Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.

A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassaemia. This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

Inhibition of bacterial adherence by secretory immunoglobulin A: a mechanism of antigen disposal.

Preparations of secretory iminunoglobuilin A (S-IgA) isolated from human parotid fluid specifically inhibited the adherence of Streptococcus strains to epithelial cells. Since bacterial adherence is a prerequisite for colonization of mucous surfaces. S-IgA-mediated inhibition of adherence would limit bacterial colonization. This mechanism can explain how secretory immunoglobulins function in the disposal of bacterial antigens.

Threshold values for preserved viability with a noninvasive measurement of collateral blood flow during acute myocardial infarction treated by direct coronary angioplasty.

BACKGROUND: Quantitative measures of myocardial perfusion defect severity from acute (99m)Tc-sestamibi tomographic images (nadir) have correlated closely with collateral and residual antegrade blood flow during acute myocardial infarction. The purpose of this study was to determine whether a viability threshold could be identified from this measure in patients with acute myocardial infarction treated in a homogeneous manner with successful reperfusion therapy. METHOD AND RESULTS: The study group consisted of 61 patients with acute myocardial infarction with a risk area of >6% LV treated with primary angioplasty between 120 and 240 minutes after symptom onset. All patients were injected with 20 to 30 mCi of (99m)Tc-sestamibi before primary angioplasty and imaged after the procedure. Acute myocardium at risk (MAR) and subsequent infarct size (IS) were quantified by a threshold program. Severity (nadir) from the acute image was the lowest ratio of minimal/maximum counts from 5 short-axis slices. Infarct location was anterior in 22 and inferior in 39 patients. MAR was 33+/-15% LV and IS was 13+/-15% LV: 23 patients had no infarction despite MAR similar to those with infarction. Receiver-operator characteristic curve analysis identified a nadir value of 0.26 as providing the best separation of patients with and without infarction (sensitivity, 74%; specificity, 74%). This nadir threshold varied by infarct location: anterior defect, 0.21; inferior defect, 0.31. The sensitivity and specificity for absent infarction for these values were anterior, 69% and 67%, and inferior, 88% and 84%, respectively. CONCLUSIONS: In a time frame in which the presence of residual blood flow is important, the severity of the acute (99m)Tc-sestamibi defect can be used to predict whether infarction will develop despite successful reperfusion.

Similarity of ventricular function in patients alive 5 years after randomization to surgery or angioplasty in the BARI trial.

BACKGROUND: Left ventricular ejection fraction (LVEF) is a recognized determinant of survival in patients with coronary artery disease. In major trials comparing surgical and percutaneous revascularization approaches, the long-term effect of the coronary revascularization strategy on LVEF has not been reported. METHODS AND RESULTS: In the NHLBI-sponsored Bypass and Angioplasty Revascularization Investigation (BARI) randomized trial comparing angioplasty and bypass surgery as initial treatment strategies, 1220 (75%) of the 1617 surviving randomized patients had their EF measured by radionuclide ventriculography 5 years after study entry. For the total study group, the 5-year EF in the CABG group (n=623) was 55.8+/-12.3, compared with 55.7+/-12.7 in PTCA group (n=597, P:=0.82). There was no significant difference in measured EF between the CABG group and the PTCA group within multiple subgroups determined by the presence or absence of diabetes, 3-vessel disease, complete revascularization, or prior myocardial infarction. In a multiple linear regression model developed to predict 5-year EF, treatment assignment to PTCA or CABG was not significant (P:=0.95). If an EF of 0 was imputed for patients who were dead and missing EF data, however, there was a higher EF in the CABG group (P:=0.0018) among diabetic patients only. CONCLUSIONS: In the BARI randomized trial, initial treatment assignment to angioplasty was not associated with any difference in long-term ventricular function compared with initial treatment assignment to surgery. These results apply, however, only to patients who were alive at 5 years.

Long-term outcome of patients with intermediate-risk exercise electrocardiograms who do not have myocardial perfusion defects on radionuclide imaging.

BACKGROUND: The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging. METHODS AND RESULTS: The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (-10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement. CONCLUSIONS: Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.

Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study.

BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.

Severity and response of chest pain during thrombolytic therapy for acute myocardial infarction: a useful indicator of myocardial salvage and infarct size.

OBJECTIVES: The purpose of this study was to determine noninvasively whether chest pain severity is predictive of the amount of myocardium at risk and whether the response of pain during thrombolysis is associated with myocardial salvage during acute myocardial infarction. BACKGROUND: The perception of chest pain and response to reperfusion therapy during acute myocardial infarction may provide important information for treatment benefit. Previous studies have been limited by the inability to measure myocardium at risk and myocardial salvage. METHODS: Sixty-two patients with acute myocardial infarction received an injection of technetium-99m sestamibi before thrombolysis and again at hospital discharge. Tomographic imaging was performed 1 to 6 h later. Myocardium at risk, infarct size and absolute myocardial salvage were derived from these images using previously described techniques and were expressed as a percent of the left ventricle. Salvage index was calculated by dividing myocardial salvage by the myocardium at risk. Chest pain severity was graded before thrombolysis as none, mild, moderate or severe. Chest pain response during thrombolytic therapy was graded as none, partial or completely resolved. RESULTS: There was no association between chest pain severity and myocardium at risk, but there was a weak trend toward greater myocardial salvage and salvage index (p = 0.09 and p = 0.12, respectively) for patients with more severe symptoms. Patients without chest pain at the start of thrombolysis still demonstrated significant salvage (11 +/- 11% of the left ventricle, p = 0.009). There was a significant association between chest pain response to therapy and both myocardial salvage (p = 0.03) and salvage index (p = 0.01). By multivariate analysis, chest pain severity and response of chest pain during thrombolysis were significant independent predictors of myocardial salvage, salvage index and infarct size. Thrombolysis was most effective in the 20 patients (32%) with moderate or severe chest pain and complete resolution of symptoms during thrombolysis (salvage of 79% to 89% of the area at risk). In the remaining 32 patients with chest pain, salvage of the area at risk was only 32%. CONCLUSIONS: These findings suggest that the assessment of chest pain before and after thrombolytic therapy is a readily available, useful indicator of the efficacy of the therapy.

Exercise response of the systolic pressure to end-systolic volume ratio in patients with coronary artery disease.

The exercise response of the ratio of systolic blood pressure to end-systolic volume was studied in 243 patients with chest pain and coronary artery disease who underwent supine rest and exercise equilibrium radionuclide angiography. There was a wide variation in both rest and exercise variables in this group. The exercise response of the systolic pressure/volume ratio also varied greatly, ranging from a decrease of 59% to an increase of 136%. Twenty-one clinical, catheterization and radionuclide angiographic variables were examined to determine their relation to the exercise response of the systolic pressure/volume ratio; nine variables were individually correlated with this ratio. Multiple regression analysis identified the change in end-diastolic volume index with exercise, rest systolic blood pressure, coronary artery Gensini score and peak work load as significant independent predictors of the exercise response of the systolic pressure/volume ratio; the latter correlated significantly with the change in ejection fraction with exercise (r = 0.73, p less than 0.0001). Its sensitivity for the detection of coronary artery disease in the study group (84%) and its "normalcy rate" in a group of 120 patients with a low likelihood of coronary artery disease (81%) were similar to those of the peak exercise ejection fraction (75 and 82%, respectively). These results demonstrate that the exercise response of the systolic pressure/end-systolic volume ratio is a complex response that is influenced by several pathophysiologic variables in the presence of coronary artery disease. It does not offer any advantage over ejection fraction measurements for the detection of exercise-induced ischemia.

Coronary artery venous bypass graft aneurysm with symptomatic coronary artery emboli.

A 53 year old man, asymptomatic for 9 years after aorto-right coronary artery venous bypass surgery, developed two prolonged episodes of myocardial ischemia during a 7 month interval. Diagnostic exercise tests subsequent to each episode were normal. Coronary angiography demonstrated marked dilation with filling defects of the venous bypass graft. A large thrombus-filled venous bypass graft aneurysm was excised at surgery. Spontaneous coronary artery embolization related to a venous bypass graft aneurysm has not been described previously, but may become more frequent as survival and follow-up after coronary bypass surgery lengthen.

Prognosis in patients with an abnormal exercise radionuclide angiogram in the absence of significant coronary artery disease.

To investigate the prognostic importance of abnormal exercise left ventricular function on radionuclide angiography in the absence of significant angiographic coronary artery disease, 79 consecutive patients with these findings were followed up for a mean of 25 months (range 12 to 55). All patients had 1) an ejection fraction at rest greater than or equal to 0.40, 2) an ejection fraction that decreased with exercise or peak exercise ejection fraction less than 0.60, and 3) no significant coronary artery disease. The mean change in ejection fraction was a decrease of 0.07. In 63 patients (80%), the ejection fraction decreased during exercise; in 45 patients, it decreased by greater than or equal to 0.05. Twenty patients (25%) had a peak exercise ejection fraction less than 0.50. All patients were alive at follow-up study. One patient had a nonfatal myocardial infarction, and three patients were hospitalized for recurrent chest pain. No patient underwent coronary angioplasty or bypass surgery. The calculated infarction-free survival rate at 4 years by life table analysis was 97%. Patients with an abnormal exercise radionuclide angiogram in the absence of significant angiographic coronary artery disease have an excellent short-term prognosis.

Prospective identification of myocardial stunning using technetium-99m sestamibi-based measurements of infarct size.

OBJECTIVES: We sought to prospectively identify patients with stunning and hyperkinesia at hospital discharge on the basis of mismatches between left ventricular (LV) function and infarct size as assessed by technetium-99m (Tc-99m) sestamibi perfusion tomographic imaging. BACKGROUND: Mechanical indexes of LV function may not accurately reflect myocardial damage after acute myocardial infarction (MI) because of myocardial stunning and compensatory hyperkinesia in noninfarct-related territories. Myocardial perfusion techniques are unaffected by these variables. METHODS: Eighty-four patients with acute MI underwent hospital admission and discharge Tc-99m-sestamibi tomographic imaging. Global LV ejection fraction (LVEF) was measured at hospital discharge and 6 weeks later. The perfusion defect size was quantified and expressed as a percentage of the LV. The discharge perfusion defect, which is a measure of infarct size, was used to predict the 6-week LVEF for each patient based on a previously reported regression equation. Patients were classified into one of three groups depending on whether their LVEF at hospital discharge fell within, above or below one standard error (6.8 LVEF points) of the predicted 6-week LVEF. RESULTS: There were 48 patients classified as having a "match" between function and infarct size; these patients demonstrated no significant change in LVEF at 6 weeks. There were 21 patients (25%) classified as "mismatch stunned" who had discharge LVEFs lower than those predicted by infarct size. These patients demonstrated a significant improvement in mean LVEF at 6 weeks (mean [+/-SD] discharge LVEF 0.41 +/- 0.08, 6-week LVEF 0.47 +/- 0.10; p = 0.003). Fifteen patients (18%) were classified as "mismatch-hyperkinetic." The mean LVEF for these patients significantly declined at 6 weeks (discharge LVEF 0.64 +/- 0.06, 6-week LVEF 0.58 +/- 0.09; p = 0.002). There was a marked increase in LVEF within the infarct zone (8 +/- 15 LVEF points; p = 0.03) for patients predicted to have stunning and a marked decline in LVEF outside the infarct zone (9 +/- 15 LVEF points; p = 0.06) in patients predicted to have hyperkinesia. Both discharge LVEF (p < 0.0001) and group classification (p = 0.005) were independent predictors of LVEF 6 weeks later. CONCLUSIONS: Perfusion imaging with Tc-99m-sestamibi can identify post-MI patients at hospital discharge in whom LV function is discordant with the measured infarct size. Patients with stunning have late increases in LVEF; patients with hyperkinesia have late decreases. This methodology, performed at discharge, is predictive of late changes in LV function.

Effect of infarct location on myocardial salvage assessed by technetium-99m isonitrile.

To investigate the influence of infarct location on myocardial salvage, technetium-99m isonitrile was injected into 43 patients with a first myocardial infarction before early reperfusion therapy. Primary coronary angioplasty was performed in 22 patients and successful intravenous thrombolytic therapy was given to 15 patients, both within 6 h of the onset of chest pain. Patency of the infarct-related artery was confirmed by angiography in all 37 patients. In the remaining six patients (three with and three without early thrombolytic therapy) the infarct-related artery remained occluded. Single photon emission computed tomography was performed within 6 h of the administration of technetium-99m isonitrile and repeated at the time of hospital discharge. Radionuclide ejection fraction at discharge was significantly lower for patients with anterior infarction (0.41 +/- 0.12) than for those with inferior infarction (0.56 +/- 0.09, p less than 0.001). Early perfusion defect size, a measure of myocardium at risk, was greater in patients with anterior than in those with inferior infarction (52 +/- 9% vs. 18 +/- 10% of the left ventricle, p = 0.0001) as was final defect size (30 +/- 20% vs. 9 +/- 8%, p less than 0.01). The change in myocardial perfusion, an estimate of myocardial salvage, was also greater in patients with anterior infarction (24 +/- 16% vs. 10 +/- 7%, p less than 0.01). However, the proportion of jeopardized myocardium salvaged (salvage index) was not significantly different between patients with anterior or inferior infarction (0.49 +/- 0.34 vs. 0.59 +/- 0.35, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Myocardium at risk and infarct size after thrombolytic therapy for acute myocardial infarction: implications for the design of randomized trials of acute intervention.

OBJECTIVES: The purpose of this study was to estimate the effect of an improved reperfusion therapy for acute myocardial infarction on myocardial salvage and ventricular function for anterior and inferior infarctions and to ascertain the sample size required to detect such an effect. BACKGROUND: There are significant differences in myocardium at risk between anterior and inferior infarctions that affect the benefit of reperfusion therapy. METHODS: We studied 58 patients with acute myocardial infarction (24 anterior, 34 inferior) treated with intravenous recombinant tissue-type plasminogen activator and angioplasty when necessary. Tomographic imaging with technetium-99m sestamibi was performed to measure myocardium at risk, final infarct size and myocardial salvage and to estimate the beneficial effects of an improved therapy. RESULTS: A new therapy that was 30% more effective than existing therapy (with respect to salvage) would increase salvage (and reduce mean infarct size) by 5.2% of the left ventricle and increase late ejection fraction by only 0.012 (95% confidence interval [CI] 0.009 to 0.015) in inferior infarction and by 0.038 (95% CI 0.027 to 0.047) in anterior infarction. If anterior and inferior infarctions occurred with equal frequency, a sample size of 140 patients in each treatment group would be required to detect such a change with 80% power. In a trial of interior infarctions alone, a sample size of 236 patients in each treatment group would be required compared with only 98 patients in a trial of anterior infarctions alone. CONCLUSIONS: The anticipated mean benefit from an improved reperfusion therapy in individual patients with inferior infarction is very small and of questionable clinical significance. The anticipated benefit in anterior infarction is greater and easier to detect. Future randomized trials should be stratified for infarct location and should consider the greater absolute benefit of treatment in anterior infarction.

Measurement of myocardium at risk by technetium-99m sestamibi: correlation with coronary angiography.

Previous studies have shown that tomographic perfusion imaging with technetium-99m sestamibi (RP-30A) can accurately measure the myocardium at risk during acute myocardial infarction. The ability of coronary angiography to predict the wide variability in myocardium at risk was studied in 21 patients with their first acute myocardial infarction. In blinded fashion, two experienced angiographers provided an overall "best estimate" of the percent of left ventricular myocardium at risk considering multiple angiographic variables--infarct-related artery, location of stenosis (proximal or nonproximal), vessel diameter, length, territory and the number and size of proximal branches and collateral vessels. Many of these individual variables showed a significant association with myocardium at risk. The most important angiographic variable was the mean best estimate of the two angiographers (r = 0.89, p less than 0.0001). However, the SEE was large (8.6% of the left ventricle) and angiography significantly (p less than 0.002) overestimated myocardium at risk. When patients with an anterior or an inferior infarct were considered separately, the angiographic best estimate had a weaker correlation with myocardium at risk measured by technetium-99m sestamibi in patients in both groups (anterior infarction r = 0.65, p = 0.04; inferior infarction r = 0.65, p = 0.04. Seven patients with an inferior infarct and myocardium at risk ranging from 7% to 32% of the left ventricle had identical angiographic best estimates. Although angiographic estimates correlate closely with measurements of myocardium at risk in groups of patients, their ability to predict the myocardium at risk in individual patients is limited.

Identification of severe coronary artery disease in patients with a single abnormal coronary territory on exercise thallium-201 imaging: the importance of clinical and exercise variables.

OBJECTIVES: The aim of this study was to determine which clinical, exercise and thallium variables can aid in the identification of three-vessel or left main coronary artery disease (3VLMD) in patients with one abnormal coronary territory (either a reversible or fixed defect) on exercise thallium testing and to test the prognostic value of these variables. BACKGROUND: Although the sensitivity of detection of coronary artery disease by thallium-201 imaging is high, the actual detection of 3VLMD by thallium tomographic images alone is not optimal. METHODS: A multivariate model for prediction of 3VLMD was developed from several clinical, exercise and thallium-201 variables in a training population of 264 patients who had one abnormal coronary artery territory on exercise thallium testing and had undergone coronary angiography. Using this model, patients were stratified into risk groups for prediction of 3VLMD. A separate validation cohort of 474 consecutive patients who were treated initially with medical therapy and who had one abnormal coronary territory were divided into identical risk groupings by the variables derived from the training population, and they were followed for a median of 7.0 years to evaluate the prognostic value of this model. RESULTS: The prevalence of 3VLMD was 26% in the training population despite one abnormal thallium coronary territory. Four clinical and exercise variables--diabetes, hypertension, magnitude of ST segment depression, and exercise rate-pressure product-were found to be independent predictors of 3VLMD. In the training population, the prevalence of 3VLMD in low-, intermediate- and high-risk groups was 15%, 22% and 51%, respectively. When the multivariate model was applied to the validation population, the eight-year overall survival rates in the low-, intermediate- and high-risk groups were 89%, 73% and 75%, respectively (p < 0.001). CONCLUSIONS: A substantial proportion of patients with one abnormal thallium coronary territory have 3VLMD with subsequent divergent outcomes based upon risk stratification by clinical and exercise variables. Consequently, the finding of only a single abnormal coronary territory by thallium-201 perfusion imaging does not necessarily confer a benign prognosis in the absence of consideration of nonimaging variables.

Prognostic value of exercise thallium-201 imaging performed within 2 years of coronary artery bypass graft surgery.

OBJECTIVES: We sought to determine the prognostic capabilities of exercise thallium (Tl)-201 tomographic imaging performed relatively early (within 2 years) after coronary artery bypass graft surgery (CABG). BACKGROUND: Exercise testing is commonly performed after CABG, but few data exist demonstrating its prognostic value in this setting. METHODS: Four hundred eleven patients were followed up for a median duration of 5.8 years. Eleven prospectively chosen clinical, exercise and Tl-201 variables were tested for their associations with outcome end points by means of proportional hazards regression models. RESULTS: During follow-up there were 60 deaths from any cause, 53 initial cardiac deaths or nonfatal myocardial infarctions (MIs) and 22 late (>3 months after the Tl-201 study) revascularization procedures. The number of abnormal Tl-201 segments on the postexercise image was the only variable in the multivariate analyses to show a significant association with all three outcome end points: chi-square 7.3, p = 0.007 for overall mortality; chi-square 8.1, p = 0.004 for cardiac death or MI; chi-square 7.8, p = 0.005 for any cardiac event. Other independent predictors of outcome were exercise duration (chi-square 10.7, p = 0.001) and age (chi-square 3.9, p = 0.049) for overall mortality and exercise angina score (chi-square 8.7, p = 0.003) for cardiac death or MI. The 5-year survival rate free of cardiac death or MI was 93% for patients without angina and a normal image or small postexercise perfusion defect versus 71% for patients with angina and a medium or large defect. CONCLUSIONS: Exercise Tl-201 imaging performed within 2 years of CABG can stratify patients into low and high risk subgroups.

Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m isonitrile.

Technetium-99m-hexakis-2-methoxy-2-isobutyl-isonitrile (technetium-99m isonitrile) is a new radiopharmaceutical compound that reflects myocardial perfusion. Its kinetics, especially its lack of redistribution after intravenous administration, permits the assessment of changes in myocardial perfusion without delay of therapy. Tomographic images at rest were obtained immediately and 6 to 10 days later in 17 consecutive patients undergoing successful primary angioplasty during their first transmural myocardial infarction. Thirteen patients had anterior infarction. The initial (acute) defect size before angioplasty of 48 +/- 17% of the left ventricle decreased significantly (p less than 0.0001) to 29 +/- 19% on the late scans. There was no correlation between the time to therapy and the reduction in defect size. Twelve of the 17 patients, including 7 of the 11 patients treated after 4 h, demonstrated a definite reduction in the initial defect size. Eight patients with angiographically proved persistent coronary occlusion underwent a similar imaging sequence. The initial defect size in this group remained unchanged on the late scans (24 +/- 16% versus 26 +/- 18%, p = NS). Primary angioplasty is an effective approach toward salvaging myocardium; comparison with thrombolytic drug therapy must await the results of controlled clinical trials.

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.