Lifetime Measurements of Excited States in

Lifetimes of the first excited 2^{+} and 4^{+} states in the extremely neutron-deficient nuclide ^{172}Pt have been measured for the first time using the recoil-distance Doppler shift and recoil-decay tagging techniques. An unusually low value of the ratio B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+})=0.55(19) was found, similar to a handful of other such anomalous cases observed in the entire Segré chart. The observation adds to a cluster of a few extremely neutron-deficient nuclides of the heavy transition metals with neutron numbers N≈90-94 featuring the effect. No theoretical model calculations reported to date have been able to explain the anomalously low B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+}) ratios observed in these cases. Such low values cannot, e.g., be explained within the framework of the geometrical collective model or by algebraic approaches within the interacting boson model framework. It is proposed that the group of B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+}) ratios in the extremely neutron-deficient even-even W, Os, and Pt nuclei around neutron numbers N≈90-94 reveal a quantum phase transition from a seniority-conserving structure to a collective regime as a function of neutron number. Although a system governed by seniority symmetry is the only theoretical framework for which such an effect may naturally occur, the phenomenon is highly unexpected for these nuclei that are not situated near closed shells.

Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients.

BACKGROUND: Patients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known. PATIENTS AND METHODS: Two thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding. RESULTS: Compared with patients without cancer, active cancer patients (n=493) had more venous thromboembolism (VTE) complications (1.2% versus 0.2%; P=0.001), major bleeding (3.4% versus 1.7%; P=0.02) and reduced survival (95% versus 99%; P<0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2% versus 0.16%; P=0.002) and major bleeding (3.7% versus 0.6%; P<0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5% versus 1%; P=0.03) without impacting the VTE rate (0.7% versus 1.4%, P=0.50). CONCLUSIONS: Cancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.

Body fat distribution, serum glucose, lipid and insulin response to meals in Alström syndrome.

BACKGROUND: Alström syndrome is an autosomal recessive condition characterized by obesity, insulin resistance and hypertriglyceridaemia. Responses to fat and carbohydrate ingestion are important in planning dietetic advice and may help to explain the mechanism of metabolic disorder in the syndrome. METHODS: After a 12-h fast, five Alström subjects received a 3.1 MJ (742 kcal), 75.8% fat breakfast on day 1, and a 3.3 MJ (794 kcal), 77.5% carbohydrate breakfast on day 2. Serum glucose, triglyceride and insulin levels were measured at baseline, and 2 and 3.5 h post-meal. Abdominal computerized tomography in three subjects and magnetic resonance imaging in one demonstrated distribution of abdominal fat. RESULTS: Body fat was distributed subcutaneously, as well as viscerally. There were no changes in serum glucose, insulin or triglycerides after the high fat meal. Triglycerides remained stable after the high carbohydrate meal but glucose and log insulin levels increased [8.4 +/- 4.1 to 13.4 +/- 6.9 mmol L(-1) (P < 0.05) and 2.6 +/- 0.27 to 3.15 +/- 0.42 pmol L(-1) (P < 0.05), respectively]. CONCLUSIONS: Dietetic advice in Alström syndrome must include calorie restriction to reduce obesity, which is predominantly subcutaneous. This study has shown that low carbohydrate advice may prove more effective than fat restriction in control of hyperglycaemia and hyperinsulinism. A single high energy meal does not exacerbate hypertriglyceridaemia.

Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome.

CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.

Interaction of ETS-1 and ERGB/FLI-1 proteins with DNA is modulated by spacing between multiple binding sites as well as phosphorylation.

ETS is a family of transcription factors that contain a highly conserved ETS DNA binding domain. Various members of the ETS family are expressed in cells of hematopoietic lineage. ETS-1, ETS-2 and ERGB/FLI-1 are expressed at high levels in T-lymphocytes. HIV-1 infects T-cells and it has been shown that its LTR contains binding sites for various transcription factors. In this study we show that the HIV-1 core enhancer is directly regulated by ERGB/FLI-1 protein positively, as well as, negatively, depending upon the presence or absence of accessory factors in different cell types. In addition, we show that the ETS-1 transactivation activity is enhanced upon dephosphorylation of the Calmodulin-dependent Protein Kinase II phosphorylation site located in exon VII. Finally, we demonstrate that the spacing between the two EBS cores in palindromic or direct repeat sites play a crucial role in binding of ETS proteins to DNA.

ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction.

p53 is an extensively studied tumor suppressor gene implicated in the genesis of a large number of varied tumors. However, the pathways of regulation for the wild-type p53 gene and its product are as yet unknown. In situ hybridization analyses of ETS1 and ETS2 expression during mouse embryogenesis, have shown a pattern similar to that of p53 gene expression. Significantly, we have identified several ETS-binding sites (EBS) in the promoter regions of the human and mouse p53 genes. In the human promoter two of these EBS are present in the form of a palindrome, with the two EBS cores being separated by four nucleotides. This report shows that the EBS palindrome of the human p53 promoter has a high affinity for ETS1 and ETS2 and that such binding interaction intracellularly is able to activate the transcription of a CAT reporter gene by 5-10-fold using COS cells. To investigate whether the spacing between the two EBS cores influences the DNA binding activity, we synthesized oligonucleotides with increasing distances (4,12,16, and 20 bases respectively) between the two EBS cores of the palindrome. We observed an inverse correlation between an increasing distance in the two EBS cores of the palindrome and the ETS1 and ETS2 DNA binding activity respectively. Interestingly, optimal DNA binding activity was observed when the distance between the two EBS cores was four bases, identical to that which occurs in the natural promoter. Furthermore we show that the p53 mRNA is expressed at higher levels in NIH3T3 cells overexpressing ETS2 gene product, suggesting that the ETS2 transcription factor is a likely candidate for regulating the expression of p53 in vivo.

FLI1 and EWS-FLI1 function as ternary complex factors and ELK1 and SAP1a function as ternary and quaternary complex factors on the Egr1 promoter serum response elements.

The ETS gene products are a family of transcriptional regulatory proteins that contain a highly conserved and structurally unique DNA binding domain, termed the ETS domain. Several ETS proteins bind to DNA as monomers, however it has been shown that the DNA binding activity is enhanced or modulated in the presence of other factors. By differential display and whole genome PCR techniques, we have recently shown that the Erg1 gene is a target for ETS proteins. The Egr1 promoter contains multiple ETS binding sites, three of which exist as parts of two serum response elements (SREI and SREII). The SRE is a cis-element that regulates the expression of many growth factor responsive genes. ELK1 and SAP1a have been shown to form ternary complexes with SRF on the SRE located in the c-fos promoter. Similarly, we examined whether the ELK1, SAP1a, FLI1, EWS-FLI1, ETS1, ETS2, PEA3 and PU.1 proteins can form ternary complexes with SRF on the Egr1 SREI and II. Our results demonstrate that indeed ELK1, SAPla, FLI1 and EWS-FLI1 are able to form ternary complexes with SRF on Egr1 SREs. In addition, ELK1 and SAP1a can also form quarternary complexes on the Egr1 SREI. However, the proteins ETS1, ETS2, PEA3 and PU.1 were unable to form ternary complexes with SRF on either the Egr1 or c-fos SREs. Our data demonstrate that FLI1 and EWS-FLI1 constitute new members of a subgroup of ETS proteins that can function as ternary complex factors and further implicate a novel function for these ETS transcription factors in the regulation of the Egr1 gene. By amino acid sequence comparison we found that, in fact, 50% of the amino acids present in the B-box of SAP1a and ELK1, which are required for interaction with SRF, are identical to those present in both FLI1 (amino acids 231- 248) and EWS-FLI1 proteins. This B-box is not present in ETS1, ETS2, PEA3 or PU.1 and these proteins were unable to form ternary complexes with SRF and Egrl-SREs or c-fos SRE. Furthermore, deletion of 194 amino terminal amino acids of FLI1 did not interfere with its ability to interact with SRF, in fact, this truncation increased the stability of the ternary complex. The FLI1 protein has a unique R-domain located next to the DNA binding region. This R-domain may modulate the interaction with SRF, providing a mechanism that would be unique to FLI1 and EWS-FLI1, thus implicating a novel function for these ETS transcription factors in the regulation of the Egr1 gene.

The EndoA enhancer contains multiple ETS binding site repeats and is regulated by ETS proteins.

EndoA is a type II keratin and with EndoB (type I keratin), constitutes intermediate filaments in various simple epithelial tissues. EndoA is developmentally regulated and has an enhancer that is located at the 3'- end of the gene. This enhancer contains two single and five dual Ets binding sites. Thus far, no other promoter or enhancer has been shown to contain as many potential clustered Ets binding sites. To study the transcriptional regulation of EndoA by the ETS family proteins, we amplified the EndoA enhancer fragment from mouse genomic DNA by PCR, and cloned it into the pBLCAT2 vector upstream from the CAT reporter gene. Several pBLCAT-ENDOA clones were sequenced to verify the presence of all the ETS binding sites. Clones that did not show any point mutations in the ETS binding sites were chosen to study the transcription regulation by ETS1, ETS2 and ERGB/FLI-1 gene products. EMSA results indicated that the ETS1, ETS2 and ERGB/FLI-1 proteins bind to the enhancer sequence, and DNase I protection data demonstrated that the ETS proteins protect all seven EBS core sequences. Cotransfection of the COS cells with the pBLCAT-ENDOA construct, along with increasing amounts of different ETS expression vectors, resulted in a significant induction of CAT reporter gene expression. Previously, we have shown that the overexpression of the ETS1 gene transforms NIH3T3, and these transformed cells (7AQS2.1) produce high levels of ETS1 protein (Seth & Papas, 1990). In this report, we show that the undifferentiated P19 EC cells do not express detectable levels of ETS1; however, an elevated level of ETS1 is expressed in differentiated derivatives of these cells. We therefore used these two cell lines to examine the activity of the EndoA enhancer with the ETS1 product. Transfection of the pBLCAT-ENDOA construct alone in undifferentiated P19 EC cells results in very low CAT gene expression; however, upon differentiation with retinoic acid the level of CAT gene activity increases dramatically. Similarly, an increase in CAT expression from the same construct (pBLCAT-ENDOA) was also observed in 7AQS2.1 cells. Our results therefore indicate that the EndoA enhancer is regulated by ETS proteins via interaction with multiple ETS-binding site sequences.

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.

Severe aortic stenosis with low transvalvular gradient and severe left ventricular dysfunction:result of aortic valve replacement in 52 patients.

BACKGROUND: The outcome of aortic valve replacement in patients with severe aortic stenosis, low transvalvular gradient, and severe left ventricular dysfunction is not well known. METHODS AND RESULTS: Between 1985 and 1995, 52 patients with left ventricular ejection fraction (EF) < or =35% and aortic stenosis with transvalvular mean gradient <30 mm Hg underwent aortic valve replacement. The mean (+/-SD) preoperative characteristics included EF, 26+/-8%; aortic valve mean gradient, 23+/-4 mm Hg; aortic valve area, 0.7+/-0.2 cm(2); and cardiac output, 3.7+/-1.2 L/min. Simultaneous coronary artery bypass graft surgery was performed in 32 patients (62%). Perioperative (30-day) mortality was 21% (11 of 52 patients). Ten additional patients died during follow-up. Advanced age (P=0.048) and small aortic prosthesis size (P=0.03) were significant predictors of hospital mortality by univariate analysis. By multivariate analysis, the only predictor of surgical mortality was smaller prosthesis size. The only predictor of postoperative survival was improvement in postoperative functional class (P=0.04). Postoperative functional improvement occurred in most patients. Postoperative EF was assessed in 93% of survivors; 74% demonstrated improvement. Positive change in EF was related to smaller preoperative aortic valve area and female sex. CONCLUSIONS: Despite severe left ventricular dysfunction, low transvalvular mean gradient, and increased operative mortality, aortic valve replacement was associated with improved functional status. Postoperative survival was related to younger patient age and larger aortic prosthesis size, and medium-term survival was related to improved postoperative functional class.

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.

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.

Doppler index combining systolic and diastolic myocardial performance: clinical value in cardiac amyloidosis.

OBJECTIVES: This study was designed to determine the clinical value of a Doppler-derived index of combined systolic and diastolic myocardial performance in the assessment of cardiac amyloidosis. BACKGROUND: Cardiac amyloidosis is an infiltrative disease with diastolic and systolic dysfunction. Therefore, the index of myocardial performance combining systolic and diastolic time intervals could be a useful predictor of clinical outcome in cardiac amyloidosis. METHODS: The study included 45 patients with biopsy-proved amyloidosis and 45 age-matched normal subjects. All patients had typical echocardiographic features of amyloid cardiac involvement. A Doppler-derived index, defined as the sum of isovolumetric contraction time and isovolumetric relaxation time divided by ejection time, was measured from left ventricular outflow and mitral inflow Doppler velocity profiles recorded during routine echocardiography. The index as well as conventional systolic or diastolic echocardiographic/Doppler variables were related to subsequent outcome. RESULTS: The isovolumetric contraction and relaxation times were prolonged and ejection time was shortened (p < 0.001) in patients with amyloidosis compared with that in normal subjects, resulting in a marked increase of the index from normal values (p < 0.001). In the amyloid group the index was highest in patients with a low stroke index or with both shortened mitral deceleration time and lower ejection fraction. By univariate analysis, New York Heart Association functional class, the index, ejection fraction and mitral deceleration time were significant predictors of outcome. However, by multivariate stepwise regression analysis, functional class and the index were the only independent predictors of survival. CONCLUSIONS: The Doppler-derived index of combined systolic and diastolic myocardial performance correlates with global cardiac dysfunction and is a useful predictor of clinical outcome in patients with cardiac amyloidosis.

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.

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.

Distinct hemodynamic profiles in patients with vasovagal syncope: a heterogeneous population.

OBJECTIVE: The objective was to investigate mechanisms of vasovagal syncope by identifying laboratory techniques that characterize cardiovascular profiles in patients with vasovagal syncope. BACKGROUND: The triggering mechanisms of vasovagal syncope are complex. The patient population is likely heterogeneous. We hypothesized that distinct hemodynamic profiles are definable with provocative maneuvers. METHODS: Three groups of subjects were matched for age and gender: 16 patients with a history of syncope and an inducible vasovagal response during passive tilt table testing (70 degrees, 45 min, group I), 16 with a history of syncope, negative passive tilt table testing but positive isoproterenol tilt table testing (0.05 microg/kg per min, 70 degrees, 10 min, group II), and 16 control subjects. Beat-to-beat hemodynamic functions were determined noninvasively by photo-plethysmography and impedance cardiography. RESULTS: At baseline, hemodynamic functions were not different among the three groups (supine). In response to tilt before any symptoms developed, total peripheral resistance decreased 9% +/- 14% in group I from baseline supine to tilt position but increased 27% +/- 18% in group II and 28% +/- 17% in controls (p < 0.001). Responses to isoproterenol were not significantly different between group II and controls in supine position. In response to tilt during isoproterenol infusion before any symptoms developed, total peripheral resistance decreased 24% +/- 20% in group II and increased 20% +/- 48% in controls (p = 0.002). CONCLUSIONS: Group I patients may have impaired ability to increase vascular resistance during orthostatic stress. The inability to overcome isoproterenol-induced vasodilatation during tilt is important in triggering a vasovagal response in group II patients. These data suggest that the population with vasovagal response is heterogeneous. Distinct hemodynamic profiles in response to various provocative maneuvers are definable with noninvasive, continuous monitoring techniques.

Epicardial vasomotor responses to acetylcholine are not predicted by coronary atherosclerosis as assessed by intracoronary ultrasound.

OBJECTIVES: The purpose of this study was to use intravascular ultrasound to determine the morphologic appearance of the coronary arteries, relating the absence, presence and extent of atherosclerosis to the response of the coronary arteries to acetylcholine infusion. BACKGROUND: Endothelial function plays a major role in the pathophysiology of myocardial ischemia and angina pectoris. The response of the coronary arteries to selective infusion of acetylcholine has been used to examine endothelial function, with vasoconstriction occurring in the absence of intact endothelial function. Vasoconstriction to acetylcholine infusion in humans without overt coronary artery disease has been attributed to early atherosclerosis not detected by coronary angiography. METHODS: Twenty-nine patients without overt coronary artery disease underwent selective coronary angiography and selective intracoronary infusion of increasing concentrations of acetylcholine (10(-6), 10(-5) and 10(-4) mol/liter), followed by intravascular ultrasound imaging. RESULTS: The response of the coronary arteries to acetylcholine infusion was not dependent on the absence or presence of atherosclerotic plaque, as detected by intravascular ultrasound. The percent change in epicardial coronary artery diameter during acetylcholine infusion versus baseline was -14 +/- 28% (mean +/- SD) in the seven patients with no visible atherosclerosis on intravascular ultrasound versus -9 +/- 20% in the 22 patients with visible atherosclerosis on intravascular ultrasound (p = NS, confidence interval -14% to 25%). There was a greater vasoconstrictive response to acetylcholine infusion in patients with risk factors for coronary artery disease than in those without risk factors (p = 0.003). CONCLUSIONS: The vasoreactive response to acetylcholine is not necessarily dependent on ultrasound detection of the presence or absence of atherosclerosis.

Utility of a single-stage isoproterenol tilt table test in adults: a randomized comparison with passive head-up tilt.

OBJECTIVES: This study was conducted to develop a time-efficient tilt table test. BACKGROUND: Current protocols of tilt table testing are quite time-consuming. This study was designed to assess the diagnostic value, tolerance and procedural time of a single-stage isoproterenol tilt table protocol. METHODS: A single-stage isoproterenol tilt table test was compared with the passive tilt table test. The study was prospectively designed in a randomized and crossover fashion. RESULTS: The study population consisted of 111 patients with a history of syncope (mean age 55 +/- 20 years). Of the total, 62 patients (56%; 95% confidence interval, 46% to 65%) had a positive vasovagal response during isoproterenol tilt table testing and 35 (32%; 23% to 41%) during passive tilt table testing (p = 0.002). The mean procedural times of the study population were 11.7 +/- 3.6 min and 36.9 +/- 13.3 min for isoproterenol and passive tilt table testing, respectively (p < 0.001). All patients tolerated single-stage isoproterenol testing. In the 23 control subjects (mean age 34 +/- 11 years), the apparent specificities were 91% (72% to 99%) and 83% (61% to 99%) for passive and single-stage tilt table testing, respectively. CONCLUSIONS: The single-stage isoproterenol tilt table test was more effective in inducing a positive vasovagal response in an adult population than the standard passive tilt table test, and it significantly reduced the procedural time. The increase in positive yield was associated with a moderate decrease in apparent specificity. These observations support the conclusion that single-stage tilt table testing could be a reasonable diagnostic option in patients undergoing syncope evaluation.

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.

Relation between mode of pacing and long-term survival in the very elderly.

OBJECTIVES: This study analyzes the relationship between pacing mode and long-term survival in a large group of very elderly patients (> or = 80 years old). BACKGROUND: The relationship between pacing mode and long-term survival is not clear. Because the number of very elderly who are candidates for pacing is increasing, issues related to pacemaker (PM) use in the elderly have important clinical and economic implications. METHODS: We retrospectively reviewed 432 patients (mean age, 84.5+/-3.9 years) who received their initial PM (ventricular in 310 and dual chamber in 122) between 1980 and 1992. Follow-up was complete (3.5+/-2.6 years). Observed survival was estimated by the Kaplan-Meier method. Age- and gender-matched cohorts from the Minnesota population were used for expected survival. Log-rank test and Cox regression hazard model were used for univariate and multivariate analyses. RESULTS: Patients with ventricular PMs appeared to have poor overall survival compared with those with dual-chamber PMs. Observed survival after PM implantation in high grade atrioventricular block (AVB) patients was significantly worse than expected survival of the age- and gender-matched population (p < 0.0001), whereas observed survival of patients with sinus node dysfunction was not significantly different from expected survival of the matched population (p = 0.413). By univariate analysis, ventricular pacing in patients with AVB appeared to be associated with poor survival compared with dual-chamber pacing (hazard ratio [HR] 2.08; 95% confidence interval [CI] 1.33 to 3.33). After multivariate analysis, this difference was no longer significant (HR 1.41; 95% CI 0.88 to 2.27). Independent predictors of all-cause mortality were number of comorbid illnesses, New York Heart Association functional class, left ventricular depression and older age at implant. Pacing mode was not an independent predictor of overall survival. Older age at implantation, diabetes mellitus, dementia, history of paroxysmal atrial fibrillation and earlier year of implantation were independent predictors of ventricular pacemaker selection. CONCLUSIONS: After PM implantation, long-term survival among very elderly patients was not affected by pacing mode after correction of baseline differences. Selection bias was present in pacing mode in the very elderly, with ventricular pacing selected for sicker and older patients, perhaps partly explaining the apparent "beneficial impact on survival" observed with dual-chamber pacing.