Application of technetium-99m sestamibi single photon emission computed tomography in acute myocardial infarction: measuring the efficacy of therapy.

Infarct size and myocardial salvage measured by technetium (Tc)-99m sestamibi single photon emission computed tomography (SPECT) imaging have been applied as surrogate endpoints in clinical trials of acute myocardial infarction (MI). The major advantage of these endpoints over mortality is the ability to use much smaller sample sizes to compare different treatment strategies in acute MI. Multiple categories of evidence validate SPECT infarct size and myocardial salvage as surrogate endpoints, including: association with other variables used to measure infarct size; association with markers of myocardial perfusion; identification of myocardial fibrosis in pathology specimens; prediction of improvement in dysfunctional myocardial segments following revascularization; correlation between infarct size and mortality; and, demonstration that therapies which result in smaller infarct size also result in better clinical outcome in the same patients. These SPECT endpoints have been applied in over 30 clinical acute MI trials. Approximately one-third of these trials reported positive results in the intervention group or a subset of the intervention group. SPECT infarct size and myocardial salvage are the most extensively validated and widely applied surrogate endpoints in the setting of acute MI.

Low-dose nesiritide in human anterior myocardial infarction suppresses aldosterone and preserves ventricular function and structure: a proof of concept study.

BACKGROUND: B-type natriuretic peptide (BNP, nesiritide) has anti-fibrotic, anti-hypertrophic, anti-inflammatory, vasodilating, lusitropic and aldosterone-inhibiting properties but conventional doses of BNP cause hypotension, limiting its use in heart failure. OBJECTIVE: To determine whether infusion of low-dose BNP within 24 h of successful reperfusion for anterior acute myocardial infarction (AMI) would prevent adverse left ventricular (LV) remodelling and suppress aldosterone. METHODS: A translational proof-of-concept study was carried out to determine tolerability and biological activity of intravenous BNP at 0.003 and 0.006 microg/kg/min, without bolus started within 24 h of successful reperfusion for anterior AMI. 24 patients with first anterior wall ST elevation AMI and successful revascularisation were randomly assigned to receive 0.003 (n = 12) or 0.006 (n = 12) microg/kg/min of IV BNP for 72 h in addition to standard care during hospitalisation for anterior AMI. RESULTS: Baseline characteristics, drugs and peak cardiac biomarkers for myocardial damage were similar between both groups. Infusion of BNP at 0.006 microg/kg/min resulted in greater biological activity than infusion at 0.003 microg/kg/min as measured by higher mean (SEM) plasma cGMP levels (8.6 (1) vs 5.5 (1) pmol/ml, p<0.05) and suppression of plasma aldosterone (8.0 (2) to 4.6 (1) ng/dl, p<0.05), which was not seen in the 0.003 microg/kg/min group. LV ejection fraction (LVEF) improved significantly from baseline to 1 month (40 (4)% to 54 (5)%, p<0.05) in the 0.006 group but not in the 0.003 group. Infusion of BNP at 0.006 microg/kg/min was associated with a decrease of LV end-systolic volume index (61 (9) to 43 (8) ml/m(2), p<0.05) at 1 month, which was not seen in the 0.003 group. No drug-related serious adverse events occurred in either group. CONCLUSIONS: 72 h infusion of low BNP at the time of anterior AMI is well tolerated and biologically active. Patients treated with low-dose BNP had improved LVEF and smaller LV end-systolic volume at 1 month.

Detection of myocardial infarction by dual-source coronary computed tomography angiography using quantitated myocardial scintigraphy as the reference standard.

BACKGROUND: Dual-source coronary computed tomography angiography (DS-CTA) has the potential to assess both coronary anatomy and myocardial perfusion. We studied the ability of DS-CTA to detect myocardial infarction (MI) compared to a reference standard of technetium Tc(99)m sestamibi single photon emission computed tomography (SPECT). METHODS: 122 patients with suspected or known coronary artery disease (age 60 (SD 11) years, 36% females) were evaluated by both DS-CTA and SPECT. SPECT-MI size was quantitated using a threshold value of 60% of peak counts on the resting images. MI on DS-CTA was defined as transmural or subendocardial hypoenhancement (<50% of surrounding myocardium), which persisted in both diastolic and systolic reconstructions and was concordant with a coronary artery territory. The performance of DS-CTA to detect SPECT-MI was determined in a blinded, vessel-based analysis. RESULTS: 366 vessel territories were analysed (122 patients x3). SPECT revealed 20 vessel territories with MI (involving 17 patients). 15/20 (75%) of these vessel territories were also detected by DS-CTA. An additional seven MIs were detected by DS CTA only (considered as false positive). Thus, the sensitivity of DS-CTA for detection of SPECT-MI was 75% (95% CI 56% to 94%), specificity 98% (97% to 100%), positive predictive value 68% (49% to 88%) and negative predictive value 99% (97% to 100%). DS-CTA detected 10/11 (91%) larger MIs (involving >5% of left ventricular (LV) mass by SPECT). For the 15 concordant MIs (in both SPECT and DS-CTA) the mean difference in MI size between modalities was 0.5% (4.6%) of LV mass (95% CI -8.6% to 9.5%). CONCLUSIONS: DS-CTA myocardial perfusion imaging showed moderate sensitivity and positive predictive value but high specificity and negative predictive value for detection of SPECT-MI. Most large infarcts (>5% of LV mass) were detected by DS-CTA. When MI was detected by both modalities, there was a good correlation between infarct sizes quantitated by DS-CTA vs SPECT.

The value of 24-hour images after rest thallium injection.

Rest (201) Tl imaging has been used for detecting viability, but the ideal timing for imaging after injection to maximally estimate viability is not well established. Thirty patients with fixed or incompletely reversible defects on 4 h redistribution SPECT imaging after thallium rest injection underwent 24 h imaging. Global redistribution was subjectively rated none, minimal or meaningful by two experienced observers. Fourteen patients had no meaningful redistribution at either 4 h or 24 h. Ten patients had meaningful redistribution at 4 h only. Six patients had no meaningful redistribution at 4 h but did at 24 h. Defect size was quantified using a 70% threshold. For the total group, defect size was smaller at 4 h compared to immediate imaging (38+/-18% vs 41+/-19%, P=0.06) and smaller still at 24 h (36+/-16% vs 38+/-18%, P=0.02). Later (24 h) redistribution images detected additional redistribution in 30% of the patients who did not have meaningful redistribution on early (4 h) images, and in 8% of the segments which were abnormal at 4 h. It is concluded that, in patients who have incompletely reversible defects on early redistribution imaging at 4 h, late redistribution imaging after 24 h will demonstrate additional redistribution in 30% of the patients.

Clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h) and late (>4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction.

AIMS: We examined the clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h) and late (>4 h) presentation treated by primary angioplasty or thrombolytic therapy for acute myocardial infarction. METHODS AND RESULTS: We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n=1302) vs thrombolytic therapy (n=1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (<2 h), intermediate presentation (2-4 h), and late presentation (>or=4 h). At 30 days the combined rate of death, non-fatal reinfarction and stroke in patients presenting early was 5.8% in the angioplasty group vs 12.5% in the thrombolysis group, in patients with intermediate presentation, 8.6% vs 14.2%, respectively, and in patients presenting late 7.7% vs 19.4%, respectively. With increasing time from symptom onset to presentation, all major adverse cardiac event rates show a trend to a larger increase in the thrombolysis group compared to the angioplasty group, both at 30 days and at 6 months after the acute event. CONCLUSIONS: Major adverse cardiac event rates are lower after angioplasty compared to thrombolysis, irrespective of time to presentation. With increasing time to presentation major adverse cardiac event rates increase after thrombolysis but appear to remain relatively stable after angioplasty.

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.

Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy.

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.

Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification.

Patients with suspected chronic stable angina can be evaluated in three stages. In stage one, the clinician uses information from the history, physical examination, laboratory tests for diabetes and hyperlipidemia, and resting electrocardiography to estimate the patient's probability of coronary artery disease (CAD). In stage two, additional testing for patients with a low probability of CAD focuses on diagnosing noncoronary causes of chest pain. Patients with a high probability of CAD have stress tests to assess their risk from CAD, and patients with an intermediate probability of CAD have stress tests to estimate the probability of CAD and assess their risk from CAD. Most patients with new-onset angina can start stress testing with exercise electrocardiography. The initial stress test should be a stress imaging procedure for patients with rest ST-segment depression greater than 1 mm, complete left bundle-branch block, ventricular paced rhythm, preexcitation syndrome, or previous revascularization with percutaneous coronary angioplasty or coronary artery bypass grafting. Patients who cannot exercise can have an imaging procedure with stress induced by pharmacologic agents. In stage three, patients with a predicted average annual cardiac mortality rate between 1% and 3% should have a stress imaging study or coronary angiography with left ventriculography. Those with a known left ventricular dysfunction should have cardiac catheterization. Patients with CAD who have an estimated annual mortality rate greater than 3% should have cardiac catheterization to determine whether their anatomy is suitable for revascularization. Patients with an estimated annual mortality rate less than 1% can begin to receive medical therapy.

Guidelines for the management of patients with chronic stable angina: treatment.

The dual aims of treating patients with chronic stable angina are 1) to reduce morbidity and mortality and 2) to eliminate angina with minimal adverse effects and allow the patient to return to normal activities. In the absence of contraindications, beta-blockers are recommended as initial therapy. All beta-blockers seem to be equally effective. If the patient has serious contraindications to beta-blockers, unacceptable side effects, or persistent angina, calcium antagonists should be administered. Long-acting dihydropyridine and nondihydropyridine agents are generally as effective as beta-blockers in relieving angina. Long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid developing tolerance. All long-acting nitrates seem to be equally effective. Patients with angina should take 75 to 325 mg of aspirin daily unless they have contraindications. Such risk factors as smoking, elevated low-density lipoprotein cholesterol level, diabetes, and hypertension should be treated appropriately. Coronary revascularization has not been shown to improve survival for most patients with chronic angina but may be required to control symptoms. However, coronary artery bypass grafting (CABG) is often indicated for symptomatic patients with left-main disease, three-vessel disease, or two-vessel disease including proximal stenosis of the left anterior descending coronary artery; it improves their survival. Percutaneous transluminal coronary angioplasty is an alternative to CABG for patients with normal left ventricular function and favorable angiographic features. Coronary artery bypass grafting is initially more effective in relieving angina than medical therapy, but the two procedures yield similar results after 5 to 10 years. Eighty percent of patients who undergo CABG remain angina-free 5 years after surgery. In low-risk patients, percutaneous transluminal coronary angioplasty seems to control angina better than medical therapy, but recurrent angina and repeated procedures are more likely than with CABG. Patient education is an important component of management. Long-term follow-up should be individualized to ascertain clinical stability at regular intervals and to reassess prognosis when warranted.

Prediction of severe coronary artery disease and long-term outcome in patients undergoing vasodilator SPECT.

BACKGROUND: Vasodilator perfusion imaging has not been extensively evaluated for predicting severe coronary artery disease (CAD) or long-term prognosis. METHODS AND RESULTS: The goals of this study were to develop a model to predict left main/3-vessel CAD in patients undergoing vasodilator thallium 201 imaging and coronary angiography (angiographic population) and to test the long-term prognostic value of this model in a separate cohort of patients who were not referred for angiography (prognostic population). In the angiographic population (n = 653) the chi2 value of the clinical model (containing the variables age, sex, and prior myocardial infarction) in the prediction of severe CAD was 32. The addition of 3 vasodilator Tl-201 variables (magnitude of ST-segment depression, summed reversibility score, and increased lung uptake) increased the model chi2 value to 114 (P <.001). Only 9% of predicted low-risk patients versus 57% of predicted high-risk patients had severe CAD. In the prognostic population (n = 521) survival rates free of cardiac death or myocardial infarction at 7 years were 91%, 73%, and 51%, respectively, for patient groups predicted to be at low, intermediate, and high risk of severe CAD (P <.001). CONCLUSIONS: Clinical and vasodilator Tl-201 variables can accurately predict the risk of severe CAD. Stress Tl-201 variables add incremental information to clinical variables. The same model also predicts patient outcome.

Gender differences and temporal trends in clinical characteristics, stress test results and use of invasive procedures in patients undergoing evaluation for coronary artery disease.

OBJECTIVES: This study examined gender differences and temporal changes in the clinical characteristics of patients referred for nuclear stress imaging, their imaging results and subsequent utilization of coronary angiography and revascularization. BACKGROUND: Gender bias may influence resource utilization in patients with coronary artery disease (CAD). No study has analyzed gender differences and time trends in patients referred for noninvasive testing and subsequent use of invasive procedures. METHODS: Between January 1986 and December 1995, 14,499 patients (5,910 women and 8,589 men) without established CAD underwent stress myocardial perfusion imaging. The clinical characteristics, imaging results, coronary angiograms and revascularization outcomes were compared in women and men over time. RESULTS: The mean pretest probability of CAD was lower in women (45%) than in men (70%) (p < 0.001). More women (69%) than men (42%) had normal nuclear images (p < 0.001). Men (17%) were more likely than women (8%) to undergo coronary angiography (p < 0.001). Male gender was independently associated with referral for coronary angiography (multivariate model: chi-square = 16, p < 0.001) but was considerably weaker than the imaging variables (summed reversibility score: chi-square = 273, p < 0.001). Revascularization was performed in more men (46% of the population undergoing angiography) than women (39%) (p = 0.01), but gender was not independently associated with referral to revascularization. There were no significant differences in clinical, imaging or invasive variables between the genders over time. CONCLUSIONS: There was little evidence for a bias against women in this study. Women were somewhat less likely to undergo coronary angiography but were referred for stress perfusion imaging more liberally. Practice patterns remained constant over this 10-year period.

An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study).

Maximal benefits of coronary reperfusion after acute myocardial infarction (AMI) with ST-segment elevation may be attenuated by neutrophil-mediated reperfusion injury. Inflammatory mediators released from potentially viable myocytes cause activation of neutrophils, which traverse the endothelium and enter the myocardium. This process involves interaction between the neutrophil-expressed CD11/CD18 and endothelial-expressed intercellular adhesion molecule-1 (ICAM-1). Preclinical studies have shown that monoclonal antibodies (MAb) to CD18 can limit infarct size and preserve left ventricular function. We sought to determine the initial clinical safety and tolerability of Hu23F2G (LeukArrest), a humanized MAb to CD11/CD18, in patients with AMI who underwent percutaneous transluminal coronary angioplasty (PTCA). Sixty patients with AMI were randomized to low- (0.3 mg/kg) or high-dose (1.0 mg/kg) Hu23F2G or to placebo immediately before PTCA. We found no clinically significant differences in vital signs, physical examination, laboratory evaluation, or need for subsequent cardiac interventions. In Hu23F2G treatment groups, serum concentration of Hu23F2G increased rapidly to 3,234 +/- 1,298 microg/L (low-dose group) and 15,558 +/- 4409 microg/L (high-dose group) between 5 and 60 minutes, then declined over 72 hours to near-baseline values. Myocardial single-photon emission computed tomographic imaging 120 to 260 hours after PTCA showed no statistically significant differences in final left ventricular defect size. Hu23F2G was well tolerated, with no increase in adverse events, including infections. Thus, Hu23F2G appears safe and well tolerated in patients undergoing PTCA for AMI.