Rate of progression of valvular aortic stenosis in patients > or = 60 years of age.

A retrospective analysis of 171 women and 119 men, mean age 76 +/- 9 years, with aortic stenosis diagnosed by Doppler echocardiography, who had follow-up Doppler echocardiograms, showed that the reduction in aortic valve area per year was not significantly different in older persons with mild, moderate, and severe aortic stenosis. The decrease in aortic valve area per year was significantly greater in men 60 to 74 years old than in women 60 to 74 years old (p = 0.025), in women > or =75 years old than in women 60 to 74 years old (p = 0.006), and in persons with mitral annular calcium than in persons without mitral annular calcium (p = 0.046).

Comparison of four echocardiographic techniques for measuring left ventricular ejection fraction.

Accurate quantitative measurement of left ventricular (LV) ejection fraction (EF) by 2-dimensional echocardiography is limited by subjective visual endocardial border detection. Both harmonic and precision contrast microbubbles provide better delineation of endocardial borders than fundamental imaging. The aim of this study was to correlate 2-dimensional echocardiographic quantification of LVEF measured by 4 currently available techniques with radionuclide angiography. A total of 50 patients who underwent radionuclide (EF) measurement (47 of 50 had technically difficult echocardiograms by fundamental imaging) underwent echocardiography by 4 methods: fundamental alone, fundamental with contrast, harmonic alone, and harmonic with contrast. Three echocardiologists measured the biplane 2-dimensional echocardiographic LVEF independently and were blinded to radionuclide angiography. The correlation of echocardiographic EF with radionuclide EF improved incrementally with each method. However, contrast with harmonic imaging provided the closest correlation (r = 0.95, 0.96, and 0.95 as assessed by the 3 independent analysts.

Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].

We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.

Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images.

Suboptimal left ventricular (LV) cavity visualization and endocardial border delineation often compromise the clinical utility of echocardiography. This study examines the safety and efficacy of perflutren, a novel ultrasound contrast agent, for LV cavity opacification and endocardial border delineation in patients with suboptimal baseline echocardiograms. In a multicenter, randomized, placebo-controlled, double-blind trial, 211 patients with suspected cardiac disease and suboptimal baseline echocardiograms were enrolled at 17 sites. Two intravenous injections of either placebo (saline) or perflutren (5 or 10 microl/kg) were given approximately 30 minutes apart. Images of the apical 4- and 2-chamber views were acquired and scored. Perflutren opacified the LV cavity after both dosages (5 and 10 microl/kg dosages). Clinically useful contrast was observed in 89% of patients who received perflutren and in 0% of patients who received placebo (p < 0.01). Quantitative assessment of LV opacification with videodensitometry showed similar results. The mean duration of clinically useful contrast was 90 seconds. Improvement in endocardial border delineation was demonstrated in 91% of patients who received perflutren and in 12% of those who received placebo (p < 0.001). Following perflutren, an average of 4 more segments per patient were evaluable compared with baseline. Salvage of nondiagnostic baseline examinations by perflutren was demonstrated in 48% of eligible subjects. The safety profile of perflutren was similar to placebo. These data indicate that administration of perflutren to patients with suboptimal baseline images is well tolerated and provides substantial LV cavity opacification and improvement in endocardial border delineation.

Evaluation of myocardial viability in asymptomatic patients early after infarction with perfusion/metabolism single-photon-emission computed tomographic imaging and dobutamine echocardiography.

OBJECTIVE: To study the impact of detection of viability of myocardium in asymptomatic patients early (3-10 days) after Q-wave myocardial infarction on segmental recovery of left ventricular function after elective revascularization. METHODS: Patients were studied with low-dose dobutamine echocardiography (LDDE) and single photon-emission computed tomography with 99mTc sestamibi and [18F]-fluorodeoxyglucose (FDG) imaging. Viability of myocardium was defined as detection of improvement in segmental thickening of left ventricle by LDDE (versus baseline echocardiographic data), uptake of 99mTc sestamibi > 50% of maximum counts, uptake of [18F]-FDG > 50% of maximum normal, combined uptake of 99mTc sestamibi or [18F]-FDG > 50% of normal maximum, uptake of [18F]-FDG > 50% or mismatched pattern (uptake of [18F]-FDG greater than that of 99mTc sestamibi). Functional recovery was defined as improvement of segmental thickening of left ventricle detected at follow-up 8 weeks after infarction (versus baseline resting echocardiographic data). Interpretation of the tests was blinded with respect to the angiographic data and the results of the alternative method. RESULTS: In total 18 patients with 133 left-ventricle segments with abnormal contractile function at baseline were analysed; 29% were hypocontractile and 71% were noncontractile. Examination with LDDE showed that 18% of the segments had normal contractility and 26% were hypocontractile; the respective percentages were 29 and 28% according to follow-up resting echocardiography. Radionuclide tests for viability of myocardium gave positive results in 57% (uptake of [18F]-FDG > 50%) and 62% (uptake of 99mTc sestamibi > 50%) of cases. With respect to segmental analysis, there was a 25-27% positive concordance, a 24-27% negative concordance, and a 48-50% discordance between the LDDE and the radionuclide definitions of viability of myocardium. Additionally, there was no significant difference among sensitivities and specificities for the definitions of viability. The sensitivity was 69% for the uptake of 99mTc sestamibi > 50% criterion, and the highest specificity was 66% for the LDDE. Incorporation of imaging with [18F]-FDG into the analysis yielded a marginally higher sensitivity of 71% for the criterion of uptake of [18F]-FDG or 99mTc sestamibi > 50%, versus imaging with the 99mTc sestamibi alone. CONCLUSION: LDDE was more specific and radionuclide imaging more sensitive for detection of viability of myocardium in asymptomatic patients early after infarction. Possibly defective myocardial metabolization of glucose in the period early after infarction and the specific LDDE protocol applied account for the limited benefit of these studies in terms of facilitating prediction of segmental functional recovery after revascularization in this clinical setting.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.

Antiphosphatidyl serine antibodies are independently associated with ischemic stroke.

OBJECTIVE: To determine whether elevated titers of antiphosphatidyl serine antibodies (aPS) are associated with an increased risk of ischemic stroke in a general stroke population. BACKGROUND: aPS are members of the family of antiphospholipid antibodies that has been associated with increased stroke risk. Although aPS have been demonstrated to occur in 18% of a group of young patients with cerebrovascular symptoms, their prevalence in the general stroke population is unknown, and no controlled study to assess the strength of their association with ischemic stroke has been undertaken previously. METHODS: A case-control study comparing 267 acute ischemic stroke patients and 653 community controls. Sera were obtained immediately after acute stroke in patients. Titers of IgG aPS >16 IgG phospholipid units or IgM aPS >22 IgM phospholipid units were considered positive. Odds ratios (ORs) were obtained by logistic regression, adjusting for age, gender, race/ethnicity, history of hypertension, diabetes mellitus, cardiovascular disease, and cigarette smoking. RESULTS: The adjusted OR was 5.6 (95% confidence interval [CI] 1.8, 18.0) for IgG aPS and 2.9 (95% CI 1.6, 5.3) for IgM aPS. The adjusted OR for either an elevated IgG or IgM aPS was 3.2 (95% CI 1.8, 5.5). CONCLUSIONS: This study demonstrates that elevated IgG and IgM antiphosphatidyl serine antibodies titers are associated with increased risk of ischemic stroke. The prevalence of these antibodies is lower, but the associated stroke risk is comparable with that of anticardiolipin antibodies.

Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity.

BACKGROUND AND PURPOSE: Previous studies have produced conflicting results regarding the putative association between anticardiolipin antibodies (aCL) and infarction in the general stroke population. These inconsistencies may be a function of sample size and methodological differences among the studies. The purpose of the present study, the largest case-control study of this issue to date, was to assess aCL status as an independent risk factor for ischemic stroke in a multiethnic, urban population. METHODS: We obtained aCL titers in 524 hospitalized acute stroke patients and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study. The results were interpreted as negative (30.0 GPL or 15.0 MPL units). Odds ratios (ORs) were adjusted for age, sex, race/ethnicity, history of diabetes, hypertension, atrial fibrillation, coronary artery disease, and current cigarette smoking. RESULTS: A positive aCL titer was present in 11% (111/1020) of controls and 34% (180/524) of cases. The adjusted OR for any positive aCL titer was 4.0 (95% CI, 3.0 to 5.5). For any positive IgG aCL titer this value was 3.9 (95% CI, 2.8 to 5.5), and for any positive IgM aCL titer it was 3.4 (95% CI, 2.1 to 5.5). There were no significant differences in ORs associated with high- or low-positive IgG or IgM aCL titers. CONCLUSIONS: In the largest study of its kind to date, aCL antibodies were demonstrated to be independent stroke risk factors across the 3 ethnic groups studied, conferring a 4-fold increased risk of ischemic stroke. IgG and for the first time IgM aCL were each shown to be associated with increased stroke risk. The prevalence of these antibodies and the stroke risk associated appear greater than previously reported.

The effect of early postinfarction revascularization of asymptomatic patients on left ventricular remodeling.

BACKGROUND: Patients with angina after a Q-wave myocardial infarction benefit from elective revascularization, but it is not known whether asymptomatic patients, including those with a totally occluded infarct-related artery, improve after revascularization. OBJECTIVE: To determine the effect of early postinfarction revascularization of asymptomatic patients on left ventricular remodeling. METHODS: We prospectively studied 31 consecutive asymptomatic patients (aged 57 +/- 2 years, 24 with anterior infarcts) after Q-wave myocardial infarction with > or = 70% stenosis of the infarct-related artery (IRA) who underwent early elective revascularization (days 4-10 after myocardial infarction). Group I consisted in patients with a totally occluded IRA (n = 10), and group II consisted in patients with a patent, though stenosed, IRA (n = 21). Resting echocardiography and low-dose dobutamine echocardiography were performed at baseline (day 3 +/- 1), and rest echocardiography was repeated after an 8-week follow-up. Significant myocardial viability was defined as > or = 2 wall segments improved (in a 16-segment model of left ventricle) versus baseline, and significant functional recovery as > or = 2 segments improved versus baseline on follow-up examination. Left ventricular end-systolic volume indices (ESVI) and end-diastolic volume indices and ejection fractions were measured by using a modified version of Simpson's rule (using apical two-chamber and four-chamber views). RESULTS: The left ventricular ESVI of patients in group I had decreased by 4.2 +/- 1.9 ml/m2, whereas for patients in group II the left ventricular ESVI had increased by 4.2 +/- 1.7 ml/m2 (P = 0.006). Similarly, the left ventricular end-diastolic volume index had decreased by 0.7 +/- 2.4 ml/m2 versus baseline at follow-up for patients in group I and increased by 7.8 +/- 2.1 ml/m2 for patients in group II (P = 0.02). The left ventricular ejection fraction increased by 7.3 +/- 3% for patients in group I and decreased by 0.4 +/- 2% for patients in group II (P = 0.04). CONCLUSION: There is less global left ventricular remodeling, a potentially deleterious process, after elective revascularization early after Q-wave myocardial infarction in asymptomatic patients who had had a totally occluded IRA before revascularization than there is in patients who had already had a patent, though stenosed, IRA before revascularization. These results suggest that restoration of patency of IRA after a Q-wave myocardial infarction is beneficial even for asymptomatic patients.

Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one.

A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.

Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.

A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2, 4-trimethyl-6-phenylquinoline) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. This is the first disclosure of orally active nonsteroidal antiprogestins.

2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3',5'- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-kappa B- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry.

Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-kappa B. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-kappa B and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-kappa B as potential therapeutic targets. The synthesis and preliminary structure-activity relationships of these compounds is addressed.

Nonsteroidal progesterone receptor antagonists based on a conformationally-restricted subseries of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines.

A series of nonsteroidal human progesterone receptor (hPR) antagonists based on conformationally-restricted analogues of a 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline pharmacophore were synthesized and evaluated for their ability to bind to the human progesterone receptor and inhibit progesterone-stimulated reporter gene expression in mammalian cells.

Transesophageal echocardiography: diagnostic and clinical applications in the evaluation of the stroke patient.

OBJECTIVES: Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) in diagnosing cardiac abnormalities that may result in cerebral embolism. The clinical importance of these abnormalities is unclear. METHODS: We classified 96 consecutive stroke patients into high- or low-risk groups for cardioembolism based on historical criteria. The presence of left atrial thrombus, atrial smoke, patent foramen ovale, atrial septal aneurysm, and plaque in the ascending aorta was assessed with TEE. Stroke type and other possible stroke mechanisms were evaluated. RESULTS: Left atrial thrombus occurred only in the high-risk group. Patent foramen ovale, atrial septal aneurysm, and most cases of left atrial smoke occurred in the presence of another embolic source or were associated with a stroke related to hypertensive small vessel disease. Protruding atherosclerotic plaque in the ascending aorta and aortic arch was the most significant cause of stroke diagnosed by TEE because it frequently occurred in those without other risk factors for stroke. TEE identified aortic plaque in one and left atrial smoke in two patients with lacunar infarction without risk factors for small vessel disease. CONCLUSIONS: TEE should be considered in both lacunar and nonlacunar stroke that occur in the absence of stroke risk factors, although optimal management of most TEE findings is yet to be determined.

The Women's Health Curriculum by a problem-based learning method for medical students at the University of California, San Francisco.

OBJECTIVES: Our objectives were to (1) expand and strengthen the women's health curriculum at the University of California, San Francisco, and (2) evaluate the responses of both medical students and faculty to this curriculum. STUDY DESIGN: A written evaluation of the curriculum in women's health was completed by both students and faculty. Variables studied included mean scores of cases, the overall course score, and the preferences of medical students for faculty specialty in teaching the small groups. RESULTS: The overall course evaluation score was 7.81 (range 1 to 10). For those students who had both faculty from internal medicine or family medicine and obstetrics and gynecology, there was a strong preference that obstetrician-gynecologists teach the majority of the cases. CONCLUSIONS: The new case-based curriculum in women's health was enthusiastically received by both medical students and faculty.

The Minorities Risk Factors and Stroke Study (MRFASS). Design, methods and baseline characteristics.

African-Americans and probably Latinos are at increased risk of stroke compared with white, non-Latino Americans. This study seeks to determine if the known risk factors for stroke can account for this increased risk. In this case-control study controls (neighborhood volunteers) were group-matched to acute stroke cases by ethnicity in a ratio of approximately 2:1 for African-Americans and Latinos and 1:1 for whites. Extensive historical, clinical and laboratory data were collected on each subject. For each ethnic group cases were somewhat older and less well-educated than the volunteer controls. Patients in each ethnic group were similar with regard to time from stroke onset to hospital admission, stroke severity, length of stay, discharge disposition and mortality rate. With minor exceptions the distributions of stroke subtypes within each ethnic group appeared similar to those previously reported. Subject recruitment for this case-control study was completed in the manner and time frame planned. Analysis of risk factor information from this sample should provide valuable information regarding the relative risk associated with the major modifiable risk factors for stroke in the minority groups studied.