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Introduction: Depression is a mental illness (MI) characterized by a process of behavioral withdrawal whereby people experience symptoms including sadness, anhedonia, demotivation, sleep and appetite change, and cognitive disturbances. Frontal alpha asymmetry (FAA) differs in depressive populations and may signify affective responses, with left FAA corresponding to such aversive or withdrawal type behavior. On an acute basis, exercise is known to positively alter affect and improve depressive symptoms and this has been measured in conjunction with left FAA as a post-exercise measure. It is not yet known if these affective electroencephalography (EEG) responses to exercise occur during exercise or only after completion of an exercise bout. This study therefore aimed to measure EEG responses during exercise in those with MI. Materials and methods: Thirty one participants were allocated into one of two groups; those undergoing management of a mental health disorder (MI; N = 19); or reporting as apparently healthy (AH; N = 12). EEG responses at rest and during incremental exercise were measured at the prefrontal cortex (PFC) and the motor cortex (MC). EEG data at PFC left side (F3, F7, FP1), PFC right side (F4, F8, FP2), and MC (C3, Cz, and C4) were analyzed in line with oxygen uptake at rest, 50% of ventilatory threshold (VT) (50% VT) and at VT. Results: EEG responses increased with exercise across intensity from rest to 50% VT and to VT in all bandwidths (P < 0.05) for both groups. There were no significant differences in alpha activity responses between groups. Gamma responses in the PFC were significantly higher in MI on the left side compared to AH (P < 0.05). Conclusion: Alpha activity responses were no different between groups at rest or any exercise intensity. Therefore the alpha activity response previously shown post-exercise was not found during exercise. However, increased PFC gamma activity in the MI group adds to the body of evidence showing increased gamma can differentiate between those with and without MI.

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The safety of a replication-deficient, human adenovirus-vectored foot-and-mouth disease virus (FMDV) serotype A24 Cruzeiro capsid-based subunit vaccine (AdtA24) was evaluated in five independent safety studies. The target animal safety studies were designed in compliance with United States (U.S.) regulatory requirements (Title 9, U.S. Code of Federal Regulation [9CFR]) and international standard guidelines (VICH Topic GL-44) for veterinary live vaccines. The first three studies were conducted in a total of 22 vaccinees and demonstrated that the AdtA24 master seed virus (MSV) was safe, did not revert to virulence and was not shed or spread from vaccinees to susceptible cattle or pigs. The fourth safety study conducted in 10 lactating cows using an AdtA24 vaccine serial showed that the vaccine was completely absent from milk. The fifth safety study was conducted under typical U.S. production field conditions in 500 healthy beef and dairy cattle using two AdtA24 vaccine serials. These results demonstrated that the vaccine was safe when used per the product label recommendations. Additional data collected during these five studies confirmed that AdtA24 vaccinees developed FMDV A24 and the HAd5 vaccine vector serum neutralization antibodies that test negative in a FMDV non-structural protein antibody test, confirming AdtA24 vaccine's capability to differentiate infected from vaccinated animals (DIVA). In conclusion, results from this comprehensive set of cattle studies demonstrated the safety of the replication-deficient AdtA24 vaccine and fulfilled safety-related requirements for U.S. regulatory requirements.

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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.

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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.

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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.

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The role of patent foramen ovale (PFO) in patients with cryptogenic stroke (stroke of unknown cause) remains controversial, although an association seems likely in younger patients with atrial septal aneurysms and PFO. The mechanism of cryptogenic stroke in these patients is presumed to be paradoxical embolism via right-to-left shunt across the PFO. The available options for treatment include medical therapy with antiplatelet or anticoagulant therapy or closure of the PFO surgically or with use of transcatheter PFO closure devices. We describe 2 cases of bilateral device thrombosis associated with use of a transcatheter PFO closure device (CardioSEAL). To our knowledge, only 1 other case of thrombosis associated with use of this device has been reported.

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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.

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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.

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The exercise electrocardiogram (ECG) is widely believed to be less accurate in women, primarily due to a high prevalence of false-positive tests. The purpose of this study was to examine the relative accuracy of the exercise ECG in women versus men in 8,671 patients (3,213 women, 5,458 men) using myocardial perfusion imaging as the reference standard. More women (14%) than men (10%) had a false-positive ECG (p <0.001), but the absolute difference was relatively small. The false-negative rate was considerably lower in women (17% vs 32%, p <0.001). Compared with men, women had lower test sensitivity (30% vs 42%, p <0.001) and positive predictive value (34% vs 70%, p <0.001) but higher specificity (82% vs 78%, p = 0.002), negative predictive value (78% vs 52%, p <0.001), and accuracy (69% vs 58%, p <0.001). In patients with a false-negative exercise ECG, "high-risk" scans were less prevalent in women (12% vs 19%, p <0.001). In the smaller subset of patients referred for coronary angiography (205 women, 838 men), the false-positive electrocardiographic rate was again higher in women (13% vs 7%, p = 0.003), but neither specificity (69% vs 74%, p = NS) nor accuracy (60% vs 66%, p = NS) was different between the sexes. Thus, the percentage of patients with a false-positive exercise ECG was higher in women than men but low in absolute terms (<15%) for both sexes. Test specificity was not lower in women. These results suggest that gender should not be a major determinant for selecting stress imaging over standard treadmill testing.

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BACKGROUND: In patients taking digoxin, the exercise electrocardiogram has a lower specificity for detecting coronary artery disease. However, the effect of digoxin on adenosine-induced ST-segment depression is unknown. The purpose of this study was to evaluate the specificity of the electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin. METHODS: Between May 1991 and September 1997, patients (n = 99) taking digoxin who underwent adenosine stress imaging with thallium-201 or technetium-99m sestamibi and coronary angiography within 3 months were retrospectively identified. Exclusion criteria included prior myocardial infarction, coronary artery angioplasty or bypass surgery, left bundle branch block, paced ventricular rhythm, or significant valvular disease. Twelve-lead electrocardiograms were visually interpreted at baseline, during adenosine infusion, and during the recovery period. The stress electrocardiogram was considered positive if there was > or =1 mm additional horizontal or downsloping ST-segment depression or elevation 0.08 seconds after the J-point compared with the baseline tracing. RESULTS: ST-segment depression and/or elevation occurred in 24 of 99 patients. There were only 2 false-positive stress electrocardiograms, yielding a specificity of 87% and positive predictive value of 92%. All 8 patients with > or =2 mm ST segment depression had multivessel disease by coronary angiography. CONCLUSIONS: ST-segment depression or elevation during adenosine myocardial perfusion imaging in patients taking digoxin is highly specific for coronary artery disease. Marked (> or =2 mm) ST-segment depression and/or ST-segment elevation is associated with a high likelihood of multivessel disease.

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To test the hypothesis that, in a population-based cohort of persons undergoing stress tests, female sex was negatively associated with the use of cardiology visits in persons with no documented coronary artery disease (CAD) but that this association did not exist when CAD was established. Sex differences in the use of invasive cardiac procedures have been clearly documented, but data on physician encounters, an integral part of care, are lacking. A population-based cohort consisting of all Olmsted County, Minnesota residents who underwent an initial stress test in 1987, 1988, and 1989 in Olmsted County was examined. Medical records were reviewed for baseline characteristics including CAD diagnosis status, test results, and cardiology visits in the year following the stress test. Regression models were constructed to determine whether sex is independently associated with the probability of a visit. In the year after stress testing, there was no difference between the sexes in the use of inpatient (OR for female sex 0.88, 95% CI 0.62-0.97, P = 0.365) and outpatient/consultative (OR for female sex 1.24, 95% CI 0.95-1.61, P = 0.6) cardiology visits. Women were, however, less likely to receive preventive cardiology visits (OR for female sex 0.77, 95% CI 0.62-0.97, P = 0.02). This was largely related to less use of preventive visits among older women with documented coronary artery disease (CAD). In the absence of documented CAD, when the stress test was positive, women were less likely to receive preventive visits. In this geographically defined population within one year after an initial stress test, there was no sex difference in the use of in-patient or out-patient visits but women were less likely to receive preventive cardiology visits in the year after stress testing. Further studies are needed to understand the reasons for and impact of these care patterns.

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BACKGROUND: Recent exercise testing guidelines recognized a gap in knowledge about the prognostic value of treadmill exercise testing in elderly persons. OBJECTIVE: To test the hypothesis that treadmill exercise testing has equal prognostic value among elderly (> or =65 years of age) and younger (<65 years of age) persons and to examine the incremental value of this testing over clinical data. DESIGN: Inception cohort with a median follow-up of 6 years. SETTING: Olmsted County, Minnesota. PATIENTS: All elderly (n = 514) and younger (n = 2593) residents of Olmsted County who underwent treadmill exercise testing between 1987 and 1989. MEASUREMENTS: Overall mortality and cardiac events (cardiac death, nonfatal myocardial infarction, and congestive heart failure). RESULTS: Compared with younger patients, elderly patients had more comorbid conditions, achieved a lower workload (6.0 and 10.7 metabolic equivalents; P < 0.001), and had a greater likelihood of a positive exercise electrocardiogram (28% and 9%; P < 0.001). With median follow-up of 6 years, overall survival (63% and 92%; P < 0.001) and cardiac event-free survival (66% and 95%; P < 0.001) were worse among elderly persons than among younger persons. Workload was the only treadmill exercise testing variable associated with all-cause mortality in both age groups, and the strength of association was similar. Workload and angina with exercise testing were associated with cardiac events in both age groups, whereas a positive exercise electrocardiogram was associated with cardiac events only in younger persons (P < 0.05 for all comparisons). After adjustment for clinical variables, workload was the only additional treadmill exercise testing variable that was predictive of death (P < 0.001) and cardiac events (P < 0.05); the strength of the association was similar in both age groups. Each 1-metabolic equivalent increase in exercise capacity was associated with a 14% and 18% reduction in cardiac events among younger and elderly persons, respectively. CONCLUSIONS: In elderly persons, treadmill exercise testing provided prognostic information that is incremental to clinical data. After adjustment for clinical factors, work-load was the only treadmill exercise testing variable that was strongly associated with outcome, and its prognostic effect was of the same magnitude in elderly and younger persons.

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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.

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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.

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STUDY OBJECTIVES: To determine if a history of hypertension or an exaggerated rise in exercise systolic BP is associated with a false-positive exercise ECG. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of the associations between exercise-induced ST-segment depression and a history of hypertension, exercise systolic BP, and several other clinical and exercise test variables. Among 20,097 patients referred for exercise tomographic thallium imaging in a nuclear cardiology laboratory at a tertiary care center, 1,873 patients met inclusion criteria for this study, which included no history of myocardial infarction or coronary artery revascularization, a normal resting ECG, and normal exercise thallium images. RESULTS: False-positive ST-segment depression occurred in 20% of the population. A history of hypertension was actually associated with a lower likelihood of ST-segment depression (odds ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.89; p = 0. 004). A higher peak exercise systolic BP was associated with a higher likelihood of ST-segment depression (odds ratio, 1.08 for each 10-mm Hg increase in systolic BP; 95% CI, 1.03 to 1.14; p < 0. 001). However, the association between peak exercise systolic BP and ST-segment depression was so weak that this measurement could not be predictive in the individual patient (R(2) = 0.2%). For every 20-mm Hg increase in peak exercise systolic BP, the percentage of patients with ST-segment depression increased by only 3%. CONCLUSIONS: In patients with normal resting ECGs, we conclude the following: (1) a history of hypertension is not a cause of a false-positive exercise test, and (2) higher exercise systolic BP is a significant but weak predictor of ST-segment depression.

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The value of exercise nuclear perfusion imaging performed beyond the 6-month restenosis window for percutaneous transluminal coronary angioplasty (PTCA) has not been explored. This study evaluates the long-term prognostic value of exercise thallium (Tl)-201 imaging after PTCA. We studied the late outcome of a series of 211 patients with tomographic Tl-201 exercise studies performed between 1 to 3 years after PTCA. Follow-up was 96% complete at a median duration of 7.3 years. Most (73%) had 1- or 2-vessel coronary artery disease and normal left ventricular function and 193 (91%) had successful PTCA. Two thirds of the patients were symptomatic at the time of testing. The mean Duke score was 5+/-6 and 125 (60%) patients had a low-risk Duke score. Mean summed stress score was 50+/-9 and mean summed reversibility score was 3+/-4. The 5-year overall survival was 95%, yielding a low annual mortality rate of 1%/year. The summed stress score exhibited a significant association (p = 0.047) with the end point of cardiac death or myocardial infarction. The Duke score was predictive of the combination end point of hard and soft cardiac events (p = 0.002). This study demonstrates that exercise Tl-201 perfusion imaging performed 1 to 3 years after PTCA was predictive of cardiac events.

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Older patients have higher in-hospital and longer term mortality after myocardial infarction. To determine if larger infarct size correlates with this observation, myocardium at risk was measured on arrival to the hospital in 347 patients with acute myocardial infarction, and final infarct size was measured at hospital discharge in a subset of 274 of these patients. Myocardium at risk and final infarct size were quantified by tomographic technetium-99m sestamibi imaging. Statistical analyses examined the associations between age, myocardium at risk, final infarct size, and both in-hospital and postdischarge mortality. Median value for age was 64 years, and myocardium at risk was 24% and final infarct size was 12% of the left ventricle. There was no correlation between age and myocardium at risk (r = 0.04, p = NS) or final infarct size (r = 0.06, p = NS). In-hospital mortality was 4% overall and was 2% for patients <65 years old versus 6% for those > or =65 years old (chi-square 11.3, p<0.001). In-hospital mortality was not associated with myocardium at risk (chi square <1, p = NS). For the subset of 274 patients in whom final infarct size was measured, the subsequent 2-year mortality rate was 3% and was independently associated with both age (chi-square 15.6, p<0.001) and final infarct size (chi-square 9.7, p = 0.002). Survival was excellent for patients who were either <65 years old (2-year mortality 1%) or had an infarct size <12% (2-year mortality 0%). For patients > or =65 years old with infarct size > or =12%, 2-year mortality was 13%. These results demonstrate that older patients do not have larger infarcts. Advanced age is associated with higher in-hospital and postdischarge mortality, independent of infarct size.

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