Timothy F. Christian

Infarct Size After Acute Myocardial Infarction Measured by Quantitative Tomographic 99mTc Sestamibi Imaging Predicts Subsequent Mortality

BACKGROUND 99mTc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated. METHODS AND RESULTS Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic 99mTc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of < or = 10%. The median amount of myocardium salvaged was 9% (range, -31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (chi 2 = 8.66, P = .003) and cardiac mortality (chi 2 = 11.89, P < .001). Two-year mortality was 7% for patients whose infarct size was > or = 12% versus 0% for patients whose infarct size was < 12%. There also was a significant association between myocardium at risk and cardiac mortality (chi 2 = 6.87, P = .009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality. CONCLUSIONS Larger infarct size measured by 99mTc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.

Infarct Size Measured by Single Photon Emission Computed Tomographic Imaging With 99mTc-Sestamibi A Measure of the Efficacy of Therapy in Acute Myocardial Infarction

BACKGROUND Use of mortality as an end point in randomized trials of reperfusion therapy requires increasingly large sample sizes to test advances compared with existing therapy, which is already highly effective. There has been a growing interest in infarct size measurements by (99m)Tc-sestamibi SPECT (single photon emission computed tomographic) imaging as a surrogate end point. METHODS AND RESULTS We reviewed the reports published in English regarding infarct size measurements by (99m)Tc-sestamibi. Four separate lines of published evidence support the validity of SPECT imaging with (99m)Tc-sestamibi for determination of infarct size. This end point has been used in a total of 7 randomized trials-1 single center and 6 multicenter. The end point compares favorably with left ventricular function and infarct size measurements with the use of other radiopharmaceuticals. The most important limitation of this approach is the absence thus far of a randomized trial that has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size. CONCLUSIONS SPECT imaging with (99m)Tc-sestamibi is the best available measurement tool for infarct size. It has already served as an end point in early pilot studies to evaluate potential efficacy and in dose-ranging studies. It has the potential to serve as a surrogate end point to uncover advantages of new therapies that may be equivalent to existing therapies with respect to early mortality.

Determinants of infarct size in reperfusion therapy for acute myocardial infarction.

BackgroundExperimental animal studies have demonstrated that myocardium at risk, residual collateral flow, and duration of coronary artery occlusion are important determinants of final infarct size. The present study examined these variables in patients with acute myocardial infarction in relation to final infarct size. Methods and ResultsMyocardium at risk was assessed with hexakis(2-methoxyisobutyl isonitrile) technetium (I) (99mETc sestamibi) in 89 patients with first-time myocardial infarction (anterior, 48 patients; inferior, 41 patients). All patients had successful reperfusion therapy with either intravenous thrombolysis (32 patients) or primary coronary angioplasty (57 patients) within 24 hours of the onset of chest pain (4.7±3.9 hours; range, 0.5–21.5 hours) documented by coronary angiography. 99mTc sestamibi was injected intravenously before reperfusion therapy, and tomographic imaging was performed 1–6 hours later. Myocardium at risk was quantitated for each patient and expressed as a percentage of the left ventricle: 35±19%; range, 2–73%. Collateral flow was estimated by both invasive and noninvasive methods. Fifty-three patients with TIMI grade 0 or I flow who underwent primary coronary angioplasty had collateral flow graded angiographically (0–3) before the first balloon inflation. All patients had collateral flow estimated noninvasively from the acute sestamibi short-axis profile curve by three methods that assess the severity of the perfusion defect. Each of these three methods was significantly associated with angiographic collateral grade. Final infarct size was determined at hospital discharge by a second sestamibi study (17±17%; range, 0–59%). Myocardium at risk (r = 0.61, p<0.0001), angiographic collateral grade (p = 0.0003), and radionuclide estimates of collateral flow (r = 0.69–0.70, all p<0.0001) were all significantly associated with final infarct size. The time to reperfusion therapy was not significantly associated with final infarct size by univariate analysis (r = 0.18, p = 0.10). Two multivariate models were constructed to determine which variables were independently associated with final infarct size. In the invasive model, myocardium at risk, angiographic collateral grade with an interaction term for infarct location, and time to reperfusion were all independently significant and accounted for 70% of the variability in final infarct size. The noninvasive model, which substituted a radionuclide estimate of collateral flow for angiographic collateral grade, showed nearly identical results, accounting for 68% of the variability in infarct size in patients where the infarct artery was known to be occluded. When all patients were included (patients with and without acute angiography), the noninvasive model accounted for 59% of the variability in infarct size. ConclusionsMyocardium at risk, collateral flow, and duration of coronary occlusion are each independently associated with final infarct size and account for most of its variability. Ideally, all three parameters should be examined in evaluation of the efficacy of new treatment strategies for acute myocardial infarction.

Relation of initial infarct size to extent of left ventricular remodeling in the year after acute myocardial infarction

OBJECTIVES This study attempted to determine the relation between infarct size after acute myocardial infarction and subsequent left ventricular remodeling using precise clinical measurements. BACKGROUND Animal studies have demonstrated that the degree of left ventricular remodeling after myocardial infarction is linearly related to infarct size. Clinical studies have not clearly replicated these results because of imprecise measurements and failure to adjust for patency of the infarct-related artery. METHODS Infarct size was measured from technetium-99m (Tc-99m) sestamibi perfusion images in 14 patients (12 with an anterior, 2 with an inferior infarction) by a threshold method previously described and expressed as percent of the left ventricle (32 +/- 17% left ventricle [mean +/- SD], range 6% to 58%). Absolute end-systolic volume, end-diastolic volume and ejection fraction were determined by electron beam computed tomographic images performed at discharge and at 6 weeks, 6 months and 1 year after myocardial infarction. All patients had documented infarct-related artery patency after reperfusion therapy. RESULTS At hospital discharge, there was no correlation between infarct size and end-systolic and end-diastolic volumes or ejection fraction. There was significant left ventricular dilation in the study group over the next year. As remodeling progressed, there was closer correlation between infarct size and ejection fraction and end-systolic volume measures (infarct size vs. end-systolic volume, from r = 0.43 at discharge to r = 0.80 at 1 year; infarct size vs. ejection fraction, from r = -0.39 at discharge to r = -0.84 at 1 year). There was a strong inverse correlation between infarct size at discharge and subsequent changes over the next year in end-systolic volume (r = 0.63, p = 0.02) and ejection fraction (r = -0.66, p = 0.01). CONCLUSION Infarct size as measured by Tc-99m sestamibi at hospital discharge after an index infarction is predictive of subsequent change in left ventricular volume and function in the year after myocardial infarction. Patients with a large infarct demonstrated the greatest degree of dilation in the setting of patency of the infarct-related artery.

Noninvasive identification of severe coronary artery disease using exercise tomographic thallium-201 imaging

The ability of exercise thallium-201 tomographic imaging to predict the presence of left main or 3-vessel coronary artery disease (CAD) was examined in 688 patients who underwent both exercise thallium-201 testing and coronary angiography. Significant differences existed for multiple variables between patients with (n = 196) and without (n = 492) severe left main or 3-vessel CAD. Logistic regression analysis identified 4 variables as independently predictive of left main or 3-vessel CAD. These variables were the magnitude of ST-segment depression with exercise, the number of visually abnormal short-axis thallium-201 segments, the presence or absence of diabetes mellitus, and the change in systolic blood pressure with exercise. Using these variables, patients were classified by nomograms into low-, intermediate- and high-probability groups. Patients at high probability (n = 205) had a 52% prevalence of 3-vessel or left main CAD, whereas those at low probability (n = 170) had only a 12% prevalence. Only 53 patients (29%) with 3-vessel or left main CAD had perfusion abnormalities in all 3 coronary territories. Clinical and exercise parameters provide important independent information in the identification of left main or 3-vessel CAD by exercise thallium-201 tomographic imaging, because thallium scintigraphy alone is suggestive of extensive CAD in few patients.

Independent and incremental value of coronary artery calcium for predicting the extent of angiographic coronary artery disease: Comparison with cardiac risk factors and radionuclide perfusion imaging☆

OBJECTIVES The study was done to test the ability to predict the extent of angiographically determined coronary artery disease (CAD) by quantification of coronary calcium using electron-beam computed tomography (EBCT) and to compare it with more conventional parameters for delineating the angiographic extent of CAD, that is, cardiovascular risk factors and radionuclide single-photon emission computed tomography (SPECT). BACKGROUND The angiographic extent of CAD is a powerful predictor of subsequent events. Use of EBCT may be able to define it by virtue of its ability to determine plaque burden. METHODS We examined 308 patients presenting with suspected but not previously known CAD who underwent selective coronary angiography. As measures of the angiographic extent of CAD, coronary artery greater even 20 (CAGE > or =20) and CAGE > or =50 scores represented the total number of coronary segments with > or =20% or > or =50% stenoses, respectively. The EBCT-derived total calcium scores were obtained in 291 patients, risk factors as defined by the National Cholesterol Education Program in 239 patients, and SPECT scans in 136 patients. RESULTS Using multiple linear regression analysis, total calcium scores were better independent predictors of both CAGE > or =20 and CAGE > or =50 scores than either a SPECT-derived radionuclide perfusion score or the risk factors age, male gender and ratio of total/high-density lipoprotein (HDL) cholesterol. The association between EBCT and angiographic scores remained highly significant after excluding the influence of all interrelated risk factors and SPECT variables (r = 0.65; p < 0.001 for CAGE > or =20 scores, r = 0.50; p < 0.001 for CAGE > or =50 scores). CONCLUSIONS Coronary calcium predicts the angiographic extent of CAD in symptomatic patients and provides independent and incremental information to the more conventional clinical parameters derived from SPECT or risk assessment.

Time to therapy and salvage in myocardial infarction

OBJECTIVES This study sought to examine the influence of time to reperfusion on myocardial salvage. BACKGROUND Major trials of reperfusion therapy for myocardial infarction (MI) have demonstrated improved outcome for patients achieving earlier reperfusion. However, some patients experience significant benefit despite delayed reperfusion. METHODS Fifty-five patients with a first anterior MI underwent successful reperfusion therapy (angioplasty or thrombolysis). Technetium-99m (Tc-99m) sestamibi was injected before reperfusion therapy and again at hospital discharge to determine the myocardial salvage index for each patient. Residual flow to the infarct territory was assessed by the nadir of the Tc-99m sestamibi count-profile curve. RESULTS The salvage index showed wide variability (range -0.04 to 1.0), and extreme values were seen in 34.5% of the group (<0.10 in 9%, >0.90 in 25%). A high salvage index was associated with reperfusion therapy before 2 h (p=0.02) or good residual blood flow (p < 0.01). For the 10 patients who received reperfusion therapy within 2 h, residual blood flow was not correlated with salvage (p=0.12). For the 45 patients treated after 2 h, residual blood flow correlated significantly with salvage (r=0.57, p < 0.0001). There was a significant interaction (p < 0.05) between residual blood flow and time to therapy, indicating that the effect of each variable on salvage depended on the value of the other. Multiple historic and hemodynamic variables were examined, but none demonstrated any association with residual flow or myocardial salvage. CONCLUSIONS In patients with acute MI, successful reperfusion therapy within 2 h is associated with the greatest degree of myocardial salvage. For patients treated after 2 h, residual blood flow to the infarct-related territory appears to be the most important determinant of myocardial salvage.

Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction : identification of myocardial stunning and hyperkinesia

Quantitation of perfusion defect size using tomographic imaging with technetium-99m-hexakis-2-methoxy isobutyl isonitrile was performed at the time of hospital discharge in 32 patients with a first myocardial infarction who underwent successful coronary reperfusion within 8 h of the onset of chest pain. Reperfusion was accomplished with thrombolysis or primary coronary angioplasty. Radionuclide angiography was performed at discharge and 6 weeks later. There was a close correlation between perfusion defect size and values for ejection fraction and regional wall motion both at discharge (r = -0.80 and -0.75, respectively) and 6 weeks later (r = -0.81 and -0.81, respectively). There was no overall group difference in ejection fraction between the value at discharge and at 6 weeks; however, five patients had a significant increase (greater than or equal to 0.08) and six had a significant decrease (greater than or equal to 0.08) in ejection fraction. In patients with a significant increase at 6 weeks, ejection fraction was significantly lower at discharge than the value predicted from perfusion defect size (0.37 +/- 0.09 measured versus 0.47 +/- 0.13 predicted, p less than 0.05) and it improved at 6 weeks to near predicted values (0.51 +/- 0.07). In patients with a significant decrease at 6 weeks, ejection fraction was significantly higher at discharge than the value predicted from perfusion defect size (0.60 +/- 0.10 measured versus 0.50 +/- 0.10 predicted, p less than 0.05) and it decreased at 6 weeks to near predicted levels (0.51 +/- 0.09). Left ventricular ejection fraction at the time of hospital discharge is a potentially misleading index of the efficacy of reperfusion therapy for myocardial infarction. In a significant minority (34%) of patients this index does not accurately reflect perfusion defect size, apparently because of the effects of myocardial stunning and compensatory hyperkinesia.

Estimates of myocardium at risk and collateral flow in acute myocardial infarction using electrocardiographic indexes with comparison to radionuclide and angiographic measures.

OBJECTIVES This study sought to determine the accuracy of the initial 12-lead electrocardiogram (ECG) in predicting final infarct size after direct coronary angioplasty for myocardial infarction and to examine which physiologic variables known to be determinants of outcome the ST segment changes most closely reflect. BACKGROUND Myocardium at risk, collateral flow and time to reperfusion have been shown to be independent physiologic predictors of infarct size in animal and clinical models. However, such measurements may be difficult to perform on a routine basis in patients with myocardial infarction. The standard 12-lead ECG is inexpensive and readily available. METHODS Sixty-seven patients with acute myocardial infarction, ST segment elevation and duration of chest pain < 12 h had an initial injection of technetium-99m sestamibi. Tomographic imaging was performed 1 to 8 h later (after direct coronary angioplasty), and the images were quantified to measure perfusion defect size (myocardium at risk) and severity (a measure of collateral flow). Contrast agent injection and tomographic acquisition were repeated at hospital discharge to measure infarct size. The ST segment elevation score was calculated for each patient according to infarct location and using previously described formulas. RESULTS ST segment elevation score correlated closest with the radionuclide measure of collateral flow (r = -0.44, p < or = 0.0001), as well as an angiographic measure of collateral flow (r = -0.38, p = 0.05). Although ST segment elevation score correlated weakly with the magnitude of myocardium at risk by technetium-99m sestamibi, it was not as strong as infarct location alone in predicting myocardium at risk ([mean +/- SD] anterior 51 +/- 13% left ventricle vs. inferior 17 +/- 10% left ventricle, p < 0.0001). ST segment elevation score was weakly associated with final infarct size (r = 0.34, p = 0.005). A multivariate ECG model was constructed with infarct location as a surrogate for myocardium at risk, ST segment elevation score as a surrogate for estimated collateral flow, and elapsed time to reperfusion from onset of chest pain. All three variables were independently associated with infarct size. CONCLUSIONS The initial standard 12-lead ECG can provide insight into myocardium at risk and, to a greater extent, collateral flow and can consequently provide some estimate of subsequent infarct size. However, the confidence limits for such predictors are wide.

Exercise Tomographic Thallium-201 Imaging in Patients with Severe Coronary Artery Disease and Normal Electrocardiograms

Thallium-201 scintigraphy has significantly increased the ability of exercise testing to help identify patients with coronary artery disease [1-3] and localize diseased vessels [4-6]. In a previous study, we showed that the extent of the postexercise perfusion defect on tomographic thallium-201 images, the magnitude of ST-segment depression during exercise, the presence of diabetes mellitus, and the change in systolic blood pressure during exercise were independent predictors of three-vessel or left main coronary artery disease [7]. However, the effect of thallium-201 scintigraphy varied considerably depending on the clinical and exercise data. Thallium-201 exercise testing provides important prognostic information that compares favorably with that provided by coronary anatomy and left ventricular function [8-10]. However, in clinical practice, the data are available in increments that start with the history and physical examination and are followed by an exercise study with or without cardiac imaging. Diamond [11, 12] has proposed that the predictive value of a test should be evaluated in the context of what is already known about a patient because these data influence the pretest probability of developing disease. Our previous reports, for which we used exercise radionuclide angiography [13, 14], and those by others who used thallium-201 scintigraphy [15-17], have suggested that radionuclide imaging adds little diagnostic or prognostic information for patients with normal at-rest electrocardiograms. Therefore, we sought to determine the incremental diagnostic information obtained from tomographic thallium-201 scintigraphy for predicting three-vessel or left main coronary artery disease in patients with normal at-rest electrocardiograms and to estimate the cost-effectiveness of this approach. Methods We selected the study group from 18 076 consecutive patients who were referred to the Mayo Clinic Nuclear Cardiology Laboratory for exercise thallium studies between November 1986 and June 1992. Of these, 2638 patients had coronary angiography within 6 months of the exercise study and had no intervening cardiac event, valvular heart disease, previous revascularization, or left bundle-branch block. Patients were excluded from the study if they had previous myocardial infarction (n = 1194), digitalis within 48 hours of the exercise thallium-201 study (n = 175), a technically unsatisfactory study (n = 14), or any abnormalities shown on the at-rest electrocardiogram (n = 844) other than sinus bradycardia, as defined by Gibbons and colleagues [13]. These abnormalities included pathologic Q-waves, abnormalities of rhythm, ventricular conduction, QRS voltage, and axis or any ST-T wave changes, including minor nonspecific abnormalities. The study group comprised 411 patients who met all of the entry criteria and none of the exclusion criteria. We prospectively collected data for clinical, exercise, and thallium-201 variables for each patient at the time of the thallium-201 exercise study, as detailed in previous reports Table 1 [7, 18]. Diabetes was classified for each patient as present or absent; when present, the diabetes was classified as that which either required insulin or did not require insulin. Table 1. Clinical, Exercise, and Thallium-201 Variables Exercise Protocol All patients had treadmill exercise using either the Bruce protocol (n = 368) or the Naughton protocol (n = 43). For patients using the Naughton protocol, we applied a conversion factor to equate exercise duration with the Bruce protocol [19]. Heart rate and electrocardiographic rhythm strips (leads II, aVF, and V5) were obtained continuously; blood pressure by cuff sphygmomanometry and 12-lead electrocardiograms were obtained for each level of exercise. We measured ST-segment displacement 80 ms after the J point and classified it as less than 1, 1 to 1.9, or 2 mV depression. At peak exercise, 4 mCi of thallium-201 was injected intravenously, and patients (n = 161) exercised an additional minute. Because of a change in protocol in January 1991, 250 patients received 3 mCi of thallium-201 at peak exercise and an additional 1 mCi of thallium-201 3.5 hours after exercise (30 minutes before delayed imaging). Tomographic Thallium-201 Imaging Imaging was done while patients were in the supine position 10 to 15 minutes after exercise and again 4 hours later. We initially obtained a single 5-minute anterior planar image to assess cardiac size and the ratio of pulmonary-to-myocardial thallium-201 uptake. Tomographic imaging was then done over a 180-degree arc for 30 images using previously described techniques [7]. Filtered back projection was done using a Ramp-Hanning filter and previously described methods[7]. Visual Analysis of Tomographic Images Two experienced observers visually assessed the thallium tomographic images. Cardiac enlargement and increased pulmonary uptake were graded as present or absent. In borderline cases, pulmonary uptake was quantified; a ratio of maximal pulmonary-to-myocardial counts of greater than 0.50 was considered elevated. We then divided short-axis images into 14 segments as previously described [20]. We used a 5-point scoring system to assess each segment on both the postexercise and delayed images (4 = normal, 0 = no perfusion). We calculated a global score for each set of images by adding the values assigned to each of the 14 short-axis segments. Therefore, a maximum global score was 4 14, or 56, for a normal set of images. An abnormal segment was considered present if perfusion improved one or more grades from the post-stress to the delayed images or if a fixed defect of at least moderate severity was present ( 2 grades). We did not consider mild fixed defects (3 grades post-stress and 3 grades delayed) to be abnormal so that potential breast and diaphragmatic attenuation would not be labeled as abnormal. Short-axis segments were also grouped into three coronary distributions as previously described [7]. Coronary Angiography All patients had coronary angiography within 6 months of thallium-201 exercise testing. A review of patients with normal at-rest electrocardiograms studied in our laboratory between 1986 and 1992 showed that the odds for being referred for coronary angiography was 4:1 for patients with an abnormal thallium scan compared with those with a normal scan. We visually estimated coronary artery narrowing and expressed it as percent luminal diameter stenosis. A 70% narrowing of the internal diameter of the left-anterior descending, left circumflex, and right coronary arteries or their major branches and a 50% narrowing of the left main coronary artery were considered significant [21]. Follow-up All patients were contacted by letter or telephone. Events were determined by physician contact or hospital records. We defined significant cardiac events as nonfatal myocardial infarction or cardiac death. For the primary analysis, patients who had coronary artery bypass grafting or coronary artery angioplasty were not censored at the time of revascularization. A secondary analysis was done with patients censored (that is, not included in the survival analysis) at the time of revascularization. Cost Analysis We determined all costs for tests using 1992 reimbursement fees by Medicare in the State of Minnesota. The cost of exercise thallium scintigraphy includes the cost of a standard exercise treadmill. Statistical Analysis We used an unpaired t-test or Pearson chi-square test to identify variables significantly associated with three-vessel or left main coronary artery disease. Logistic regression analysis was used to develop multivariable models for predicting the presence or absence of three-vessel or left main coronary artery disease [22]. Variables were considered for stepwise inclusion in the model until a simultaneous test of all variables not entered was not significant (that is, P > 0.05). We used this strict criteria for model entry to prevent the detection of spurious associations. First, to construct a clinical model, we considered clinical variables alone. Exercise variables and, subsequently, thallium-201 variables were then considered for inclusion in the model to determine whether they added independent predictive value. No thallium-201 variables met the strict entry criteria once the clinical and exercise variables were considered. Because thallium-201 variables have previously been shown to be highly predictive of severe coronary disease [6, 7], the inclusion criteria were relaxed and thallium-201 variables were entered into the model based on their individual P value rather than on the simultaneous test of residual variables. We then used each logistic regression model to estimate the probability of developing three-vessel or left main coronary artery disease for each patient by classifying them as having low (<15%), intermediate (15% to 35%), or high (>35%) probability. We chose these probability groupings because they corresponded to those of previous studies [7, 18]. Patients were considered to be correctly classified if their predicted probability was low and they did not have three-vessel or left main coronary artery disease or if they were predicted to be at high risk and had severe disease. Incorrect classification was the reverse case: patients classified as having low probability who were ultimately found to have three-vessel or left main disease or those classified as having high probability who had no such disease. Patients with intermediate probability were not considered as correctly or incorrectly classified. We repeated the analysis with a second set of probability cutoff values (low, <10%; intermediate, 10% to 25%; high, >25%) to assess the sensitivity of the results to the cutoff values. We did a cross-validation multivariate analysis to remove any bias in estimates of correct classification rates. In this analysis, we randomly divided the patients into 10 groups. Using 9 of the 10