with the severity of pulmonary vascular resistance in patients with pulmonary artery
hypertension. In contrast to these results, a similar study by
Kluge et al37 suggested that in patients with pulmonary artery
hypertension, the increased ratio of right-left FDG accumulation with increased pulmonary vascular resistance was
unrelated to increased RV FDG, but a corresponding decreased LV FDG accumulation. Importantly, these authors
did identify a significant linear relation between RV FDG
uptake and increasing Tei index, an echocardiographic
marker of progressive RV dysfunction.38
Consistent with the work of Kluge and colleagues,37 the
current study also demonstrated a linear relation between RV
function and RV FDG uptake and a weak but statistically
significant relation between worsening pulmonary pressure and
increased RV FDG.37 However, in contrast to Kluge et al, we did
not identify any relation between RVSP and changes in LV FDG
uptake. This difference may be explained by the fact that in the
study by Kluge et al, all subjects had normal LV systolic
function, whereas in the current study, all subjects had significant LV dysfunction. It is possible that differences in methodology, including glucose loading protocols (with or without
acipamox), and patient populations may explain the heterogeneity of the results regarding RV FDG and pulmonary vascular
resistance. For example, the presence of RV infarction could
potentially contribute to decreased RV FDG uptake. However,
the relation between RVEF and RV FDG metabolism was
similar when the data were stratified by ischemic and nonischemic cardiomyopathy. In addition, the findings were not altered
when corrected for the peak LV SUV in normally perfused
segments. Finally, some heterogeneity may have been due to the
potential time delay between PET scanning and echocardiographic assessment of pulmonary pressures, owing to underlying
lability in this measurement. Further studies are needed to
determine whether the increased RV FDG accumulation promotes or results from progressive RV failure.
Some methodologic limitations require discussion. It is
known that FDG uptake is only a surrogate for true glucose
metabolism; thus, it is possible that the true difference in glucose
metabolism between the 2 ventricles or as it relates to RV
function or afterload might be missed or underestimated. Nevertheless, FDG uptake does provide an in vivo means to probe
alterations in glucose metabolism in the human right ventricle.
Although our inter- and intra-observer variabilities were excellent, data on the reproducibility of RV FDG measurements are
limited. Future studies should consider defining its reliability to
further characterize potential utility in measuring RV metabolism. RVEF and volumes were measured with planar ERVG
imaging. Although planar ERVG is accurate and reproducible
for the left ventricle, the technique is less robust for the right
ventricle. This methodology may also contribute to some underestimation of the correlation between RVEF and RV metabolism. Cardiac magnetic resonance imaging is often considered
the best technique to quantify RV volumes and size.39 However,
in this population, 25% of the patients had either a pacemaker or
an implantable cardioverter/defibrillator, thus making a significant proportion of the study population ineligible for magnetic
resonance imaging. Measurements of RV hypertrophy were
estimated by echocardiographic analysis, which also has limitations owing to poorer resolution compared with magnetic resonance imaging.
Nevertheless, given the potential impact of the partial-volume
effect due to differences in RV wall thickness, we evaluated the
relations of RV SUV parameters to RVEF in a subset of patients.
After correction for partial volume, correlation coefficients were
either similar or numerically increased when compared with the
data without partial-volume correction. This has 2 important
implications: (1) the relations of RV FDG SUV parameters and
RVEF are likely valid observations and (2) the partial-volume
Mielniczuk et al
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correction is important when measuring and interpreting glucose
utilization in the right ventricle.
The correlation coefficients for the relation of RV SUV
parameters to RVSP numerically decreased in the echocardiography subset and after partial-volume correction. These relations
were no longer significant (with or without a partial-volume
correction). This was likely due to loss of statistical confidence
from a much smaller sample size. As such, conclusions regarding RVSP and RV FDG relations must be made with caution.
Whether the relation is partly driven by a partial-volume effect
(in contrast to the RVEF vs RV FDG parameters, which were
not adversely affected by partial-volume correction) will require
evaluation in larger studies.
Many of the patients in the current study were evaluated on
the Siemens/CTI ECAT ART PET system, which has a resolution inferior to most current PET/computed tomography systems. This may have contributed to some of the variability
observed and further emphasizes the importance of partialvolume correction. Data on invasive pulmonary pressures were
not available for all subjects, thus limiting the robustness of
conclusions regarding FDG and pulmonary artery pressure
relations. Although there was a good correlation between invasively measured RVSP and echocardiographic estimates,40 the
relation between hemodynamics and RV metabolism in patients
with left HF needs to be confirmed in future studies involving an
invasive assessment of pulmonary pressures.
The LV SUV values were somewhat lower than previously
reported by Morita et al.41 This likely reflects the nature of
our population, which included patients with ischemic heart
disease and prior infarction as well as those with diabetes. In
addition, 75% of the patient cohort in the current study had a
baseline left bundle branch block, which can also decrease
FDG uptake. Importantly, the RV-LV ratios were comparable
to those in the literature and are the primary focus of our
findings. Finally, an experiment-wide Type I error was not
controlled by any formal procedure and may therefore be
inflated owing to multiple testing.
Right HF worsens the prognosis in patients with cardiopulmonary disease. There is a need for novel management strategies
and patient-specific markers to identify and treat patients at risk.
Accordingly, there are 2 clinically important findings from this
study. First, RV dysfunction appears to be associated with
metabolic changes in substrate utilization. Whether this is an
adaptive or maladaptive response in the pathophysiology of right
HF requires further study. Either way, the relations observed
support the need for investigation of FDG PET as a novel
biomarker that could be a therapeutic target in the treatment of
right HF, whereby determining RV FDG uptake and/or monitoring its response may help optimize treatment to improve RV
function and outcomes. Secondly, partial-volume correction for
PET is important when measuring and interpreting glucose
utilization as a potential biomarker of RV metabolism and needs
to be considered in future studies.
Conclusions
RV FDG accumulation increased with progressive RV dysfunction in a cohort of patients with left HF. The findings support the
need for further research to confirm the utility and prognostic
significance of RV FDG PET imaging. Although partial-volume
RV Metabolism in Heart Failure
65
effects may be problematic in the right ventricle, when a
correction was applied the correlations observed with RV
function did not appear to be adversely affected, and at least 1
parameter trended toward improvement. This supports the validity of the RVEF versus RV FDG parameter observations and
the importance of partial-volume correction in the analysis of
RV metabolism by PET. Whether a shift toward glucose
metabolism in the failing right ventricle has potential long-term
significance as a marker that could influence therapy for RV
dysfunction and failure requires further evaluation in prospective
studies. Such studies are now ongoing.
Sources of Funding
The PREDICT study was funded by a project grant from the J.P.
Bickell Foundation, Toronto (to D.B., primary investigator) and was
supported in part by a program grant from the Heart and Stroke
Foundation of Ontario (No. PRG6242 to R.B., primary investigator).
D.B. is a clinician scientist supported by the Heart and Stroke
Foundation of Ontario, Ottawa. R.B. is a career investigator supported by the Heart and Stroke Foundation of Ontario. M.C.Z. is a
clinical research fellow supported by the University of Ottawa
International Fellowship Award and the Molecular Function and
Imaging Program and supervised by R.S.B. R.S.B., and D.B. were
joint senior investigators for this work.
Disclosures
R.S.B. is a consultant for Lantheus Medical Imaging and DraxImage
and has received research funding from MDS, Nordion, and GE for
unrelated projects and honoraria from Merck. R.A.d.K. is a consultant for DraxImage for unrelated projects.
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CLINICAL PERSPECTIVE
Despite significant improvements in the management of heart failure, morbidity and mortality remain high. The comorbid
association of right ventricular (RV) dysfunction with left heart failure identifies patients with a particularly poor prognosis.
There has been recent clinical interest in the role of metabolic modulation in the treatment of left ventricular dysfunction.
An understanding of the metabolic changes in the right ventricle may serve as a potential target for the management of RV
failure. This study was designed to characterize myocardial metabolism in the right ventricle of patients with left
ventricular failure. RV dysfunction was associated with an increase in RV glucose uptake. This metabolic change was
correlated with the severity of RV dysfunction. Larger, prospective studies are required to define the potential clinical
implications of this metabolic adaptation.
Relation Between Right Ventricular Function and Increased Right Ventricular [18
F]Fluorodeoxyglucose Accumulation in Patients With Heart Failure
Lisa M. Mielniczuk, David Birnie, Maria C. Ziadi, Robert A. deKemp, Jean N. DaSilva, Ian
Burwash, Anthony T. Tang, Ross A. Davies, Haissam Haddad, Ann Guo, May Aung, Kathryn
Williams, Heikki Ukkonen and Rob S.B. Beanlands
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Circ Cardiovasc Imaging. 2011;4:59-66; originally published online November 5, 2010;
doi: 10.1161/CIRCIMAGING.109.905984
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