Patterns of DNA Methylation Across the Leptin Core Promoter in Four Diverse Asian and North American Populations.

DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA that are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process. Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative functions include regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism, and reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examined the significance of variation in DNA methylation patterns along the leptin core promoter in four populations (phase 1) and used biomarkers reflecting leptin's functional process in two of those populations, western Buryat of Siberia and the Mennonite of central Kansas, to investigate the relevance of the ethnic variation identified in the DNA methylation (phase 2). LEP's core promoter region contains both the binding site for C/EBPα (CCAAT/enhancer binding protein alpha), which tempers the final step in adipocyte maturity and capacity to synthesize leptin, and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, suggesting tissue-specific methylation variation at this region ( Melzner et al. 2002 ). We hypothesized that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers that reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system, and anthropometric measures. In phase 1, our combined analyses of 313 individuals documented a distinct and consistent overall pattern of differential DNA methylation across seven CpG sites of LEP core promoter in all ethnicities and both sexes. This pattern replicates those identified in previous studies, suggesting a conserved core promoter region across populations. Phase 2 analyses of two of the four populations (n = 239), correlating methylation at the C/EBPα transcription binding site (TBS) with metabolic and anthropometric biomarkers reflecting LEP roles, showed that stature, which reflects bone growth and remodeling, was significantly and inversely correlated with the percentage of DNA methylation at this site in both sexes. We suggest that variation in DNA methylation along the LEP core promoter plays a substantial role in energy signals affecting both adipogenesis and bone metabolism.

Quantitative and depth-resolved deep level defect distributions in InGaN/GaN light emitting diodes.

Deep level defects in the multi-quantum well (MQW) region of InGaN/GaN light emitting diodes (LEDs) were investigated. InGaN quantum well and GaN quantum barrier defect states were distinguished using bias-dependent steady-state photocapacitance and deep level optical spectroscopy, and their possible physical origin and potential impact on LED performance is considered. Lighted capacitance-voltage measurements provided quantitative and nanoscale depth profiling of the deep level concentration within the MQW region. The concentration of every observed deep level varied strongly with depth in the MQW region, which indicates evolving mechanisms for defect incorporation during MQW growth.

Quantitative and depth-resolved deep level defect distributions in InGaN/GaN light emitting diodes.

Deep level defects in the multi-quantum well (MQW) region of InGaN/GaN light emitting diodes (LEDs) were investigated. InGaN quantum well and GaN quantum barrier defect states were distinguished using bias-dependent steady-state photocapacitance and deep level optical spectroscopy, and their possible physical origin and potential impact on LED performance is considered. Lighted capacitance-voltage measurements provided quantitative and nanoscale depth profiling of the deep level concentration within the MQW region. The concentration of every observed deep level varied strongly with depth in the MQW region, which indicates evolving mechanisms for defect incorporation during MQW growth.

Unangan past and present: the contrasts between observed and inferred histories.

Academic research focusing on the population and culture history of the Aleut (Unangan) people began in the late 19th century and continues to the present. The papers in this special issue of Human Biology summarize the latest results from archaeological, linguistic, genetic, and morphometric research approaches that bear on our current understanding of Unangan history and prehistory. Although these new analyses have provided a level of description and resolution previously unattainable, explanatory models and mechanisms for the patterned variation observed over time in the biological and cultural record of the Aleutian region remains elusive. Bringing the diverse data sets into concordance to represent an integrated synthesis of Aleut population and culture history and of Unangan origins and their relationships with other groups in the region remains a goal for future investigators.

Anthropometric variation among Bering Sea natives.

Recent research indicates that anthropometrics can be used to study microevolutionary forces acting on humans. We examine the use of morphological traits in reconstructing the population history of Aleuts and Eskimos of the Bering Sea. From 1979 to 1981, W. S. Laughlin measured a sample of St. Lawrence Island Eskimos and Pribilof Island Aleuts. These samples included adult participants from St. George and St. Paul in the Pribilof Islands and from Gambell and Savoonga on St. Lawrence Island. The Relethford-Blangero method was used to examine the phylogenetic relationship between Aleuts and Eskimos. Anthropometric measurements for Native North Americans (measured by Boas and a team of trained anthropometrists in 1890-1904) and Native Mesoamericans (compiled from the literature for 1898-1952) were used for comparison. A principal components analysis of means for measurements and a neighbor-joining tree were constructed using Euclidean distances. All these tests revealed the same strong relationship among the focus populations. The R matrix from the Relethford-Blangero method clusters Aleuts and Eskimos separately and accounts for 97.3% of the variation in the data. Phenotypic variation within the population is minimal and therefore minimum F(ST) values are low. Genetic distances were compared to a Euclidean distance matrix of anthropometric measurements using a Mantel test and gave a high but not significant correlation. Our results provide evidence of a close phylogenetic relationship between Aleut and Eskimo populations in the Bering Sea. However, it is apparent that history has affected the relationship among the populations. Despite previous findings of higher European admixture in Gambell (based on blood group markers) than in Savoonga, Savoonga has greater within-group variation in anthropometric measurements. Anthropometrics reveal a close relationship between Gambell and St. Paul as a result of European admixture. The St. George population was the most divergent of the populations, indicating that it diverged from the Eskimos and St. Paul because of the compounding effects of genetic drift and limited European gene flow. These findings are in agreement with previous anthropometric and genetic studies of the Aleut and Eskimo populations and support the utility of anthropometrics in inferring population history and structure.

Mitochondrial DNA diversity in Mennonite communities from the midwestern United States.

We examined mitochondrial DNA (mtDNA) variation in six Mennonite communities from Kansas (Goessel, Lone Tree, Garden View, Meridian, and Garden City) and Nebraska (Henderson) to determine their genetic structure and its relationship to population history. Mitochondrial DNA haplogroup and haplotype information were obtained from blood samples from 118 individuals. Molecular genetic variation was analyzed using diversity measures, neutrality test statistics, spatial analysis of molecular variance (SAMOVA), and multidimensional scaling plots. The Mennonite samples exhibited eight western European mtDNA haplogroups: H, HV0, I, J, K, T, U, and X. Comparable to other populations of European descent, haplogroup H was the most frequent in all six communities and ranged from 35% in Lone Tree to 75% in Old Order Mennonites from Garden City. Fifty-eight different mtDNA haplotypes were found in these groups with only one shared among all six populations. Haplotype diversities varied from 0.81 in Goessel to 0.96 in Henderson and Garden View. Multivariate statistical analysis of these populations indicates that these Anabaptist communities formed new congregations by fissioning along familial lines. Population subdivision of these communities into congregations supports previously documented patterns of fission-fusion. These haploid molecular data provide a more accurate reflection of biological relationships between midwestern Mennonite communities than evidence based on classical genetic markers.

Hemoglobin polymorphism in Macaca nemestrina.

Four hemoglobin phenotypes have been noted in the pigtailed monkey ( Macaca nemestrina). Pedigree studies suggest a simple codominant Mendelian explanation for inheritance of three of these phenotypes, including one electrophoretically identical with human type A. The fourth type occurred in only one animal in this series.

Complement localization and mediation of ischemic injury in baboon myocardium.

We sought to determine whether the third component of complement (C3) is localized in ischemic baboon myocardium after coronary artery ligation. Furthermore, we assessed the effects of prior C3 depletion on myocardial necrosis. We studied seven control baboons (group I) and seven C3-depleted (group II) baboons that were killed 24 h after ligation of the anterior descending coronary artery. Multiple tissue samples were obtained from infarct, intermediate, and normal myocardial sites as defined by serial unipolar epicardial ECG mapping. In group I baboons, myocardial creatine kinase content from infarct sites was reduced as compared with normal sites (12.6+/-0.92 [SE] vs. 24.4+/-0.75 IU/mg protein, P < 0.001). The intermediate sites from group I contained more creatine kinase (19.0+/-1.25 IU/mg protein) than infarct sites (P < 0.001), but less (P < 0.025) than normal sites. In group II, intermediate sites showed no significant reduction in creatine kinase from normal sites and there was significantly less creatine kinase depletion in infarct sites when compared with group I animals (33.7+/-4.6 and 51.4+/-1.8% depletion, respectively, P < 0.001). In all seven group I baboons, uniform C3 localization was observed in infarct sites by direct immunofluorescence but appeared in mosaic patterns in intermediate sites. C3 was not demonstrated in any normal sites, nor in any site from group II baboons. Additional studies on baboons killed at earlier times after ligation indicated that C3 was localized focally on swollen myocytes in infarct sites as early as 4 h after coronary ligation. These results strongly implicate the active participation of the complement system of inflammatory proteins in the pathogenesis of myocardial tissue injury following coronary occlusion.

Estrogen and cardiovascular function after menopause.

Nonrandomized trials of postmenopausal estrogen replacement have shown a benefit in the prevention of coronary artery disease. Less clear are the specific mechanisms by which this occurs. Estrogen has beneficial effects on the lipid profile, with significant elevations in high density lipoprotein cholesterol and reductions in low density lipoprotein cholesterol reported. Also, antioxidant properties have been ascribed to estrogen. In addition, estrogen has been shown to prevent paradoxic vasoconstriction in atherosclerotic coronary arteries after acetylcholine and may have calcium channel-blocking and alpha2-inhibiting properties. Other proposed mechanisms of cardiovascular protection include reductions in serum fibrinogen and increases in prostacyclin biosynthesis. There is some evidence that cardiovascular biomechanics may be mildly depressed after menopause and that estrogen may normalize these changes by increasing ventricular contractility and, possibly, relaxation. Far less is known about the cardiovascular effects of progesterone, but overall it does not appear that the less androgenic progestins substantially modify the effects of estrogen. Because more women > 50 years old die of cardiovascular disease than any other cause, further clinical investigations of the risks and benefits of estrogen replacement and combined estrogen and progesterone therapy are clearly needed.

Valve excrescences: prevalence, evolution and risk for cardioembolism.

OBJECTIVES: We sought to determine prospectively the prevalence, evolution and embolic risk of valve excrescences in normal subjects and patients with and without suspected cardioembolism. BACKGROUND: Valve excrescences detected by transesophageal echocardiography (TEE) have been considered a cardioembolic substrate in selected patients. METHODS: Ninety healthy volunteers (Group I) and 88 patients without suspected cardioembolism and a normal TEE (Group II) were studied and followed up clinically for 58 +/- 21 and 48 +/- 20 months, respectively. To assess the evolution of valve excrescences, 45 of these subjects underwent repeat TEE at 31 +/- 13 months. The findings in Groups I and II were compared with those of Group III--49 patients referred for TEE for suspected cardioembolism. RESULTS: Valve excrescences were detected in 34 subjects (38%) in Group I and in 41 patients (47%) in Group II. In Group III, 20 patients (41%) had excrescences, but 85% of them had other potential cardiac or vascular sources of embolism. In all groups, mitral valve excrescences were predominant (68% to 76%), followed by aortic (38% to 50%) and right-sided valves (<10%). Excrescences were equally frequent in men and women and between all age groups studied. During follow-up in Groups I and II, excrescences persisted unchanged, and 1 (1.4%) of 74 patients with and 2 (2%) of 99 subjects without excrescences had cerebral ischemic events (80% power to detect a clinically meaningful difference of 4%). CONCLUSIONS: Valve excrescences are common on the left-sided heart valves of normal subjects and patients regardless of gender and age; they persist unchanged over time and do not appear to be a primary source of cardioembolism.

Regional left atrial stasis during atrial fibrillation and flutter: determinants and relation to stroke.

OBJECTIVES: This study sought to 1) determine the location of left atrial stasis during atrial arrhythmia; 2) define the degree of stasis associated with significant risk of stroke; and 3) identify clinical or transthoracic echocardiographic data useful for predicting left atrial stasis. BACKGROUND: Prior studies suggest that stroke during atrial arrhythmia is related to stasis in either the body of the left atrium or the appendage. Recent data indicate that appendage stasis is associated with appendage thrombus formation, but stroke during atrial arrhythmia occurs frequently in the absence of appendage stasis. METHODS: Blood flow velocity was measured in multiple sites in the body of the left atrium and in the appendage by transesophageal pulsed wave Doppler echocardiography in 89 patients with atrial fibrillation or flutter. Regional velocities were related to the frequency of probable embolic stroke and to clinical and transthoracic echocardiographic variables. RESULTS: The lowest velocity region was either the posterior left atrium or the appendage. Stroke frequency increased progressively and steeply with velocity < 15 cm/s in either region; this cutoff value had an 87% sensitivity and 40% specificity for stroke. Factors related to stasis were low left atrial ejection fraction, mitral regurgitation < 3+, fibrillation (vs. type I flutter), left ventricular dilation and mitral valve area < 2.0 cm2. CONCLUSIONS: Posterior left atrial stasis appears to be as important as appendage stasis for the risk of stroke, which increases steeply with lower blood flow velocity in either region. Patients likely to have severe stasis during atrial arrhythmia are those with left ventricular dilation and low atrial ejection fraction accompanying left atrial dilation. Direct measurement of atrial velocity by transesophageal echocardiography appears to be useful for the identification of patients at risk for stroke during atrial arrhythmia.

Flow dependence of valve area in aortic stenosis: relation to valve morphology.

OBJECTIVES: We sought to develop an index of flow dependence of valve area in aortic valve (AoV) stenosis and to determine whether this index is related to structural characteristics of the diseased valve. BACKGROUND: Many studies of AoV stenosis using Gorlin or continuity equation methods have demonstrated flow dependence (an increase in valve area with increased flow). Variation in flow dependence between patients despite similar flow rates remains unexplained. METHODS: Dobutamine Doppler echocardiography was used to calculate flow rate and valve area by the continuity equation in 27 patients with aortic stenosis. For each patient the slope of the regression line of valve area to flow rate was determined (slope of flow dependence). Transesophageal echocardiography was used to evaluate features of valve morphology potentially related to the etiology of AoV stenosis and the mechanism of flow dependence. RESULTS: Mean slope of flow dependence was 0.28 cm2/100 ml per s (range -0.06 to 0.53); flow dependence was significantly >0 in 21 patients and was lower for bicuspid valves (slope 0.21 cm2/100 ml per s) than for tricuspid valves with <10% commissural fusion (slope 0.35, p < 0.01). Off-center/ovoid orifices demonstrated the least flow dependence (slope 0.19), whereas star-shaped orifices showed the most (slope 0.36, p < 0.01). Greater flow dependence was related to a lower percentage of commissural fusion (r = -0.46, p = 0.02) as well as diffuse sclerosis, primarily involving the cusp bodies, rather than localized sclerosis, with involvement of cusp margins. CONCLUSIONS: The slope of flow dependence of valve area in AoV stenosis differs markedly between patients. More flow dependence was associated with tricuspid valves and the morphologic features characteristic of calcific AoV stenosis, whereas less flow dependence was associated with bicuspid valves and the features of rheumatic disease.

Value of noninvasive techniques for predicting early complications in patients with clinical class II acute myocardial infarction.

Twenty-six consecutive patients with acute clinical class II myocardial infarction were prospectively evaluated to assess the ability of two-dimensional echocardiography and gated equilibrium radionuclide angiography to predict early morbidity and mortality. Within 48 hours of the onset of symptoms, right heart catheterization, two-dimensional echocardiography and radionuclide angiography were performed. Serious in-hospital complications developed in 7 patients (27%, Group I), while the remaining 19 patients (Group II) had no complications. Mean left ventricular stroke work index was the only hemodynamic variable that differed significantly between Group I and Group II (28 +/- 8 [standard deviation] vs. 39 +/- 13 g-m/m2, respectively, p less than 0.02). Also, Group I compared with Group II had a significantly lower mean left ventricular ejection fraction by two-dimensional echocardiography (26 +/- 5 vs. 51 +/- 10%, p less than 0.001) or by radionuclide angiography (29 +/- 9 vs. 46 +/- 12%, p less than 0.001). Similarly, Group I had a higher average wall motion index than Group II by both techniques (2.2 +/- 0.2 vs. 1.7 +/- 0.3, p less than 0.001 by two-dimensional echocardiography, and 2.1 +/- 0.3 vs. 1.7 +/- 0.3, p less than 0.001 by radionuclide angiography). Selected stepwise multiple regression analysis demonstrated that left ventricular ejection fraction or wall motion index, by two-dimensional echocardiography or radionuclide angiography, had additional value to a history of prior myocardial infarction for predicting in-hospital complications in patients with class II infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of exercise-induced myocardial ischemia on the pattern of left ventricular diastolic filling: a Doppler echocardiographic study.

Previous studies using Doppler echocardiography to evaluate left ventricular diastolic filling have shown that myocardial ischemia induced by coronary balloon angioplasty or atrial pacing results in a decrease in the left ventricular inflow peak early (E) to peak atrial (A) velocity ratio. To investigate the effects of exercise-induced ischemia on Doppler-derived filling variables, 20 patients with coronary artery disease and exercise-induced electrocardiographic changes and regional wall motion abnormalities determined by two-dimensional echocardiography were evaluated and compared with 20 patients without evidence of exercise-induced ischemia. Doppler echocardiography was performed at rest and immediately after exercise before the resolution of exercise-induced wall motion abnormalities. Peak E and A velocities increased from rest to postexercise in both the ischemic and nonischemic groups, although the ischemic group demonstrated a greater increase in peak E velocity (from 68 +/- 15 cm/s at rest to 88 +/- 22 cm/s after exercise) than the nonischemic group (70 +/- 13 to 77 +/- 18 cm/s) (p less than 0.05 for the difference in response between groups). Accompanying these changes was a slight increase in the peak E/A velocity ratio in the ischemic group (1.04 +/- 0.28 at rest to 1.13 +/- 0.42 after exercise) versus a decrease in the nonischemic group (1.07 +/- 0.30 to 0.90 +/- 0.28) (p less than 0.05 intergroup difference).(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic root disease and valve disease associated with ankylosing spondylitis.

OBJECTIVES: This study sought to determine the prevalence, characteristics, relation to clinical features and evolution of aortic root disease and valve disease associated with ankylosing spondylitis (AKS). BACKGROUND: Aortic root disease and valve disease are common in patients with AKS, but their clinical and prognostic implications have not been well defined. METHODS: Forty-four outpatients with AKS and 30 age- and gender-matched healthy volunteers underwent initial transesophageal echocardiography and rheumatologic evaluations. Twenty-five patients underwent clinical and echocardiographic follow-up 39+/-10 months later. RESULTS: Aortic root disease and valve disease were common in patients (82%) as compared with controls (27%; p < 0.001). Aortic root thickening, increased stiffness and dilatation were seen in 61%, 61% and 25% of patients, respectively. Valve thickening (41% for the aortic and 34% for the mitral valve) manifested predominantly (74%) as nodularities of the aortic cusps and basal thickening of the anterior mitral leaflet, forming the characteristic subaortic bump. Valve regurgitation was seen in almost half of patients, and 40% had moderate lesions. Except for the duration of AKS, aortic root disease and valve disease were unrelated to the activity, severity or therapy of AKS. During follow-up of 25 patients, in up to 24% new aortic root or valve abnormalities developed, in 12% existing valve regurgitation worsened significantly and in 20% abnormalities resolved. Twenty percent of patients developed heart failure, underwent valve replacement, had a stroke or died, as compared with 3% of control subjects. CONCLUSIONS: Aortic root disease and valve disease are common in patients with AKS, are unrelated to clinical features of AKS, can resolve or progress over time and are associated with clinically important cardiovascular morbidity.

Left atrial dimension and risk of systemic embolism in patients with a prosthetic heart valve. Department of Veterans Affairs Cooperative Study on Valvular Heart Disease.

The relation between left atrial dimension measured by M-mode echocardiography and systemic embolization after valve replacement was examined prospectively among 397 patients with a prosthetic valve enrolled in the Department of Veterans Affairs Cooperative Study on Valvular Heart Disease. Baseline characteristics including several measures of left atrial enlargement were compared for 31 patients who developed systemic embolism and 366 who did not develop embolism during a 5 year follow-up period. Variables that were significantly related to left atrial dimension or systemic embolization in univariate analyses were included with several others in a multiple logistic regression model. The incidence rate of systemic embolism was more than three times higher after mitral valve replacement than after aortic valve replacement (4.4 and 1.3 per 100 patient-years, respectively); this difference persisted after adjustment for other factors. Univariate analysis indicated a threefold higher incidence of systemic embolism in patients with a left atrial dimension greater than or equal to 4 cm compared with that in patients with a dimension less than 4 cm (3 versus 1 per 100 patient-years, respectively). However, when the effect of valve location (mitral versus aortic) was taken into account using either univariate or multivariate techniques, left atrial dimension was found not to be associated with systemic embolism. In multivariate analysis, atrial fibrillation, age, ejection fraction and location of the prosthetic valve were significantly associated with embolism. Results of this multicenter study suggest that left atrial dimension is not independently related to the development of systemic embolism in patients undergoing valve replacement.

Right ventricular infarction: identification by hemodynamic measurements before and after volume loading and correlation with noninvasive techniques.

To evaluate the potential occurrence of right ventricular infarction, 53 patients with acute inferior transmural myocardial infarction were studied within 36 hours of symptoms by right heart catheterization, equilibrium radionuclide angiography and two-dimensional echocardiography. Technetium-99m pyrophosphate myocardial scintigraphy was performed 3 days after the onset of symptoms. The hemodynamic standard for right ventricular infarction was defined as both a right atrial pressure of 10 mm Hg or more and a right atrial/pulmonary artery wedge pressure ratio of 0.8 or more. Eight (15%) of the 53 patients had hemodynamic measurements at rest characteristic of right ventricular infarction, and 6 (11%) additional patients met these criteria after volume loading (p less than 0.05). Nineteen (37%) of the 51 patients who had radionuclide angiography had right ventricular dysfunction manifested by both a reduced right ventricular ejection fraction (less than 40%) and right ventricular regional wall motion abnormalities (akinesia or dyskinesia). An abnormal radionuclide angiogram was observed in 12 of 13 patients with hemodynamic measurements indicating right ventricular infarction. In 12 patients with an abnormal radionuclide angiographic study, right ventricular ejection fraction improved 6 to 12 weeks after infarction (27 +/- 7 to 36 +/- 9%, p less than 0.01). Twenty-two (49%) of the 45 patients with adequate two-dimensional echocardiograms had a right ventricular regional wall motion abnormality. An abnormal two-dimensional echocardiogram was seen in 9 of 11 patients with hemodynamic measurements characteristic of right ventricular infarction. Technetium-99m pyrophosphate scintigraphy was positive for right ventricular infarction in 3 of 12 patients who had hemodynamic measurements indicating right ventricular infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies.

OBJECTIVES: The aims of this study were to better characterize valve disease in systemic lupus erythematosus and to determine its association with antiphospholipid antibodies. BACKGROUND: Estimates of the prevalence of valve disease in systemic lupus erythematosus have been higher in autopsy series than in clinical studies using transthoracic echocardiography. Antiphospholipid antibodies have been suggested to be a primary pathogenetic factor. METHODS: Transesophageal echocardiography was performed on 1) 54 patients with lupus erythematosus, 22 of them with (group I) and 32 without (group II) antiphospholipid antibody; 2) on 10 patients with antiphospholipid syndrome (group III); and 3) on 35 normal subjects (group IV). RESULTS: Patients in groups I and III had similar types and concentrations of antibodies. Leaflet thickening was found in 50% of group I, 47% of group II, 10% of group III and 9% of group IV patients (group I or II vs. group III or IV, p < 0.03). Leaflet thickening in patients with lupus erythematosus was diffuse; it usually involved the mitral and aortic valves and was associated with valve regurgitation (73%) or valve masses (50%). Valve masses were observed in 41% of group I, 25% of group II, 10% of group III and in none of group IV patients (group I or II vs. group IV, p < 0.002). Most valve masses in patients with lupus erythematosus were located near the base on the atrial side of the mitral valve or on the vessel side of the aortic valve, had variable size (0.2 to 0.85 cm2), shape and echodensity. Valve regurgitation was observed in 64% of group I, 59% of group II, 10% of group III and 20% of group IV patients (group I or II vs. group III or IV, p < 0.006). Moderate or severe regurgitant lesions were noted in 27% of group I and 25% of group II patients. CONCLUSIONS: Lupus erythematosus valve disease is frequent (74%) regardless of the presence or absence of antiphospholipid antibodies. Therefore antiphospholipid antibodies may not be a primary pathogenetic factor. The characteristic appearance of leaflet thickening and masses in patients with lupus erythematosus may be unique.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Continuous infusion of lidocaine in patients with cardiac arrhythmias. Unpredictability of plasma concentrations.

Recent studies suggest that lidocaine hydrochloride continues to accumulate during prolonged infusions. Plasma levels of lidocaine and monoethylglycinexylidide (MEGX) were measured in 26 patients with cardiac arrhythmias during lidocaine infusions of 15 to 69 hours' duration. Clearance varied, ranging from 3.2 to 14.7 mL/min/kg, and was significantly less in the ten patients with heart failure (5.8 +/- 1.7 mL/min/kg) as compared with the remaining 16 (8.4 +/- 2.6 mL/min/kg; P < .05). The MEGX levels were < 1 microgram/mL. In four patients, steady states were achieved at two different infusion rates, and changes in lidocaine plasma levels were generally proportional to changes in infusion rates. Lidocaine elimination half-lives ranged from 3.2 to 8.7 hours, and no accumulation continued beyond four half-lives. Clearance values, elimination half-lives, apparent volumes of distribution, and, consequently, steady-state levels were widely variable, which can be partly explained by the inclusion of patients with congestive heart failure. Monitoring of serum lidocaine levels may aid in individualization of therapy.