* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Relation Between Right Ventricular Function and Increased Right
Survey
Document related concepts
Electrocardiography wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Mitral insufficiency wikipedia , lookup
Heart failure wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Cardiac surgery wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Coronary artery disease wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Myocardial infarction wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Jatene procedure wikipedia , lookup
Atrial septal defect wikipedia , lookup
Dextro-Transposition of the great arteries wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Transcript
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 60 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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) Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 62 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). Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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). 64 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). Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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. References 1. Ristow B, Ali S, Ren X, Whooley MA, Schiller NB. Elevated pulmonary artery pressure by Doppler echocardiography predicts hospitalization for heart failure and mortality in ambulatory stable coronary artery disease: the Heart and Soul Study. J Am Coll Cardiol. 2007;49:43– 49. 2. Ghio S, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini F, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001;37:183–188. 3. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G, American College of Chest Physicians. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:78S–92S. 4. Massie BM, Schaefer S, Garcia J, McKirnan MD, Schwartz GG, Wisneski JA, Weiner MW, White FC. Myocardial high-energy phosphate and substrate metabolism in swine with moderate left ventricular hypertrophy. Circulation. 1995;91:1814 –1823. 5. Liao R, Nascimben L, Friedrich J, Gwathmey JK, Ingwall JS. Decreased energy reserve in an animal model of dilated cardiomyopathy: relationship to contractile performance. Circ Res. 1996;78:893–902. 6. Barger PM, Kelly DP. Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci. 1999;318: 36 – 42. 7. Chandler MP, Kerner J, Huang H. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 1994;287:H1538 –H1543. 8. Osorio JC, Stanley WC, Linke A. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-␣ in pacinginduced heart failure. Circulation. 2002;106:606 – 612. 9. Kalsi KK, Smolenski RT, Pritchard RD, Khaghani A, Seymour AM, Yacoub MH. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy. Eur J Clin Invest. 1999;29:469–477. 10. Razegh P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation. 2001;104:2923–2931. 11. Taylor M, Wallhaus TR, DeGrado TR, Rusell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F] fluoro-6-thiaheptadeconoic acid and [18F] FDG in patients with congestive heart failure. J Nucl Med. 2001;42:55– 62. 66 Circ Cardiovasc Imaging January 2011 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 12. Adrogue JV, Sharma S, Ngumbela K, Essop MF, Taegtmeyer H. Acclimatization to chronic hypobaric hypoxia is associated with a differential transcriptional profile between the right and left ventricle. Mol Cell Biochem. 2005;278:71–78. 13. Zaffran S, Kelly RG, Meilhac SM, Buckingham ME, Brown NA. Right ventricular myocardium derives from the anterior heart field. Circ Res. 2004;95:261–268. 14. Baudet S, Kuznetsov A, Merciai N, Gorza L, Ventura-Clapier R. Biochemical, mechanical and energetic characterization of right ventricular hypertrophy in the ferret heart. J Mol Cell Cardiol. 1994;26:1573–1586. 15. Bristow MR, Zisman LS, Lowes BD. The pressure-overloaded right ventricle in pulmonary hypertension. Chest. 1998;114:101S–106S. 16. Taegtmeyer H. Genetics of energetics: transcriptional responses in cardiac metabolism. Ann Biomed Eng. 2000;28:871– 876. 17. Birnie D, deKemp R, Ruddy T, Tang AT, Guo A, Williams K, Wassenar R, Beanlands R. Effect of lateral wall scar on reverse remodeling with cardiac resychronization therapy. Heart Rhythm. 2009;6:1721–1726. 18. Ziadi MC, deKemp RA, Renaud JM, Etele J, Guo A, Williams K, Davies RA, Chow B, Ruddy RD, Hessian R, DaSilva J, Iwanochko M, Marriott C, Wisenberg G, Ficaro EP, Garrard L, Beanlands RSB. PET imaging positively impacts management direction and predicts outcome in a multicenter ‘real world’ setting. Circulation. 2009;120:S349. 19. Teresa SM, Tsang TS. In: Murphy JG, Lloyd MA, eds. Principles of Echocardiography, 3rd ed. London Informa Healthcare; 2007;0267: 117–142. 20. Wackers FJTh, Bruni W, Zaret BL. Planar equilibrium radionuclide angiocardiography: acquisition and processing protocols: In: Nuclear Cardiology: The Basics. Totowa, NJ: Humana; 2003:81. 21. Starling MR, Dell’Italia DJ, Walsh RA, Little WC, Benedetto AR, Nusynowitz ML. Accurate estimates of absolute ventricular volumes from equilibrium radionuclide angiographic count data using a simple geometric attenuation correction. J Am Coll Cardiol. 1984;3:789 –792. 22. Zaret BL. Cardiac performance. In: Zaret BL, Beller GA, eds. Clinical Nuclear Cardiology: State of the Art and Future Directions. 3rd ed. Philadelphia: Elsevier; 2010:175–187. 23. Schelbert HR, Beanlands R, Bengel F, Knuuti J, Dicarli M, Machac J, Patterson R. PET myocardial perfusion and glucose metabolism imaging, part 2: guidelines for interpretation and reporting. J Nucl Cardiol. 2003; 10:557–571. 24. Yoshinaga K, Chow BJ, Willaims K, Chen L, deKemp RA, Garrard L, Lok-Tin Szeto A, Aung M, Davies RA, Ruddy T, Beanlands R. What is the prognostic value of myocardial perfusion imaging using rubidium-82 positron emission tomography? J Am Coll Cardiol. 2006;48:1029 –1039. 25. Beanlands RS, Ruddy TD, deKemp RA, Iwanochko RM, Coates G, Freeman M, Nahmias C, Hendry P, Burns RJ, Lamy A, Mickelborough L, Kostuk W, Fallen E, Nichol G. Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function. J Am Coll Cardiol. 2002;40:1735–1743. 26. Machac J, Bacharach SL, Bateman TM, Bax JJ, Beanlands R, Bengel F, Bergmann SR, Brunken RC, Case J, Delbeke D, DiCarli MF, Garcia EV, Goldstein RA, Gropler RJ, Travin M, Patterson R, Schelbert HR. Quality Assurance Committee of the American Society of Nuclear Cardiology. Positron emission tomography myocardial perfusion and glucose metabolism imaging. J Nucl Cardiol. 2006;13:e121– e151. 27. Vitale GD, deKemp RA, Ruddy TD, Williams K, Beanlands RS. Myocardial glucose utilization and optimization of 18F-FDG PET imaging in patients 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. with non–insulin-dependent diabetes mellitus, coronary artery disease, and left ventricular dysfunction. J Nucl Med. 2001;42:1730–1736. Beanlands RS, Nichol G, Huszti E, Humen D, Racine N, Freeman M, Gulenchyn KY, Garrard L, deKemp R, Guo A, Ruddy TD, Benard F, Lamy A, Iwanochko RM. PARR-2 Investigators. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized controlled trial (PARR-2). J Am Coll Cardiol. 2007;50:2002–2012. deKemp RA, Nahmias C. Automated determination of the left ventricular long axis in cardiac positron emission tomography. Physiol Meas. 1996; 17:95–108. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J, Shirato K. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45:1849 –1855. Kantor PF, Robertson MA, Coe J, Lopaschuk GD. Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J Am Coll Cardiol. 1999;33:1724 –1734. Christie ME, Rogers RL. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol. 1994; 26:1371–1375. Davila-Roman VG, Vedala G, Herrero, de las Fuentes L, Rogers J, Kelly DP, Gropler RJ. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2002;40:271–277. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K. Myocardial phosphocreatineto-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96:2190 –2196. Chiu HC, Kovacs A, Ford DA, Hsu F, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest. 2001;107:813– 822. Takeyama D, Kagaya Y, Yamane Y, Shiba N, Chida M, Takahashi T, Ido T, Ishide N, Takishima T. Effects of chronic right ventricular pressure overload on myocardial glucose and free fatty acid metabolism in the conscious rat. Cardiovasc Res. 1995;29:763–767. Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H, Seyfarth H, Steinbach J, Sabri O, Winkler J. Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension. J Nucl Med. 2005;46:25–31. Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, Seward JB. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function-a study in normals and dilated cardiomyopathy. J Cardiol. 1995;26: 357–366. Benza R, Biederman R, Murali S, Gupta H. Role of cardiac magnetic resonance imaging in the management of patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;52:1683–1692. Mukerjee D, St George D, Knight C, Davar J, Wells AU, duBois RM, Black CM, Coghlan JG. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology. 2004;43:461– 466. Morita K, Yoshinaga K, Noriyasu K, Mabuchi M, Tasubamoto T, Kageyama, Shiga T, Tamaki N. Quantitative analysis of myocardial glucose utilization in patients with left ventricular dysfunction by means of 18F-FDG dynamic positron tomography and three-compartment analysis. Eur J Nucl Med Mol Imag. 2005;32:806 – 812. 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 Circ Cardiovasc Imaging. 2011;4:59-66; originally published online November 5, 2010; doi: 10.1161/CIRCIMAGING.109.905984 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2010 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. Online ISSN: 1942-0080 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circimaging.ahajournals.org/content/4/1/59 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Imaging can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Imaging is online at: http://circimaging.ahajournals.org//subscriptions/