Differentiation of ischemic from nonischemic cardiomyopathy with positron emission tomography

METHODS

Differentiation of Ischemicfrom Nonischemic Cardiomyopathywith Positron EmissionTomography JOEL D. EISENBERG, MD, BURTON E. SOBEL, MD, and EDWARD M. GELTMAN, MD

This study was undertaken to determine whether positron emission tomography (PET) performed after the intravenous injection of “C-palmitate permits differentiation of patients with ischemic from those with nonischemic dilated cardiomyopath PET was performed after intravenous injection of Y-‘C-palmitate in 10 patients with ischemic and in 10 with nonischemic dilated cardiomyopathy. Regions of homogeneously severely depressed accumulation of l’C-palmitate, representing 15% or more of the expected myocardial cross-sectional area, were observed in 8 of 10 patients with ischemic but in none of 10 patients with nonischemic cardiomyopathy. Patients with nonischemic cardiomyopathy had marked spatial heterogeneity of the accumulation of palmitate throughout the left ventricular myocardiurn, whereas most tomographic sections from patients with ischemic cardiomyopathy accumulated

“C-palmitate more homogeneously in regions exclusive of discrete defects indicative of remote infarction. Thus, a larger number of discrete noncontiguous regions (17 f 5 compared with 12 f 4, p
H

eart failure secondary to coronary artery disease (CAD], often attributable to ischemic cardiomyopathy,? may be difficult to differentiate from idiopathic dilated cardiomyopathy without resorting to coronary angiography. The diagnosis may be suspected in patients with congestive heart failure and previous infarction, chest pain suggestive of angina pectoris, or electrocardiographic evidence of infarction.2-4 Unfortunately, neither the clinical history nor the electrocarFrom the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. This study was supported in part by Grant HL 17646 and HL13851 from the National Institutes of Health, (SCOR in Ischemic Heart Disease) (Cyclotron Produced Isotopes in Biology and Medicine], Bethesda. Maryland. Manuscript received August 24. 1984, revised manuscript received and accepted January 8, 1987.

Address for reprints: Edward M. Geltman, MD, Cardiovascular Division, Box 8086, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110.

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diogram is sufficiently sensitive or specific to differentiate these 2 entities. Differentiation of ischemic from nonischemic cardiomyopathy has important prognostic and therapeutic implications. 5-8However, clinicians may be reluctant to perform coronary angiography in patients with cardiomyopathy because the presence of a markedly depressed ejection fraction is associated with a g-fold increase of risk of death with cardiac catheterization9 Thus, a noninvasive approach for differentiation of ischemic from nonischemic cardiomyopathy would be desirable. Radionuclide procedures, including thallium-201 myocardial scintigraphy, may distinguish ischemic from nonischemic cardiomyopathy.lfl,ll However, thallium scintigraphy is not sufficiently specific to obviate the need for coronary angiography in some patients. We previously showed that positron emission tomography (PET] is useful for detection and quantitative assessment of myocardial infarction and for characterizing patients with nonischemic cardiomyopa-

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thy.” ‘Ii Accordingly, the present study was performed to determine if patients with ischemic and nonischemic cardiomyopathy could be distinguished with PET performed after intravenous injection of “Cpalmitate.

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Characteristics of Patients TABLE I Demographic lschemic and Nonischemic Cardiomyopathy

Pt

Age (~0 & Sex

Cath

EF ( ‘% )

lschemic

Methods Patients: The clinical characteristics of the patients are listed in Table I. All patients gave written informed consent. Endomyocardial biopsy specimens revealed the presence of myocarditis in 3 patients [nos. 4, 7 and 9), interstitial fibrosis in 1 patient (no. 8) and sarcoid granulomas in 1 [no. 10). The 2 oldest patients [nos. 2 and 5) had angiographically normal coronary arteries and global left ventricular dysfunction. Patient 3 did not undergo coronary angiography but had a strong history of ethanol abuse with a clinical diagnosis of alcohol-induced cardiomyopathy. He had no history of myocardial infarction or chest pain, and his radionuclide ventriculogram showed diffuse hypokinesia without focal abnormalities. Patients 1 and 6 had clinical diagnoses of peripartum and familial cardiomyopathy, respectively. All patients with ischemic cardiomyopathy had documented CAD. Most had undergone coronary angiography at our institution and were in New York Heart Association functional class III or IV. Congestive heart failure was associated with severe, usually 3-vessel, obstructive CAD. The 2 patients in whom angiography was not performed had documented myocardial infarctions with typical evolutionary electrocardiographic and enzymatic abnormalities. Four of 10 patients had diabetes mellitus. Electrocardiograms were interpreted by observers who had no knowledge of the clinical diagnosis or the results of tomography. The severity of left ventricular dysfunction was documented by contrast or equilibrium radionuclide left ventriculography. Ejection fractions calculated by radionuclide and contrast techniques correlated closely in previous studies from our laboratory.” Radiochemistry and tomography: The “C-palmitate was synthesized as previously described.lR The whole-body radiation absorbed dose in a typical study after intravenous administration of 20 mCi of ilC-palmitate was 240 mRem. The liver was the primary target organ, receiving a radiation dose of 1.1 Rem after injection of 20 mCi of “C-palmitate. Tomography was performed with a PET device (PET IV] as previously described.ld Ifi Images were reconstructed without gating of the cardiac cycle so that the data collection interval could be as brief as possible. Spatial averaging was used without correction for motion caused by either the cardiac or the respiratory cycle. No clinical complications were encountered, Data were processed as previously described and validated.‘q.“’ In brief, midventricular transverse tomographic reconstructions were displayed on a high resolution color monitor and a microprocessor-controlled joystick was used to outline the left ventricle on each reconstruction. The frequency distribution of ra-

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1 2 3 4 5 6 7 8 9 10 Mean

68F 75F 61F 61M 64M 59M 53M 63F 50M 54M 61

+ 0 + 0 0 + + t t t

1 2 3 4 5 6 7 8 9 10 Mean

Age (~0 & Sex 23F 62F 50M 37M 60M 29M 31M 32M 19F 31M 37

ECG Ewdence of Infarction

DM

+

31 26 29 21 24 25 27 21 13 ia 24 k 2%

EF (%)

0 t 0 0 t + + 0 0 +

52 28 19 13 20 15 26 10 20 37 24 f 4

t

+ + + + + t t +

+

t t

t

Cardiomyopathy

Cath

Cath = cardiac catheterization mellitus: EF = ejection fraction;

with

Cardiomyopathy

Nonischemic

Pt

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DM

t

0

Biopsy 0 0 0 + 0 0 t + t t +

ECG Evidence of Infarction

+ t t + t

and coronary angiography; DM = diabetes = yes; 0 = not performed; - = no.

dioactivity per pixel within the regions outlined was quantified by previously validated techniques.‘” All reconstructions were also displayed at each of 7 selected isocount thresholds, The number of noncontiguous regions displayed at each threshold was totaled and recorded.“’ In a homogeneous tomographic section, this analysis delineates 7 isocount regions. Metabolically heterogeneous myocardium is reflected by an increased number of regions. When the left ventricular region of interest was bisected by a zone of homogeneously severely depressed accumulation of palmitate, representing 15% or more of the expected myocardial cross-sectional area, thereby representing a zone of presumed infarction, the number of discrete zones was summed for the largest residual regions. This procedure was used to avoid an artifactual doubling of the number of apparent discrete zones. The presence of such defects was analyzed in a blinded fashion. We previously reported close agreement among independent observers performing this analytic procedure.‘-’ Distribution of “Cpalmitate was further assessedby expressing the mean radioactivity for each region of interest as a percentage of the maximal radioactivity per pixel within that region of interest.“’ Statistical analysis: Results are expressed as mean f standard deviation. Intergroup comparisons of con-

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tinuous variables were performed with the use of an unpaired Z-tailed Student t test and analysis of variance when appropriate.

Results Clinical characteristics: Electrocardiograms exhibited criteria of previous myocardial infarction in 9 of 10 patients with ischemic and 5 of 10 patients with nonischemic cardiomyopathy. Conduction abnormalities on the electrocardiogram were present in 4 of 10 patients with ischemic and 5 of 10 patients with nonischemic cardiomyopathy. Left ventricular dysfunction was documented in all patients. The degree of left ventricular dysfunction was similar in both groups (Table I). Results of positron emission tomography: PET revealed striking visual differences between the groups of patients with cardiomyopathy with respect to normal subjects and each other. The hearts of normal subjects had spatially homogeneous apparent content of radioactivity with smooth transitions between zones (Fig. 11.Large defects encompassing more than 15% of the cross-sectional area of the left ventricle in transverse tomographic reconstructions were present in 8 of 10 patients with ischemic cardiomyopathy. No normal subject or patient with nonischemic cardiomyopathy had such a defect. Independent analysis of the tomographic reconstructions by 2 observers resulted in concordance on all but 2 occasions. The heart from the patient with ischemic cardiomyopathy depicted in Figure 1 had a large homogeneous defect in the anterior and septal walls. The posterolateral wall had relatively homogeneous accumulation of radioactivity. This tomographic pattern (large dense defects with normalappearing residual myocardium) was typical of ischemic cardiomyopathy. PET reconstructions from the

NORMAL

IDIOPATHIC CARDIOMYOPATHY Anterior

Posterior

hearts of patients with nonischemic cardiomyopathy demonstrated marked diffuse spatial heterogeneity of accumulation of “C-palmitate without large zones of homogeneously depressed accumulation of tracer (Fig. 1). This pattern, devoid of large discrete defects, was seen in only 2 patients with ischemic cardiomyopathy. Thus, visual analysis of tomographic images provided a sensitivity of 80% and a specificity of 100% for detection of ischemic vs nonischemic cardiomyopathy. Among patients with ischemic cardiomyopathy, the average number of noncontiguous regions summed for 7 isocount thresholds was 12 f 4. In contrast, accumulation of tracer in patients with nonischemic cardiomyopathy was markedly heterogeneous, reflected by an increased number of isocount regions (17 f 5, p
ISCHEMIC CARDIOMYOPATHY

FIGURE 1. Positron emission tomographic images from midventricular levels in a normal subject, a patient with nonischemic cardiomyopathy and a patient with ischemic cardiomyopathy. Areas depicted in red represent regions with the highest apparent myocardial content of radioactivity. Line drawings below the colorcoded images indicate the location of the apparently normal (cross-hatching) and abnormal regions of myocardium (ouflined with inferrupfed line).

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Discussion These results confirm our previous observations of spatially heterogeneous accumulation of “C-palmitate in patients with nonischemic dilated cardiomyopathy.“’ Patients with ischemic cardiomyopathy had a distinct pattern, with homogeneous, transmural dense defects encompassing substantial regions of the myocardium. The distribution of i ‘C-palmitate in the regions extraneous to these obvious defects conformed qualitatively and quantitatively to the pattern observed in normal myocardium in normal subjects studied previously.“’ These findings suggest that previous myocardial infarction was largely responsible for the ischemic cardiomyopathy associated with CAD in the patients studied. Although dilated cardiomyopathy may occur in patients with extensive CAD in the absence of preceding infarction, we could not identify such a patient. Similarly, Dash et al”’ noted that patients with a cardiomyopathic syndrome caused bv CAD had a higher incidcnce of myocardial infarction and a particularly high incidence of transmural myocardial infarction than patients with CAD of similar severity without congestive heart failure. Morphologic studies by Virmani and Roberts-!” and Schuster and Bulkley” also demonstrated a high prevalence of healed transmural myocardial infarcts in their studies of patients with severe CAD and congestive heart failure. Although the finding of dense “metabolic defects” in patients with ischemic cardiomyopathy is most consistent with transmural infarction and depressed accumulation of “C-palmitate, the pattern observed may be influenced by the characteristics of the imaging device. PET IV has limited resolution (12.5 mm FWHM) and is operated without cardiac gating, resulting in both spatial and temporal averaging of the data. Thus, the dense tomographic defects could represent transmural infarcts or large nontransmural infarcts with an epicardial rim of viable myocardium with activity too low for detection bv the instrument. Furthermore, metabolic heterogeneity occurring at the “borders” of the infarct that might be evident with a higher resolution instrument cannot be excluded. Some of the spatial heterogeneity of “C-palmitate accumulation in patients with nonischemic cardiomyopathy could be due to partial volume effects and spatial and temporal averaging. A high incidence of diabetes mellitus has been notcd in patients with ischemic cardiomyopathy.” ?-IThe severity of congestive heart failure and left ventricular dysfunction were comparable among diabetic and nondiabetic subjects with ischemic cardiomyopathy, in concordance with the observations of Dash.” The extent of heterogeneity of apparent tissue content of “C-palmitate in regions free from infarction was slightly higher in diabetic than nondiabetic subjects with ischemic cardiomyopathv. However, the number of discrete regions observed in diabetic subjects was significantly lower than that of patients with nonischcmic cardiomyopathy. Although the data cannot exclude the possibility that a diffuse myopathic process

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exists in these diabetic patients, the small number of patients studied precludes a definitive conclusion. Because ischemic cardiomyopathy appears to reflect multiple myocardial infarcts in many subjects, procedures sensitive for detecting infarction may be considered sensitive for detecting ischemic cardiomyopathy. Unfortunately, assessment of regional wall motion by radionuclide ventriculography or Z-dimensional echocardiography does not sufficiently differentiate patients with ischemic from those with nonischemic cardiomyopathy.‘“,” Electrocardiography is neither sufficiently sensitive nor specific for this purpose.‘,:’ Thallium scintigraphy, although used often, is not ideal.” Bulkley et al”’ noted that small apical defects in patients with nonischemic cardiomyopathy could be distinguished from the large perfusion defects encompassing at least 40% of the circumference of the left ventricle observed in patients with ischemic cardiomyopathy. A subsequent study confirmed these findings.” However, the quantitative power of thallium scintigraphy is limited by poor spatial resolution, variable attenuation of the emitted photons and the relatively nonphysiologic nature of the tracer.” In the group studied here, the diagnosis of ischemic cardiomyopathy was suggested clinically by history and noninvasive testing in 9 of the 10 subjects, and the diagnosis of nonischemic cardiomyopathy was suspected based on the clinical presentation and noninvasive tests in most of the patients (6 of lo), but overall, there was sufficient question that 12 of the 20 patients studied here underwent cardiac catheterization and coronary angiography to establish a definitive diagnosis. PET after intravenous injection of llC-palmitate has quantitative power sufficient for detecting, charac-

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RELATIVE “C-PALMITATE CONTENT (%Maximum in Myocardium ) FIGURE 2. Frequency distribution of myocardial “C-palmitate content calculated for patients with ischemic (inferrupfed line) and nonischemic cardiomyopathy (solid line). Relative myocardial volume is plotted on the ordinafe and myocardial “C-palmitate expressed as a percentage of maximal myocardial “C-palmitate content is plotted on the abscissa. Data from the lowest 3 deciles were pooled and plotted at 15%. Data were calculated for each of the remaining 7 deciles and plotted at the midpoint of the decile. Brackefs indicate standard error of the mean.

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terizing and delineating the extent of myocardial infarction.l”-l5 The data reported here indicate that PET can differentiate patients with ischemic from those with nonischemic cardiomyopathy. As instrumentation with better temporal and spatial resolution becomes available, analysis of regional myocardial tracer kinetics, with a variety of metabolic substrates, is likely to facilitate differentiation among diffuse cardiomyopathic states associated with different etiologies as well as differentiation of nonischemic from ischemic cardiomyopathy. In addition, progress in the assessment of myocardial perfusion with short halflife tracers, detected tomographically, should aid in delineation of the extent to which observed regional abnormalities of myocardial metabolism associated with cardiomyopathy are reflections of altered perfusion, as opposed to altered metabolism per se.27,28 Acknowledgment: We thank Elizabeth Galie and Theron Baird for technical support, Michael Welch, PhD, and David Marshall for the preparation of the isotopes, and Joyce Kalayeh and Kelly Hall for secretarial assistance.

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