Mechanisms of deficient cardiac septation in the mouse with trisomy 16

It used to be thought that the atrioventricular septum was predominantly the product of the atrioventricular endocardial cushions. In a previous study, we have shown that multiple developmental primordia are of importance in its formation. With this in mind, we have evaluated cardiac morphogenesis in the mouse with trisomy 16, an animal model with a high incidence of atrioventricular septal defects. Normal and trisomic fetuses from an Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross were collected on days 10 to 15 of gestation and examined by scanning electron microscopy and histological serial sectioning. No evidence was found to suggest that atrioventricular septal defect could be explained simply on the basis of "failure of fusion" between the atrioventricular endocardial cushions. Rather, our findings supported two other developmental elements as being important in the genesis of atrioventricular septal defect. The first is an alteration in the configuration of the heart tube, with inadequate remodeling of the inner heart curvature. This resulted in the failure of the atrioventricular junction to expand to the right, with subsequent malalignment of the atrioventricular endocardial cushions with the proximal outflow cushions. The second is a variability in the connection of the primary atrial cardiac segment to the body of the embryo, the so-called dorsal mesocardium, which influences its relationship to the extracardiac mediastinal mesoderm. There appeared little difference in the connection between normal and trisomic embryos at the stage of 20 to 25 somites, but the area subsequently showed marked changes. In most trisomic embryos, the connection with the mediastinal mesoderm of the body was over a larger area than seen in normal embryos. As this area of attachment encloses the pulmonary pit, the entry point of the pulmonary vein, this gives potential for variation in the connection of the pulmonary vein. In addition, in the majority of trisomic embryos, the right pulmonary ridge (the spina vestibuli) did not accumulate extracardiac mesoderm, nor did it undergo the pronounced forward growth seen in normal embryos of equivalent stages. Consequently, the trisomic embryos show incomplete formation of both the atrial and the atrioventricular septal structures.     

Proinflammatory interactions of pneumolysin with human neutrophils

The effects of pneumolysin on the proinflammatory activity of human neutrophils, as well as on cation fluxes in these cells, have been investigated. Superoxide production, release of elastase, CR3 expression, phospholipase A2 activity, and alterations in membrane potential were measured by use of lucigenin-enhanced chemiluminescence and colorimetric, flow cytometric, radiometric, and spectrofluorimetric procedures, respectively; and cation fluxes were measured by use of 45Ca2+ and 86Rb+ and by fura-2 spectrofluorometry. Pneumolysin at concentrations >1.67 ng/mL caused influx of Ca2+ and increased phospholipase A2 activity and CR3 expression, which were associated with enhanced superoxide production and release of elastase after activation of the cells with the chemotactic tripeptide FMLP. At the same concentrations, pneumolysin caused efflux of K+ and membrane depolarization. The effects of pneumolysin on cation fluxes were not attributable to inhibition of Ca2+-adenosine triphosphatase (ATPase) or Na+, K+-ATPase. Pneumolysin potentiates the proinflammatory activities of neutrophils by a pore-forming mechanism resulting in Ca2+ influx.     

Intravascular ultrasound imaging of the coronary arteries: an in vitro evaluation of measurement of area of the lumen and atheroma characterisation.

OBJECTIVE--To assess the accuracy of measurement of area of the lumen, and sensitivity, and specificity of detection of atheroma in coronary arteries in vitro with a commercially available 20 MHz intravascular ultrasound system. SETTING--A teaching hospital department of cardiology with the support of the department of cardiovascular pathology. PROCEDURE--10 segments of coronary artery were removed from cadaver hearts. Intravascular ultrasound imaging was performed at fixed levels and the vessels were then sectioned and photographed before histological preparation. An independent blinded observer measured luminal area and assessed the presence of atheroma on the intravascular ultrasound images of 76 vessel sections (304 quadrants). The sensitivity and specificity of detection of atheroma was assessed in comparison with the histologically prepared sections. Luminal areas from intravascular ultrasound, photographs of cross sections of the vessels and histological sections were compared with the technique of limits of agreement. RESULTS--Overall 36% of the 304 quadrants studied histologically had identifiable atheroma. Intravascular ultrasound sensitivity for atheroma was 0.593 and the specificity was 0.839. The positive predictive value was 0.674, and the relative risk 3.139. Values for area of the vessel lumen were on average 9.4 mm2 (confidence interval (CI) 8.6-10.2 mm2) larger than those measured from photographs and 10.7 (CI 9.8-11.6 mm2) larger than those measured from the histological sections. CONCLUSIONS--The intravascular ultrasound system assessed in this study significantly overestimated coronary vessel luminal area and had low sensitivity and specificity for detection of atheroma. Improvements in image resolution are required before this system can provide useful information on coronary artery size and morphology.     

Heart rate adjustment of exercise-induced ST segment depression. Improved risk stratification in the Framingham Offspring Study

BACKGROUND. Simple heart rate adjustment of ST segment depression during exercise (delta ST/HR index) and the pattern of ST depression as a function of heart rate during exercise and recovery (the rate-recovery loop) have been shown to improve the ability of the exercise electrocardiogram to detect the presence of coronary heart disease (CHD), but the performance of these methods for the prediction of future coronary events remains to be examined. METHODS AND RESULTS. We compared the delta ST/HR index and the rate-recovery loop with standard electrocardiographic criteria for prediction of CHD events in 3,168 asymptomatic men and women in the Framingham Offspring Study who underwent treadmill exercise electrocardiography and who, at entry, were free of clinical and electrocardiographic evidence of CHD. After a mean follow-up of 4.3 years, there were 65 new CHD events: four sudden deaths, 24 new myocardial infarctions, and 37 incident cases of angina pectoris. When a Cox proportional hazards model with adjustment for age and sex was used, a positive exercise electrocardiogram by standard criteria (greater than or equal to 0.1 mV horizontal or downsloping ST segment depression) was not predictive of new CHD events (chi 2 = 0.40, p = 0.52). In contrast, stratification according to the presence or absence of a positive delta ST/HR index (greater than or equal to 1.6 microV/beat/min) and a positive (counterclockwise) rate-recovery loop was associated with CHD event risk (chi 2 = 9.45, p less than 0.01) and separated subjects into three groups with varying risks of coronary events: high risk, when both tests were positive (relative risk 3.6; 95% confidence interval, 2.4-5.4); intermediate risk, when either the delta ST/HR index or the rate-recovery loop was positive (relative risk, 1.9; 95% confidence interval, 1.3-2.8); and low risk, when both tests were negative. After multivariate adjustment for age, sex, smoking, total cholesterol level, fasting glucose level, diastolic blood pressure, and electrocardiographic evidence of left ventricular hypertrophy, the combined delta ST/HR index and rate-recovery loop criteria remained predictive of coronary events (chi 2 = 5.45, p = 0.02). CONCLUSIONS. Heart rate adjustment of ST segment depression by the delta ST/HR index and the rate-recovery loop during exercise electrocardiography can improve prediction of future coronary events in asymptomatic men and women.     

Value of radionuclide ventriculography in the immediate characterization of patients with acute myocardial infarction

The ability of admission radionuclide ventriculography to discriminate among various clinical subsets was evaluated in patients with acute myocardial infarction. One hundred patients with acute myocardial infarction were evaluated within 8 ± 3.1 hours (mean ± standard deviation) after the onset of chest pain. Forty-one patients were in Killip functional class I, 52 in class II and 7 in class III. The mean radionuclide left ventricular ejection fraction was significantly lower in patients with higher Killip classification because of significant elevation of mean left ventricular end-systolic volume rather than significantly altered mean end-diastolic volume. Killip classification frequently failed to correlate with ejection fraction in individual cases. Admission chest X-ray findings were categorized according to the presence of findings suggestive of impaired left ventricular function. Mean left ventricular ejection fraction was significantly lower in patients with abnormal than in patients with normal chest X-ray findings because of significant elevations in both mean end-diastolic and end-systolic volumes. The chest X-ray findings frequently failed to correlate with ejection fraction in individual cases.Stepwise linear regression analysis was employed to analyze the ability of historical, physical, electrocardiographic and chest X-ray findings to predict radionuclide left ventricular ejection fraction. The most predictive variables in order of decreasing significance were anterior myocardial infarction, abnormal chest X-ray findings, rales to two thirds of the posterior thorax, previous myocardial infarction, transmural myocardial infarction and heart rate greater than 100 beats/min. However, even these six optimal predictive variables could explain only 42 percent of the observed variability in left ventricular ejection fraction. Thus, early radionuclide ventriculography adds significantly to the discriminant power of clinical and radiographic characterization of ventricular function in patients with acute myocardial infarction.