| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | RSS | TABLE OF CONTENTS |
|
|
|
||||||||
|
||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Clinical Investigation |
1 Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; 2 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands; 3 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 4 Department of Cardiology, AZ Maria Middelares, Ghent, Belgium; 5 Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands; and 6 Department of Surgery, Division of Vascular Surgery, University Medical Center Groningen, Groningen, The Netherlands
Correspondence: For correspondence or reprints contact: Riemer H.J.A. Slart, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. E-mail: r.h.j.a.slart{at}ngmb.umcg.nl
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Key Words: positron emission tomography • myocardial blood flow quantification • coronary artery disease • endothelial function • prognosis • LV function
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
In previous studies, the prognostic value of myocardial perfusion reserve (MPR) was established in patients without coronary artery disease (7), in patients with hypertrophic cardiomyopathy (8,9), and in patients with idiopathic left ventricular dysfunction (10,11). Whether this prognostic value holds true for patients with epicardial IHD is unknown. Therefore, we investigated whether, in comparison with left ventricular ejection fraction (LVEF), MPR assessed with PET using absolute myocardial blood flow quantification and perfusion reserve can predict survival in a large group of patients with IHD.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
|
PET
The patients underwent dynamic rest 13N-ammonia, dipyridamole stress 13N-ammonia, and gated 18F-FDG PET using a 1-d protocol, as described previously (12). Briefly, PET studies were performed after the patients had discontinued vasoactive medication for 5 plasma half-lives and had refrained from caffeinated beverages for a minimum of 12 h. Imaging was performed with the patient supine and used an ECAT 951 positron camera (Siemens CTI). Thirty-one planes were measured simultaneously over a length of 10.8 cm. The measured resolution of the system was 6 mm in full width at half maximum. Data were automatically corrected for accidental coincidence and dead time. Patients were positioned with the help of a rectilinear scan. Photon attenuation was measured using a retractable external ring source filled with 68Ge/68Ga. Perfusion imaging was performed after dipyridamole had been infused (0.56 mg/kg in 4 min). Imaging was started by injecting 400 MBq of 13N-ammonia 6 min after the start of dipyridamole infusion and continued for 15 min.
To stimulate 18F-FDG uptake, patients were given 75 g of glucose orally just before scanning or were given 500 mg of acipimox (Nedios; Byk Pharmaceuticals) orally 90 min before scanning to lower circulating free fatty acids (13). To prevent side effects of acipimox (e.g., skin rash), 250 mg of aspirin were administered orally 5 min before acipimox. In diabetic patients, 18F-FDG imaging was done with hyperinsulinemic euglycemic glucose clamping (14). After the 13N-ammonia data had been acquired, 200 MBq of 18F-FDG were injected intravenously, followed by a PET dynamic acquisition. The total 18F-FDG PET acquisition time was 40 min, with the last 20 min acquired in gated mode with 16 frames per cardiac cycle. The length of each gate was based on the current R-R interval. The R-R interval was allowed to vary by ±10%. Data were corrected for attenuation using the transmission scan and were reconstructed using filtered backprojection (Hann filter, 0.5 pixels/cycle).
Kinetic Models and Data Analysis
From the PET data, dynamic parametric polar maps were constructed (12). PET perfusion data at rest were corrected for rate–pressure product. Myocardial blood flow data were corrected for partial-volume effect and spillover and quantified by the model of Hutchins et al. (6). Briefly, myocardial and blood time–activity curves derived from regions of interest over the heart and ventricular chamber are fitted using a 3-compartment model for 13N-ammonia, yielding rate constants for tracer uptake and retention. Perfusion flow reserve (dipyridamole-to-rest ratio) was calculated by dividing the dipyridamole 13N-ammonia stress study by the 13N-ammonia rest study.
Data analysis of 18F-FDG was performed with PATLAK analysis (15).
Mismatch was quantified by first normalizing the 18F-FDG uptake polar map and the dipyridamole blood flow polar map to their means. Then, a difference polar map was created by subtracting the normalized dipyridamole blood flow polar map from the normalized 18F-FDG uptake polar map. Mismatch was calculated as the percentage myocardium above the 95% confidence interval of the normal database, and results were expressed as percentage of the total myocardium. Similarly, matching areas were quantified by constructing a product polar map; the normalized dipyridamole blood flow polar map was multiplied by the normalized 18F-FDG uptake polar map. Match was defined as the percentage myocardium below the 95% confidence interval. The extent of mismatching areas (viable myocardium) and matching areas (nonviable myocardium) was calculated from these data as previously described (12).
The last frames (20-min acquisition time) of the dynamic gated 18F-FDG PET studies were summed and transformed into static studies and used for further data analysis with the help of the quantitative gated SPECT program (15). Based on the gated 18F-FDG images, left ventricular end-systolic and end-diastolic volumes, as well as LVEF, were computed.
Statistical Analysis
Descriptive results are expressed as mean ± SD. Categoric measures are presented as frequencies with percentages. Crude data were compared across tertiles of MPR, defined as perfusion during dipyridamole divided by resting perfusion, with the 
2 test for trend (dichotomous variables) and generalized linear models (continuous variables). The significance of MPR, controlled for important risk modifiers as presented in Table 1 (P < 0.20), was examined with multivariable Cox proportional hazards regression analyses by using fractional polynomials (16). Results are summarized by hazard (risk) ratios with confidence intervals based on robust SE estimates. To assess the prognostic value of LVEF and MPR adjusted for age and sex, Harrell's C-statistic was computed (comparable to the area under the receiver-operating-characteristic curve). Model fit was assessed with Bayesian information criterion statistics, which are goodness-of-fit measures adjusted by degrees of freedom and sample size. Smaller Bayesian information criterion values indicate that the model fits better. A difference of 10 points or more between a given model and the other model is strong evidence for a significantly better goodness of fit. The significance level was set at 0.05. Observations with missing values for contributing variables in the multivariate model were excluded. The statistical analysis was performed with SPSS (SPSS Inc.), version 9.1, and STATA statistical software, release 10.0 (StataCorp LP).
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Outcome Event
The median follow-up among survivors was 85 mo (range, 1–138 mo). Among the 344 patients in this study, there were a total of 85 deaths (25%), of which 60 (17%) were cardiac deaths. Twenty-five patients (7%) experienced a nonfatal myocardial infarction. A total of 71 patients (21%) underwent a PCI and 27 a CABG (8%) during follow-up.
Hazard Ratio of MPR
Table 2 summarizes the results of the Cox regression analysis for cardiac death. In the univariate analysis, the parameters significantly associated with cardiac death were MPR; family history; previous myocardial infarction; LVEF; left ventricular end-diastolic volume; the use of aspirin, diuretics, or digoxin; and matching. After controlling for age and sex, the following parameters were associated with cardiac death: MPR, family history, previous myocardial infarction, LVEF, left ventricular end-diastolic volume, aspirin, diuretics, and digoxin. MPR was associated with a hazard ratio for cardiac death of 4.11 (95% confidence interval, 2.98–5.67) per SD decrease, whereas the risk for LVEF was 2.76 (2.00–3.82) per SD decrease. Interestingly, the prognostic value of MPR was independent of the extent of matching and mismatching defects. Survival data for each MPR tertile are shown in Figure 1. The hazard function of MPR, when compared with LVEF, was steeper in a prognostic model adjusted for age and sex, resulting in improved C-statistics and Bayesian information criterion statistics (0.83, 605 vs. 0.77, 620) (Fig. 2). Finally, in a secondary mutually adjusted multivariate analysis of MPR; family history; previous myocardial infarction; LVEF; left ventricular end-diastolic volume; the use of aspirin, diuretics, or digoxin; and percentage matching defects, the parameters that remained statistically significant in the model were MPR, LVEF, and the use of diuretics (hazard ratios of 4.08 [2.50–6.65, P < 0.001], 1.91 [1.10–3.31, P = 0.021], and 2.19 [1.07–4.97, P = 0.033], respectively).
|
|
|
Interestingly, the prognostic value of MPR for cardiac death and major adverse cardiac events was independent of whether patients received a PET-driven medical strategy or a revascularization strategy and of the extent of matching or mismatching defects.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Although the prognostic value of MPR in subgroups of patients without obstructive coronary artery disease has been established, the prognostic value of PET in patients with obstructive coronary artery disease has been evaluated only with respect to areas of matching or mismatching defects (16). In previous studies, an association between the presence or extent of ischemic myocardial area and survival has been described (16–18). In 2 of these studies, the presence of mismatching defects (without absolute quantification) has been described in relation to prognosis (17,18). In contrast to the previous studies, we did not find an association between the presence or extent of mismatching defects and prognosis. The percentage of patients with a previous myocardial infarction (52%–87%) was comparable to that in our study group (73%). An explanation may be that in our patient group a larger proportion of patients had undergone a previous coronary intervention: 26% CABG and 43% PCI in our group, versus 6%–10% and 8%–9%, respectively, in the study of Desideri et al. (16) or even as low as 3% in the study of Wiggers et al. (18). The higher percentage of patients with a previous revascularization may have resulted in much smaller ischemic areas (10% ± 10%) in our study than in the previous study by Desideri et al. (36%–58%). Previous SPECT perfusion imaging studies are also in line with our MPR data: increasing perfusion abnormalities were associated with worsening prognosis (19). However, SPECT is not able to quantify absolute perfusion and may underdiagnose ischemia in patients with severe 3-vessel or left main coronary disease.
Our group is comparable to a previously studied group of ischemic heart failure patients with respect to the high rate of prior interventions (20). In that study, patients with ejection fractions of 23% ± 7% were evaluated. It appeared that in approximately 12% of these patients, viable myocardial segments (ischemia or hibernation) were present. These patients underwent a revascularization procedure if possible. Interestingly, in the lowest-tertile MPR group of our study, survival rates were comparable to those of the intervention group in the previous study, despite the fact that patients in our group had higher LVEFs. In contrast, patients in the higher MPR tertiles had better survival rates. Our study group consisted of a mixed population with regard to LVEF and was comparable to patients seen in clinical practice.
We did not analyze regional perfusion defects, but the fact that global perfusion reserve has such an impact on prognosis may relate to vascular dysfunction that has extended beyond the areas of stenotic coronary arteries. MPR depends mainly on the dilatory capacity of the prearteriolar sphincters in the microvasculature. Microvascular function is determined by metabolic need, structural changes, neurohumoral factors, autonomic innervation, extravascular resistance, and endothelial function. Among these factors, the endothelial component has been investigated the most extensively. Microvascular dysfunction can be found in patients without myocardial or obstructive coronary artery disease and is most often related to conventional risk factors such as smoking (21), hyperlipidemia (22,23), and diabetes (23). In addition, microvascular dysfunction can be the cause of angina pectoris in the absence of epicardial coronary disease, or the so-called syndrome-X (24). Myocardial perfusion abnormalities may influence myocardial contractility, but left ventricular dysfunction can also be mirrored by myocardial perfusion abnormalities (25).
In dilated cardiomyopathy, we have previously shown that despite the absence of IHD, regions with a lower MPR are present (11). The present study further expands these perfusion reserve data to patients with coronary artery disease. MPR can be considered a reflection of global ischemia and hence of the severity of coronary artery disease and left ventricular dysfunction. On the one hand, ischemia may lead to left ventricular dysfunction, but on the other hand, left ventricular dysfunction may cause abnormalities in the microvasculature (25).
Our study had some limitations. Because of the long follow-up period, a large proportion of patients underwent PET in the early 1990s. As a consequence, many patients with heart failure were still on digoxin therapy. However, the results did not differ between these patients and patients on angiotensin-converting-enzyme inhibitors. The metabolic state of the patients was not assessed at the moment of PET; however, neither fasting glucose levels nor diabetes mellitus influenced our multivariate model. The implication is that MPR is a robust determinant of prognosis, independent of the metabolic state of the patients. Furthermore, all scans were executed under glucose clamping.
This study did not evaluate regional MPR. Although MPR in this patient group can be expected to show regional differences, global MPR was found to be an important prognostic indicator. This finding may reflect global and not just regional coronary vascular failure. In comparison, dilated cardiomyopathy patients with a left bundle branch block have a lower global perfusion than do patients with no left bundle branch block, despite a heterogeneous perfusion pattern (26).
Finally, one could question what the clinical significance of MPR measurements in these patients is. Most of these patients were not amenable to coronary intervention. We believe that this may be quite relevant because the low MPR may argue in favor of a coronary intervention and of optimally treating patients with a tailored approach to improve endothelial and vascular function.
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
|
FOOTNOTES |
|---|
COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.
|
References |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Related articles in JNM:
This article has been cited by other articles:
|
|
 |
|
  R. J. Gibbons, P. A. Araoz, and E. E. Williamson The Year in Cardiac Imaging J. Am. Coll. Cardiol., February 2, 2010; 55(5): 483 - 495. [Full Text] [PDF]
|
|
|
|
|
|
R. S.B. Beanlands, M. C. Ziadi, and K. Williams Quantification of Myocardial Flow Reserve Using Positron Emission Imaging The Journey to Clinical Use. J. Am. Coll. Cardiol., July 7, 2009; 54(2): 157 - 159. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | RSS | TABLE OF CONTENTS |
| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
