Myocardial viability in patients with ischemic cardiomyopathy— evaluation by 3-D integration of myocardial scintigraphic data—and coronary angiographic data

doi:10.1016/j.mibio.2004.02.002

ARTICLE

Molecular Imaging and Biology Vol. 6, No. 3, 160–171. 2004 Copyright 쑖 2004 Elsevier Inc. Printed in the USA. All rights reserved. 1536-1632/04 $–see front matter

Myocardial Viability in Patients with Ischemic Cardiomyopathy— Evaluation by 3-D Integration of Myocardial Scintigraphic Data—and Coronary Angiographic Data Thomas H. Schindler, MD1,2, Egbert U. Nitzsche, MD1,2, Nobuhisa Magosaki, MD1, Michael Mix, MSc1, Alvaro D. Facta, MD2, John O. Prior, MD, PhD2, Ulrich Solzbach, MD1, Heinrich R. Schelbert, MD, PhD2, Hanjoerg Just, MD1 1

The Center of Clinical Research II: Cardiovascular Diseases at the Albert-Ludwig-University Freiburg, Division of Cardiology and Nuclear Medicine, Freiburg, Germany; 2Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA PURPOSE: To determine the prevalence of viable myocardium in patients with ischemic cardiomyopathy and, to evaluate the value of three-dimensional (3-D) fusion imaging of myocardial scintigraphic and angiographic data to assign coronary artery lesions to the corresponding viable and nonviable myocardial territory. PROCEDURES: In 105 patients, the combination of perfusion and metabolic imaging with 201thallium (201TI) single-photon emission computed tomography (SPECT) and 2-deoxy2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) determined viability in dysfunctional myocardium. In addition, the value of 3-D scintigraphic fusion imaging was assessed in these patients. RESULTS: Based on the presence of viable dysfunctional myocardium, 54% of patients with ischemic cardiomyopathy may be considered for coronary revascularization. In 31 of 105 patients, the 3-D fusion imaging was estimated to be helpful in the diagnostic and interpretative process. CONCLUSION: In patients with end-stage coronary artery disease scintigraphic imaging is most important in the decision-making process. Three-dimensional fusion imaging may add important information in approximately 30% of these patients. 쑖 2004 Elsevier Inc. All rights reserved. Key Words: Angiography; Cardiomyopathy; Coronary disease; Tomography; 3-D fusion imaging; Viability.

Introduction linical investigations1–4 have demonstrated that in patients with ischemic cardiomyopathy, restoration of coronary blood flow to viable myocardium improves prognosis and heart failure symptoms. Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoroD-glucose (FDG) and 201thallium (201TI) single-photon

C

Address correspondence to: Thomas H. Schindler, MD, Department of Molecular and Medical Pharmacology Radiological Science, Nuclear Medicine UCLA, School of Medicine B2-045J CHS, Box 956948 Los Angeles, CA 90095-6948. E-mail: [email protected]

160

emission computed tomography (SPECT) identifies viable tissue in myocardial segments demonstrating a perfusion-metabolism mismatch.1,5 Restoration of myocardial blood flow to segments with such mismatchpattern is predictive of the recovery of regional and possibly of global left ventricular function,2,3 depending on the anatomic extent of myocardial viability as determined preoperatively.3,4 Thus, the determination of presence and extent of myocardial viability is important for patients with ischemic cardiomyopathy who might benefit from coronary revascularisation, both prognostically and functionally.4,6

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

For evaluation of viable myocardium on 2-D scintigraphic images the myocardial territories are arbitrarily assigned to three major coronary artery systems.7 However, due to a considerable interpatient variability of the anatomic coronary artery tree the standard myocardial distribution correspond only in 50% to 60% of patients.8 In addition, the information of both 2-D images of coronary angiography and myocardial scintigraphy, which is typically reviewed through mental integration, does not necessarily allow an accurate assignment of regional myocardial perfusion territory to the corresponding vessel segment, in particular in patients after coronary artery bypass grafting (CABG) with further alterations of the coronary anatomy. To this end, an image approach that also presents the three-dimensional (3-D) reconstructed coronary artery tree with 3-D myocardial scintigraphic perfusion images can be applied for accurate assignment of regional myocardial territories to the corresponding vessel segment.9,10 The aims of this study were to determine the prevalence of myocardial viability in patients with ischemic cardiomyopathy; and to evaluate the value of a 3-D scintigraphic fusion technique of both myocardial scintigraphic and angiographic data to assign coronary artery lesions to the corresponding viable and nonviable myocardial territory.

Methods Patients The study population consisted of 105 patients (69 men, 36 women, mean age 61 ⫾ 7 years) who were referred to the PET center of the University of Freiburg between June 1996 and January 2000. The study protocol was approved by the local Ethics Committee of the University of Freiburg, and all patients gave written informed consent. All patients had ischemic cardiomyopathy, as documented angiographically, and a history of myocardial infarction. Patients were included in the study, if they were in the New York Heart Association (NYHA) functional class II and III and had a left ventricular ejection fraction ⱕ40% as measured by 2-D echocardiography (Figure 1). Coronary angiography was performed in all patients. The criteria for evaluating the angiographic extent of coronary artery disease was a significant stenosis defined as percent diameter stenosis of more than 50% and, for study purposes, defined as more than 90% (high grade lesion) by visual estimation.11 A complete history was available by chart review in 99 (94%) patients. Clinical data of study patients were obtained retrospectively by chart review to evaluate how the assessment of blood flow-metabolism scintigraphic imaging influenced the clinical management decision to proceed with medical therapy, revascularization, or cardiac transplantation.

161

The study protocol included following analysis (Figure 1). In each patient, FDG-PET and 201TI SPECT images were visually analyzed and graded for blood flow/metabolism match (concordant reduction in 201TI and FDG activity scores) and mismatch (more severely reduced in 201TI uptake than the reduction in glucose metabolic activity) on 2-D images. Subsequently, the influence of the match and mismatch findings on these 2-D images on the clinical management decisions was evaluated retrospectively by chart review. In addition, in 35 patients echocardiographic studies to evaluate left ventricular ejection fraction six months after coronary revascularisation were available. However, 3-D myocardial scintigraphic data and 3-D angiographic data were fusioned for an integrated 3-D display (Figure 1). An expert reading for the interpreting the of the 3-D fusion image for the assignment of match and mismatch findings to the corresponding coronary lesions was performed.

PET and SPECT Image Acquisition Myocardial viability by PET with FDG and myocardial perfusion at rest was measured by SPECT with 201TI in all patients.1,7,12 PET images were acquired with an ECAT 921/31 system (Siemens; Erlangen, Germany) (Figure 1). Myocardial scintigraphic techniques were performed within one month (mean 18 ⫾ six days) of diagnostic coronary angiography. All studies were performed after the patients had fasted for at least four hours. Using standard acquisition protocols,1,13 patients were given 50 g oral glucose one hour before the FDG injection. Serum glucose levels were measured every 30 minutes. Intravenous, regular 1 IU insulin was used if after glucose load plasma glucose levels were ⬎120mg/ dl in all patients to optimize myocardial FDG uptake. A short transmission image was performed to localize the heart within the axial field of view of the camera, followed by a 15- to 20-minute transmission image for attenuation correction. In the decline phase of serum glucose response to administered oral glucose plus insulin (when required), approximately 10mCi of FDG were injected intravenously. A single static 15- to 20-minute emission image was acquired between 30 to 60 minutes after tracer injection. Delayed imaging was performed when myocardial FDG uptake was poor. The transaxial acquired images were realigned into short axis, horizontal and long-axis, and vertical long-axis projections. 201

TI SPECT Imaging

In 74 of 105 patients a graded bicycle exercise, starting at 25 W with an increment of 25 W every three minutes, was performed, whereas the remaining patients underwent pharmacological stress with standard dose dipyridamole (0.56 mg/kg) or adenosine (140 µg/kg/min)

162 Molecular Imaging and Biology, Volume 6, Number 3

Coronary Angiography Inclusion Criteria: Patients with ischemic cardiomyopthy presenting NYHA functional class II – III and LVEF ≤ 40

18

F-FDG-PET-and 201TISPECT -Scanning

2D Visual Analysis: PET and SPECT Images

3D Integration: Myocardial Scintigraphic and Angiographic Data

Assessment of: Scintigraphic myocardial mismatch or match pattern

Echocardiographic Follow-up: 6 months after coronary revascularisation

Clinical Management Decisions

Expert Reading: Assignment of Coronary Arteries to the Myocardial Territory on corresponding 2D images and 3D Image Fusion Display

Figure 1. Study protocol. NYHA ⫽ New York Heart Association; LVEF ⫽ left ventricular ejection fraction; PET ⫽ Positron emission tomography; SPECT ⫽ single photon emission computed tomography.

stress imaging, either alone or combined with graded bicycle exercise.9,14 A series of transaxial slices were reconstructed with a filtered backprojection without using attenuation correction for uniform attenuation and compton scatter. Oblique tomograms parallel to the long and short axes of the left ventricle were also reconstructed. Redistribution 201TI images were obtained three to four hours after stress, while the patients were resting. Finally, for study purpose to assess myocardial viability only the redistribution 201TI images at rest were compared to the FDG-PET images.

2-D Visual Analysis of PET and SPECT Images In each patient, corresponding transaxial tomograms from the two sets of 201TI images representing the exercise and redistribution images were aligned for direct comparison. These, in turn were then aligned with the corresponding transaxial tomographic images of myocardial FDG uptake from the PET study. Thus, corresponding myocardial slices from the PET and SPECT data were analyzed for each patient, with an average of six tomographic planes evaluated per patient (Figure

1). The left ventricle was divided into a 19-segment model15 as reconstructed for nuclear cardiology procedures:7 the basal, middle, and apical portions of the anterior septum and anterior wall, anterolateral and inferolateral walls, and inferior wall and inferior septum; and the apex as single myocardial segment. Two readers unaware of the patients’ history independently graded FDG and 201TI uptake defects on a four-point scale: 0 ⫽ normal, 1 ⫽ mildly reduced, 2 ⫽ moderately reduced, and 3 ⫽ severely reduced. Myocardium was defined as normal when the 201TI uptake on SPECT was scored as 0, regardless of the FDG uptake on PET. A concordant reduction in 201TI and FDG activity scores was classified as a blood flow/metabolism match, subsequently referred to as nonviable myocardium. A reduction in 201TI uptake more severe than the reduction in glucose metabolic activity by ⱖ1 point was defined as a blood flow/metabolism mismatch, subsequently referred to as viable myocardium.15

3-D Scintigraphic Cardiac Fusion Image On the 3-D scintigraphic fusion images, regions with perfusion defects at rest were classified on visual analysis

163

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

as a match when both 201TI and FDG uptake were concordantly reduced, or a mismatch when regional FDGuptake was increased relative to perfusion (Figure 1).12 Detail on 3-D scintigraphic myocardial fusion images has been described previously.10,16,17 For image fusion, the meridian coordinates of the scintigraphic myocardial surfaces were shifted to corresponding values of the coronary tree.9,10,16,18

Expert Reading Scintigraphic match and mismatch findings on the 3-D image fusion display were assigned to the corresponding vascular territories by two expert readers. In the case of disagreement between observers, consent was achieved in a joint reading. The sessions for interpreting the 2D scintigraphic images and angiographic images, as well as the 3-D image fusion display were performed at least 10 days apart. Scintigraphic match and mismatch findings were assigned to the left anterior descending (LAD), left circumflex (LCX), right coronary artery (RCA), the diagonal branch (Dx), the posterolateral branch (LPL), the obtuse marginal (OM), and septal branch (S). An additional value of the 3-D scintigraphic fusion image was defined if one of two independent and experienced investigators estimated and recorded the 3-D image fusion display to be helpful to facilitate the assignment of the coronary artery lesions to the corresponding myocardial match and mismatch territory as compared to the separate analysis of 2-D images of myocardial scintigraphy and coronary angiography.

percent reported anginal symptoms. The study population consisted of patients with single and multiple coronary risk factors (Table 1). All patients were in the New York Heart Association (NYHA) functional class II and III and presented a mean left-ventricular ejection fraction of 26 ⫾ 7%. Coronary angiography performed in all patients revealed single vessels disease in 10 (10%), double vessel disease in 23 (21%), and triple vessel disease in 72 (69%) (Table 1). A total of 240 coronary lesions, as defined as ⱖ50% narrowing of the epicardial diameter, were identified in coronary angiography. Of these, 196 represented high-grade coronary lesions, as defined by ⱖ90% stenosis of epicardial diameter. Sixtyeight (35%) high-grade coronary lesions were located in the LAD; 39 (20%) in the LCX; 32 (16%) in the RCA; 29 (14%) in the Dx; 17 (9%) in the PL; and 11 (6%) in the OM.

Prevalence of Match and Mismatch Findings on 2-D Analysis Of the 105 patients who were studied, on standard visual analysis 48 (46%) showed perfusion-metabolic matches (nonviable myocardium), and 57 (54%) had perfusionmetabolic mismatches (viable myocardium) (Figure 2). Both, mismatches and matches coexisted in 47 patients (45%).

Table 1. Baseline clinical information on patients with and without evidence of myocardial viability by PET Viable

Statistical Analysis For descriptive purposes all data were presented as mean ⫾ SD. Scintigraphic variables and left ventricular ejection fraction were compared using paired Student t-test (all values were expressed as mean ⫾ SD). The Wilcoxon rank-sum test was used to compare relative reductions in myocardial blood flow between viable and nonviable myocardium. The X2 test was used to compare the frequency of possible flow reduction occurring in viable and nonviable myocardium. Test procedures were two-sided with a P-value of less than 0.05 indicating statistical significance.

Results Of 105 patients (mean age 61 ⫾ 7 years), 64% had a history of myocardial infarction, and 28% had undergone coronary artery bypass surgery. Twenty-eight

N Age (yrs) Ejection fraction (%) Prior CABG/PTCA Prior MI Hypertension Hypercholesterolemia Smoking Diabetes mellitus Positive family history of CAD Lipid status Serum cholesterol level, mg/dL Serum LDL level, mg/dL Serum HDL level, mg/dL Triglyceride level, mg/dL Glucose level, mg/dL Blood pressure, mmHg SBP DBP

Non-viable

57 60 ⫾ 10 29 ⫾ 5 22 49 19 35 14 10 7 224 150 48 143 97

⫾ ⫾ ⫾ ⫾ ⫾

38 21 11 60 14

132 ⫾ 14 75 ⫾ 8

48 59 ⫾ 8 28 ⫾ 4 18 43 14 29 10 8 9 225 152 49 142 98

⫾ ⫾ ⫾ ⫾ ⫾

38 23 12 58 13

130 ⫾ 16 75 ⫾ 10

Values are mean ⫾ SD or n (%); P ⫽ NS between groups by Kruskal Wallis Test; CABG ⫽ coronary artery bypass surgery; PTCA ⫽ percutaneous transluminal coronary angioplasty; MI ⫽ myocardial infarction; CAD ⫽ coronary artery disease; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure.

164 Molecular Imaging and Biology, Volume 6, Number 3

60

54%

50

46%

40 %

30 20 10 0 Mismatch

Match

Figure 2. Distribution of scintigraphic mismatch and match findings. Mismatch and match findings occurred in 54% and 46% of the study population.

revascularization, 10 had cardiac transplantation, and 48 remained under medical therapy (Figure 4). Of the 10 patients who underwent cardiac transplantation, five had evidence for perfusion-metabolic mismatches (Figure 4). Referral to cardiac transplantation was because the mismatches were only small in three and the target vessels were inadequate for revascularization in two patients. Finally, the majority of the 48 patients who remained on medical therapy had only matches, of these 13 patients presented perfusion-metabolic mismatches, and 35 had no evidence of myocardial mismatch patterns. In the group of patients with myocardial perfusion-mismatch inadequate target vessels in eight patients and significant comorbidity in five patients were reasons for which these patients were assigned to medical therapy.

Resting Flow and Viability Twenty-eight percent of all viable segments had mild, 46% had moderate, and 25% had severe reductions in myocardial blood flow. Mild, moderate, and severe reductions were found in 18%, 24%, and 58% of nonviable segments, respectively (all P ⬍ 0.0001). Overall, resting myocardial blood flow was less severely reduced in viable than nonviable myocardium (1.77 ⫾ 0.79 vs. 2.2 ⫾ 0.80, P ⬍ 0.0001) (Figure 3). However, there was a considerable overlap of the degree of flow reductions between viable and non-viable myocardium.

Clinical Management Decisions Based on the Evaluation of 2-D Scintigraphic Images

Visual 201 -Thallium Uptake Score

How the assessment of blood flow-metabolism scintigraphic imaging influenced the clinical management decision to proceed with medical therapy, revascularization, or cardiac transplantation was evaluated retrospectively by chart review. Of these, 47 underwent coronary Severe 3

Moderate 2

Global Left Ventricular Function Pre- and post-revascularization ejection fractions were available in 35 of 57 patients with scintigraphic mismatch findings, and in 30 of 48 patients with match findings. For the entire group of these patients, mean left ventricular ejection fraction increased significantly from 28.6 ⫾ 7 to 35.5 ⫾ 8% (P ⬍ 0.0003). However, in patients with mismatches the mean left ventricular ejection fraction improved significantly from 28.7 ⫾ 6% to 36 ⫾ 8% (P ⬍ 0.0003), but not in patients with matches (28 ⫾ 4% to 29 ⫾ 3%, P ⫽ 0.7). The extent of both matches and mismatches by visual analysis (i.e., the number of myocardial segments exhibiting a blood flow/ metabolism match or mismatch pattern) correlated with changes in left ventricular ejection fraction after revascularization (r ⫽ 0.89, P ⬍ 0.0001) (Figure 5). Further, the anatomic location of mismatch also correlated with the change in left ventricular ejection fraction after coronary revascularization. The extent of blood flow/ metabolic mismatch in the myocardial territory of the LAD and LCX showed the highest and similar correlations (r ⫽ 0.92, P ⬍ 0.0001; n ⫽ 15 and r ⫽ 0.93, P ⬍ 0.0001; n ⫽ 9), while less significant for the RCA (r ⫽ 0.86, P ⬍ 0.001; n ⫽ 11)

3-D Scintigraphic Fusion Image

Mild 1

0

Viable 201

Non-viable

Figure 3. Myocardial TI uptake score in viable and nonviable myocardium. Tracer uptake as index of blood flow was more severely reduced in viable than non-viable myocardium (1.77 ⫾ 0.79 vs. 2.2 ⫾ 0.80, P ⬍ 0.0001). Noteworthy, there is a considerable overlap in relative tracer uptake reductions between nonviable and viable tissue.

An example (Figure 6–7) of a 3-D fusion image in 50year-old patient with multivessel coronary disease, prior anterior and inferolateral myocardial infarction and aorto-coronary-bypass-surgery to the LAD, RCA, and LPL-branch as shown in Figures 6 and 7. On the biplanar coronary angiographic images, complete occlusions of the vein graft to the RCA and LPL-branch were found, whereas the vein graft to the LAD revealed normal findings. The visualization of the native coronary arteries

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

165

Clinical Decision n = 105

CABG/ PTCA n = 39 68%

Viability

No Viability

n = 57

n = 48

Medical n = 13 23%

CABG/ PTCA n=8 17%

HTX n=5 9%

demonstrated complete occlusions of the RCA (not shown) and of the proximal LAD (Figure 6, upper field). In addition, after branching of a big Ramus intermedius the LCX artery is occluded. The peripheral part of the LCX is somehow visualized through collaterals from the R. intermedius. The middle field of Figure 6 shows the middle and peripheral part of the LAD with ante- and retrograde perfusion through the vein graft. In addition, the RIVPO can be realized through collateral vessels from septal branches. After 3-D reconstruction of the

16

Medical n = 35 73%

Figure 4. Clinical management decisions. Clinical management decision was available in all patients. Sixty-eight percent of patients with viability underwent revascularization (CABG/PTCA), 23% remained on medical treatment, and 9% went on heart transplantation (HTX). Seventeen percent of patients without viable myocardium were revascularized, 73% were treated medically, and 10% underwent cardiac transplantation.

HTX n=5 10%

coronary vessel segments (Figure 6, upper and middle fields) by means of Be´zier-curves in two biplane images of different acquisition and fusion of the single reconstructed vessel segments with the help of any reference point, the structure of the coronary tree can be regarded in three dimensions from different viewing angles (Figure 6, lower field). The 3-D fusion image with 201TI perfusion at rest (Figure 7, upper panel) reveals a distinct perfusion defect in the inferolateral area with exact assignment

y = 0.61x - 2.021 r = 0.89, p< 0.0001

Number of Mismatch Segments

14 12 10

Figure 5. Correlation between changes of global left ventricular ejection fraction after myocardial revascularization and the preinterventional numbers of the PET-mismatch segments.

8 6 4 2 0 -5

0

5

10 Delta - EF

15

20

166 Molecular Imaging and Biology, Volume 6, Number 3

in the midventricular anterior wall with a reduction toward the apex due to previous infarction. In the patient presenting previous myocardial infarctions of the anterior and inferolateral wall, the viability of the left ventricle is assessed by FDG-PET (Figure 7, lower panel). In the basal-midventricular territories of the anterior and inferior wall, viable myocardium is present with reduced FDG-uptake toward the apex. In addition, the inferolateral wall shows a distinct reduction of FDGuptake, but still viable myocardium, corresponding to the vascular supply territory of the LCX artery. In summary, the 3-D fusion image reveals regional scintigraphic mismatch findings in the infero and inferolateral area, and match findings in the antero- and inferoapical area, with an accurate assignment to the corresponding vessel segments of the LAD, RCA, and LCX artery.

3-D Scintigraphic Fusion Image Analysis

Figure 6. Angiographic projections. RAO-and LAO-view of the native left coronary tree (upper panels). Biplanar display of the LAD segment from the occluded proximal part supplied by a single vein bypass (middle panels). 3-D display of the coronary tree structures from different view angles (lower panels).

to the proximal occluded LCX artery. Moreover, in the basal area of the inferior wall, a severe perfusion defect can be found corresponding to the occluded RCA territory. However, due to collateral vessels from the septal branches, myocardial perfusion can be realized in the middle and peripheral territory of the RIVPO, though it appears to be reduced after myocardial infarction. In the lateral myocardial territory supplied by the R. intermedius, normal perfusion is found. Moreover, due to the vein graft to the LAD adequate perfusion is shown

On the 3-D fusion image, 127 (65%) high-grade lesions showed a good coincidence with regional myocardial perfusion and/or metabolic abnormality on the 3-D fusion image (54 high-grade lesions and 73 occluded vessels). Of these, regional perfusion and/or metabolic abnormality demonstrated 58 (46%) match and 69 (54%) mismatch findings. Match or mismatch findings were identified in the LAD: 28/23, respectively; in the RCA: 10/18; in the LCX: 9/11; in the DX: 2/4; in the PL: 6/9; in the OM: 3/2; and in the septal branch: 1/2. However, there was no perfusion or metabolic abnormalities in myocardial regions that were assigned to 69 (35%) coronary high-grade lesions in the vessel segments. In contrast, the 3-D integration of morphology and function also revealed 19 (13%) regions with reduced myocardial perfusion and/or metabolic abnormalities (16 match and three mismatch) that could not be related to angiographically coronary artery lesions. In this setting, match or mismatch findings were identified in the LAD: 4/0, respectively; in the RCA: 6/2; in the LCX: 3/1; in the DX: 1/0; in the PL: 3/0; and in the OM: 2/0. However, adequate 3-D fusion images were not achieved in 18 patients of 105 patients (17%) due to a relative displacement of the entire coronary artery trees. Finally, two independent and experienced investigators found that in 31 out of 105 patients (30%) the 3-D fusion image facilitated the visual assignment of coronary lesions the corresponding myocardial match or mismatch findings. The myocardial regions with improved visual assignment of regional myocardial match and mismatch to the corresponding epicardial vessel segment were ascribed in the RCA: 5/8, respectively; in the LCX: 4/8; in the DX: 1/6; in the PL: 2/5; and in the OM: 2/4 (Table 2).

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

Figure 7. 3-D Fusion image from different views studied with rest and viability (with permission from Ref. 16).

Discussion The results of the present study imply that based on the presence of viable dysfunctional myocardium on 2-D scintigraphic images, 54% of patients with ischemic cardiomyopathy may be considered for coronary revascularization. In addition, 3-D integration of myocardial scintigraphic data and coronary angiographic data may add important information in the diagnostic and interpretative process in approximately 30% of these patients.

Prevalence of Myocardial Viability There is little information in regard of the prevalence myocardial viability in patients with ischemic cardiomyopathy and severely compromised left ventricular function. Recent observations by Auerbach et al.15 in 283 patients found viable myocardium in 55% of patients with ischemic cardiomyopathy. Similar findings were reported by Schinkel et al.19 with a prevalence of viable myocardium in 56 out of 104 patients (61%). The latter Table 2. Interpretation where the 3-D image fusion display facilitated the assignment of the coronary artery lesion to the corresponding myocardial match or mismatch finding Coronary Artery

Match

Mismatch

Total

LAD RCA LCX Dx PL OM S Total

0 5 4 1 2 2 0 14

0 8 8 6 5 4 0 31

0 13 12 7 7 6 0 45

201

167

TI-SPECT and FDG-PET to evaluate myocardial perfusion at

results15,19 are in close agreement with those of the actual study revealing 54% of patients with viable myocardium defined as blood flow/glucose metabolic mismatch finding. In line with previous investigations,4,15,20,21 the extent of myocardial viability correlated well with improvement of left-ventricular contractile function after coronary revascularization. Coronary revascularization of blood flow/glucose metabolic mismatches in patients with severely depressed left ventricular function resulted in a meaningful increase in global left ventricular function. In contrast, restoration of coronary blood flows in myocardial regions with concordant reduction in blood flow and glucose uptake did not manifest in significant changes of left ventricular function in these patients. Interestingly, the increases of global left ventricular function appeared also to be related somehow to the anatomic location of the mismatch between blood flow and metabolism. In particular, the association between preoperative mismatch findings and postoperative improvement of global left ventricular function was highest and similar for the LAD- and LCX- territory, but less significant for the RCA-territory. The reason for this discordant observation is not clear and may be related to differences in patients’ characteristics, relative small number of mismatches in the inferior wall and/or an advanced state of structural disintegration of the myocytes due to the blood supply-demand imbalance in hibernating myocardium.22 Nevertheless, our findings showed that restoration of myocardial flows in areas of mismatch of the inferior wall resulted in improved global left ventricular function. Thus, mismatch findings in the inferior wall present clinically relevant areas of myocardial viability that may benefit from revascularization. Notably, the improvement of left ventricular contractile function after coronary revascularization of segments

168 Molecular Imaging and Biology, Volume 6, Number 3

with scintigraphic blood flow/glucose metabolic mismatch-pattern has also been shown to result in higher daily life activity levels, and reduced congestive heart failure symptoms.4,20,21 Interestingly, Di Carli et al.23 reported that the presence of small amounts (ⱖ5%) of myocardial viability by PET might identify a high-risk subgroup with a poor one-year survival rate. However, whether patients presenting viability of even less than five percent of the left-ventricular myocardium are also at increased risk for a poor survival rate still remains uncertain and needs to be explored in further prospective studies. In regard to myocardial perfusion, the findings of the present study are in keeping with previous observations,15 demonstrating that relative myocardial perfusion at rest to be significantly lower in nonviable than in viable myocardium. However, there is a considerable overlap in relative myocardial perfusion at rest in viable and nonviable myocardial segments, pointing out that semiquantitative approaches to assess myocardial perfusion at rest without metabolic imaging cannot reliably differentiate between viable and nonviable myocardium.15,24,25 A large body of evidence, however, is in support of the value of blood flow/glucose metabolic mismatch imaging by PET to provide important predictive information on cardiac death and myocardial infarction,3,5,7,20 implicating blood-flow metabolism imaging as means of assessing cardiac risk and, at the same time, of stratifying such patients to surgical treatment. Clinical studies have demonstrated that CABG in patients with ischemic cardiomyopathy and blood flow-metabolism mismatches improves the one and five-year survival rates of such patients as much as 70% to 80%, substantially exceeding the 40% to 50% survival rates of patients with ischemic cardiomyopathy and blood flow-metabolism mismatches treated only conservatively.23,26,27 Thus, in patients with end-stage coronary artery disease, the assessment of blood-flow metabolism by scintigraphic techniques is most important and often critical in the decision-making process of therapeutic options otherwise limited to intensified medical treatment, surgical revascularization, and cardiac transplantation.

Clinical Management Decisions The presence of myocardial viability in the current study substantially influenced the clinical decision-making process. Sixty-eight percent of patients with viability, but only 17% of those without viability underwent revascularization. Twenty-three percent of patients with significant viability remained under medical therapy. Inadequate target vessels, coexisting disease such as cancer, diabetes and/or renal failure, chronic airways disease, elevated pulmonary vascular resistance, or patients’ refusal might have accounted for the decision of continued intensified

medical therapy. Thus, not all patients with blood-flow/ metabolism mismatch are appropriate candidates for surgical revascularization. Conversely, 17% of patients without extensive viability underwent coronary revascularization. The reason for these clinical management decisions remain unclear but may be related to persistent clinical symptoms such as angina, even though less likely, to improve the long-term prognosis of the patient.

Evaluation by 3-D Scintigraphic Fusion Image Scintigraphic techniques such as SPECT and PET display myocardial perfusion and viability in 2-D or, in a polar map approach, allow an accurate assessment of the severity and extent of myocardial ischemia and viable and nonviable myocardium.21,28 Recent elaborated work29 indicates the validity and value of 3-D color modulated display of myocardial SPECT perfusion distributions in the assessment of coronary artery disease. In addition Peifer et al.30 were first to show an example of a multimodality imaging in a heart model combining coronary angiographic data and 201TI scintigraphic perfusion data in a 3-D format. We extended this approach to newly developed 3-D fusion techniques of morphological data (coronary angiography) and perfusion data (myocardial scintigraphy) in patients with coronary artery disease, and reported of the feasibility of this new approach in routine clinical practice.9,18 In the present study of patients with mostly complex, coronary multivessel disease and cardiomyopathy, the 3-D scintigraphic fusion image demonstrated a good agreement in 127 of 196 (65%) severely stenosed or occluded coronary vessel segments and 201TI perfusion defects at rest, corresponding to 58 match and 69 mismatch findings in view of the FDG display. In this setting, with 3-D fusion imaging these hypoperfused areas at rest with preserved or reduced glucose uptake could indeed be related to highly narrowing of corresponding coronary vessels. These findings also provide direct evidence that regional hibernating, as indicated by mismatches, indeed present chronic hypoperfusion induced by highly narrowing of epicardial arteries.31 Interestingly, in 35% of high-grade coronary lesions, no resting perfusion or metabolic abnormalities were found. This may be explained by the role of collateral circulation in preventing perfusion defects in the myocardial territory supplied by high grade coronary lesions at resting conditions.31 Noteworthy, cumulative stunning (repetitively stress-induced myocardial ischemia) most likely accounted at least in part for dysfunctional myocardium in these regions. On the other side, some of the high grade stenosis may have been overestimated due to a well known intra- and interobserver variability based on the visual analysis of the severity of the coronary lesion.32

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

Lastly, the 3-D fusion image also revealed 13% regions with reduced myocardial perfusion and/or metabolic abnormalities (16 match and three mismatch) that could not be related to angiographically significant coronary artery lesions. This could be related to formation of thrombus due to plaque rupture with temporary occlusion of the coronary vessel segments inducing areas of myocardial necrosis as indicated by match findings. However, some of these regional perfusion defects could be related to the potential for poor specificity of myocardial scintigraphy caused by image artifacts, due to patient and technical factors. In particular, because correction for photon attenuation was performed routinely for the PET data but not 201TI data, it is most likely that a number of 201TI defects in regions considered viable by PET represented in fact attenuation artifacts.33,34 Thus, the relatively high number of mismatch findings in the infero and inferolateral wall on the 3D fusion image, though related to high grade lesions, is possibly related in part to attenuation artifacts of 201TI SPECT perfusion imaging. Moreover, the latter most likely also accounted for some false positive 201TI-SPECT perfusion findings of the inferolateral wall without coronary artery lesions. However, comparable to previous investigations,9 adequate 3-D fusion images were not achieved in 17% of patients due to a relative displacement of the entire coronary artery trees. Several sources of error could have contributed to incorrect data fusion, such as dyskinesia in nonviable myocardial areas with a possible displacement of the scintigraphic ventricular surface in relation to the coronary tree structure. Most of all, extreme movement of the patient during scintigraphic data acquisition could have induced a relative shifting of the scintigraphic data.9

Clinical Implications In the present study, the 3-D fusion image was estimated to facilitate the assignment of regional myocardial match and mismatch findings to the corresponding epicardial coronary lesions mainly in the inferolateral and lateral wall that was found to be related to interindividual variations in the right coronary artery and left circumflex artery. In addition, difficulties in the assignment of coronary artery tree branches of second order such as the diagonal, obtuse marginal and posterolateral branches to the corresponding myocardial perfusion territories could be overcome with the help of the 3-D fusion image. These findings are accord with previous observations that the standard myocardial distribution territories correspond in only 50% to 60% with the real anatomic tree.8 Thus, in these cases, cause-and-effect relations may be more obvious, and anatomy and physiology may be more easily compared to facilitate the diagnostic and interpretative making process.

169

Overall, the visual analysis of 3-D integration of myocardial scintigraphic and angiographic data was thought to have aided the diagnostic process in the assignment of coronary lesions to the corresponding viable or nonviable myocardial territory in a substantial number of approximately 30% of patients with ischemic cardiomyopathy. Although the results of the application of this new 3D scintigraphic fusion image to patients with coronary multivessel disease and cardiomyopathy in a clinical routine setting appears to be promising, the reliability and accuracy of this technique needs further evaluation. Importantly, additional studies are needed to determine whether the 3-D integration of myocardial scintigraphic data and angiographic data may indeed modify the clinical decision-making process in such patients. Yet, 3-D image fusion may help to select culprit coronary lesions in multivessel disease for angioplasty procedures or CABG.35 In addition, in patients with complex coronary multivessel disease CABG and interventional techniques may also go in line with each other as so called hybridinterventions for the revascularization of ischemic myocardial regions. Thus, in contrast to previous years not only the prove of myocardial ischemia and/or viability is of particular interest, but rather the application of cardiac diagnostic procedures for an optimal, individual coronary revascularization planning in patients with demonstrated coronary artery disease. The concept of our 3-D fusion imaging, however, is expandable to other diagnostic modalities in cardiology as well. Preliminary results of 3-D PET/computed tomography (CT) superimposition program indicate the feasibility of this method to display the location of coronary lesions by contrast-enhanced CT angiography and stress-induced perfusion defects on PET images.36,37 In addition, cardiac magnetic resonance imaging (CMRI) has become a promising technique to analyze and display angiographic and myocardial data in a 3-D mode, whereby all data are already matched and, in fact, are represented in truly 3-D formats.38,39 Conversely, the resolution of the coronary arteries by CMRI or multislice CT is much lower compared coronary angiography and, thereby, does not allow to reconstruct the coronary tree to its distal parts of coronary vessels of second or third order.9 Thus, an accurate evaluation of myocardial territories of smaller coronary vessel with 3-D PETCT superimposition or 3-D cardiac MRI display at least for the time being is not possible.36–39 Conceptually, the latter limitation could be overcome by applying the current 3-D fusion technique to PET/CT imaging. Thereby, 3-D angiographic data could be superimposed on the CT acquired 3-D coronary artery tree and fused with the myocardial perfusion and metabolic 3-D PET data.9,36,37 In future studies, however, it will be of great interest of course to determine the validity and value of these different and developing 3-D imaging

170 Molecular Imaging and Biology, Volume 6, Number 3

modalities in a comprehensive assessment of cardiovascular disease. 7.

Conclusion Based on the presence of viable dysfunctional myocardium on 2-D scintigraphic images, 54% of patients with ischemic cardiomyopathy may be considered for coronary revascularization. In addition, the visual analysis of 3-D integration of myocardial scintigraphic data and coronary angiographic data may add important information in the diagnostic and interpretative process in approximately 30% of these patients. The authors thank Ursula Sahm, Ph.D., Kenneth Stalmo, MSc, and Bernd Morasch, MSc for producing the radioisotope and radiopharmaceutical. Further, we are indebted to Claudia Santini-Bo¨ttcher, CNMT, Aasa Stalmo, CNMT, and Claudia Scheurer, CNMT, for their technical assistance. Finally, we thank the nurses of the Cardiac Catheterization Unit for their invaluable support.

8.

9.

10.

11.

Research Grants 12. This work was supported in part by a Grant from the German Research Foundation (So 241/2-2) and from the Government of Baden-Wu¨rttemberg for the “Center of Clinical Research II: Cardiovascular Diseases–Analysis and Integration of Form und Function” at the Albert-Ludwig-University Freiburg (Projekt: Sch-A1/A2) and Research Grant HL 33177 by the National Heart, Lung and Blood Institute, Bethesda, MD.

13.

14.

15.

References 1. Schelbert, H.R. Positron emission tomography for the assessment of myocardial viability. Circulation 84:1122– 1131; 1991. 2. Tamaki, N.; Yonekura, Y.; Yamashita, K.; et al. Positron emission tomography using fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting. Am. J. Cardiol. 64:860–865; 1989. 3. Allman, K.C.; Shaw, L.J.; Hachamovitch, R.; et al. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J. Am. Coll. Cardiol. 39:1151–1158; 2002. 4. Di Carli, M.F.; Asgarzadie, F.; Schelbert, H.R.; et al. Quantitative relation between myocardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation 92:3436–3444; 1995. 5. Schwaiger, M.; Bengel, F.M. From thallium scan to molecular imaging. Mol. Imaging Biol. 4:387–398; 2002. 6. Lee, K.S.; Marwick, T.H.; Cook, S.A.; et al. Prognosis of patients with left ventricular dysfunction, with and without viable myocardium after myocardial infarction.

16.

17.

18.

19.

20.

Relative efficacy of medical therapy and revascularization. Circulation 90:2687–2694; 1994. Schelbert, H.R.; Beanlands, R.; Bengel, F.; et al. PET myocardial perfusion and glucose metabolism imaging:Part 2-Guidelines for interpretation and reporting. J. Nucl. Cardiol. 10:557–571; 2003. Kalbfleisch, H.; Hort, W. Quantitative study on the size of coronary artery supplying areas postmortem. Am. Heart J. 94:183–188; 1977. Schindler, T.H.; Magosaki, N.; Jeserich, M.; et al. Fusion imaging: combined visualization of 3D reconstructed coronary artery tree and 3D myocardial scintigraphic image in coronary artery disease. Int. J. Cardiovasc. Imaging 15:357–368; discussion 369–370; 1999. Schindler, T.H.; Nitzsche, E.; Magosaki, N.; et al. Regional myocardial perfusion defects during exercise, as assessed by three dimensional integration of morphology and function, in relation to abnormal endothelium dependent vasoreactivity of the coronary microcirculation. Heart 89:517–526; 2003. Ryan, T.J.; Klocke, F.J.; Reynolds, W.A. Clinical competence in percutaneous transluminal coronary angioplasty. A statement for physicians from the ACP/ACC/ AHA Task Force on Clinical Privileges in Cardiology. J. Am. Coll. Cardiol. 15:1469–1474; 1990. Bax, J.J.; Visser, F.C.; van Lingen, A.; Cornel, J.H.; Fioretti, P.M.; van der Wall, E.E. Metabolic imaging using F18fluorodeoxyglucose to assess myocardial viability. Int. J. Cardiovasc. Imaging 13:145–155; discussion 157–160; 1997. Bom, H.S.; Vansant, J.P.; Pettigrew, R.I.; et al. Determination of myocardial viability with ECG-gated fluorodeoxyglucose F-18 positron emission tomography. Clin. Pos. Imag. 2:183–90; 1999. Garvin, A.A.; Cullom, S.J.; Garcia, E.V. Myocardial perfusion imaging using single-photon emission computed tomography. Am. J. Cardiol. Imaging 8:189–198; 1994. Auerbach, M.A.; Schoder, H.; Hoh, C.; et al. Prevalence of myocardial viability as detected by positron emission tomography in patients with ischemic cardiomyopathy. Circulation 99:2921–2926; 1999. Schindler, T.H.; Magosaki, N.; Jeserich, M.; et al. [New developments in diagnosis of coronary heart disease–3D fusion image] Z. Kardiol. 89:338–348; 2000. Schindler, T.H.; Magosaki, N.; Jeserich, M.; et al. 3D assessment of myocardial perfusion parameter combined with 3D reconstructed coronary artery tree from digital coronary angiograms. Int. J. Cardiovasc. Imaging 16:1– 12; 2000. Magosaki, N.; Schindler, T.H.; Fischer, R.; et al. Integration of coronary anatomy, perfusion and metabolism: Three-dimensional image fusion of coronary angiography and nuclear cardiac imaging. IEEE Comput Cardiol. 26:615–618; 1999. Schinkel, A.F.; Bax, J.J.; Sozzi, F.B.; et al. Prevalence of myocardial viability assessed by single photon emission computed tomography in patients with chronic ischaemic left ventricular dysfunction. Heart 88:125–130; 2002. Tillisch, J.; Brunken, R.; Marshall, R.; et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N. Engl. J. Med. 314:884–888; 1986.

Myocardial Viability and 3-D Fusion Imaging / Schindler et al.

21. Bax, J.J.; Cornel, J.H.; Visser, F.C.; et al. Prediction of recovery of myocardial dysfunction after revascularization. Comparison of fluorine-18 fluorodeoxyglucose/ thallium-201 SPECT, thallium-201 stress-reinjection SPECT and dobutamine echocardiography. J. Am. Coll. Cardiol. 28:558–564; 1996. 22. Elsasser, A.; Decker, E.; Kostin, S.; et al. A self-perpetuating vicious cycle of tissue damage in human hibernating myocardium. Mol. Cell. Biochem. 213:17–28; 2000. 23. Di Carli, M.F.; Davidson, M.; Little, R.; et al. Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction. Am. J. Cardiol. 73:527–533; 1994. 24. Duvernoy, C.S.; vom Dahl, J.; Laubenbacher, C.; et al. The role of nitrogen 13 ammonia positron emission tomography in predicting functional outcome after coronary revascularization. J. Nucl. Cardiol. 2:499–506; 1995. 25. Marshall, R.C.; Tillisch, J.H.; Phelps, M.E.; et al. Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia. Circulation 67:766–778; 1983. 26. Eitzman, D.; al-Aouar, Z.; Kanter, H.L.; et al. Clinical outcome of patients with advanced coronary artery disease after viability studies with positron emission tomography. J. Am. Coll. Cardiol. 20:559–565; 1992. 27. Di Carli, M.F.; Maddahi, J.; Rokhsar, S.; et al. Long-term survival of patients with coronary artery disease and left ventricular dysfunction: implications for the role of myocardial viability assessment in management decisions. J. Thorac. Cardiovasc. Surg. 116:997–1004; 1998. 28. Garcia, E.V.; Cooke, C.D.; Folks, R.D.; et al. Diagnostic performance of an expert system for the interpretation of myocardial perfusion SPECT studies. J. Nucl. Med. 42:1185–1191; 2001. 29. Santana, C.A.; Garcia, E.V.; Vansant, J.P.; et al. Threedimensional color-modulated display of myocardial SPECT perfusion distributions accurately assesses coronary artery disease. J. Nucl. Med. 41:1941–1946; 2000. 30. Peifer, J.W.; Ezquerra, N.F.; Cooke, C.D.; et al. Visualization of multimodality cardiac imagery. IEEE Trans. Biomed. Eng. 37:744–756; 1990.

171

31. Uren, N.G.; Melin, J.A.; De Bruyne, B.; et al. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N. Engl. J. Med. 330:1782–1788; 1994. 32. Brueren, B.R.; ten Berg, J.M.; Suttorp, M.J.; et al. How good are experienced cardiologists at predicting the hemodynamic severity of coronary stenoses when taking fractional flow reserve as the gold standard. Int. J. Cardiovasc. Imaging 18:73–76; 2002. 33. Garcia, E.V.; Hendel, R.C.; Cullom, S.J.; DePuey, E.G.; Bateman, T.M. Use of phantom studies to compare the performance of 8 different attenuation correction devices. J. Nucl. Cardiol. 10:107–108; author reply 108–109; 2003. 34. Hendel, R.C.; Corbett, J.R.; Cullom, S.J.; et al. The value and practice of attenuation correction for myocardial perfusion SPECT imaging: a joint position statement from the American Society of Nuclear Cardiology and the Society of Nuclear Medicine. J. Nucl. Cardiol. 9:135– 143; 2002. 35. Schofield, P.M. Indications for percutaneous and surgical revascularization: how far does the evidence base guide us? Heart 89:565–570; 2003. 36. Namdar, M.; Hany, T.F.; Burger, C.; et al. Combined computed tomography-angiogram and positron emission tomography perfusion imaging for assessment of coronary artery disease in a novel PET/CT: A pilot feasibility study. J. Am. Coll. Cardiol. 41:439; 2003. 37. Mullani, N.A.; Brandt, M.; Strite, D.; Hartz, R.; Allbright, M.; Boyd, D.; Gould, K.L. Superimposition of EBCT determined coronary calcium deposits onto myocardial PET perfusion images by rubidium-82 and nitrogen-13 ammonia for assessment of flow limiting defects. Clin. Pos. Imag. 3:148; 2000. 38. Sturm, B.; Powell, K.A.; Stillman, A.E.; et al. Registration of 3D CT angiography and cardiac MR images in coronary artery disease patients. Int. J. Cardiovasc. Imaging 19:281–293; 2003. 39. Swingen, C.; Seethamraju, R.T.; Jerosch-Herold, M. An approach to the three-dimensional display of left ventricular function and viability using MRI. Int. J. Cardiovasc. Imaging 19:325–336; 2003.