bluuebunny/crossref_metadata_2025 huggingface dataset:
Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease.
Authors: Adatia I , Barrow S E , Stratton P D , Miall-Allen V M , Ritter J M , Haworth S G
Published: June 2012

BACKGROUND

The pathogenesis of pulmonary vascular disease in children with congenital heart disease is incompletely understood. Thromboxane (TX) A2 and prostacyclin (PGI2) have opposing effects on platelet aggregation and pulmonary vascular smooth muscle. An imbalance in their biosynthesis could contribute to the progressive increase in pulmonary vascular resistance seen in older untreated patients with pulmonary hypertensive congenital heart disease and the thrombotic complications they may develop.

METHODS AND RESULTS

We investigated TXA2 and PGI2 biosynthesis in 15 young children (0.2 to 2.25 years old) with congenital heart disease with increased pulmonary blood flow and potentially reversible pulmonary vascular disease by measuring urinary excretion of 2,3-dinor-TXB2 and 2,3-dinor-6-oxoprostaglandin (PG) F1 alpha and compared the findings with those in 16 healthy children (0.5 to 2.8 years old). 2,3-Dinor-TXB2 excretion was greater in the patients than in control subjects (1253 +/- 161 versus 592 +/- 122 ng/g creatinine; P < .001). Excretion of 2,3-dinor-6-oxo-PGF1 alpha was 452 +/- 54 compared with 589 +/- 95 ng/g creatinine in control subjects. In 5 patients who underwent successful cardiac surgery > or = 1 year later excretion of 2,3-dinor-TXB2 decreased from 1100 +/- 298 to 609 +/- 131 ng/g creatinine (P < .05), a value comparable to those in 5 healthy children of similar age (749 +/- 226 ng/g creatinine). We also compared 15 patients (11 to 23 years old) with advanced irreversible pulmonary vascular disease with 19 healthy control subjects (10 to 23 years old). The ratio of TX to PGI2 metabolite excretion was greater in the patients than in control subjects (3.5 +/- 0.6 versus 2.0 +/- 0.3; P < .05).

CONCLUSIONS

There is increased 2,3-dinor-TXB2 excretion in children with congenital heart disease and a high pulmonary blood flow that may reflect an imbalance in biosynthesis of TXA2 and PGI2 in the pulmonary vascular bed. The imbalance may contribute to the progressive development of increased pulmonary vascular resistance and persists in older patients whose heart defects are uncorrected.
Cigarette smoking and the development and progression of aortic atherosclerosis. A 9-year population-based follow-up study in women.
Authors: Witteman J C , Grobbee D E , Valkenburg H A , van Hemert A M , Stijnen T , Hofman A
Published: June 2012

BACKGROUND

Cigarette smoking has been recognized as an important risk factor for cardiovascular disease in men and women. Whether the increased risk results from an atherogenic effect of smoking is still debated. We examined the relation between cigarette smoking and atherosclerotic changes in the abdominal aorta.

METHODS AND RESULTS

The association between cigarette smoking and atherosclerotic changes in the abdominal aorta was examined in a population-based cohort of 758 women, initially aged 45 to 64 years. All women were examined radiographically for calcified deposits in the abdominal aorta, which have been shown to represent intimal atherosclerosis. After 9 years of follow-up, atherosclerotic changes, indicating development or progression of plaques, could be demonstrated in 37% of women. A direct association was found between atherosclerotic change and number of cigarettes smoked per day. Compared with women who had never smoked, the relative risks of those who smoked 1 to 9, 10 to 19, and 20 or more cigarettes per day were 1.4 (95% confidence interval, 1.0 to 2.0), 2.0 (1.6 to 2.5), and 2.3 (1.8 to 3.0), respectively, after adjustment for age and other cardiovascular risk factors. Associations of atherosclerotic change with inhaling habit and duration of smoking were borderline significant after number of cigarettes smoked per day was taken into account. Among former smokers, the risk decreased with increasing duration of stopping but a significant excess risk was still observed after 5 to 10 years since quitting (relative risk, 1.6; 95% confidence interval, 1.1 to 2.2).

CONCLUSIONS

These follow-up data support the evidence for an effect of cigarette smoking on atherosclerosis. The findings suggest that the rate of atherosclerotic change may be reduced by cessation of smoking, but a residual effect appears to be present for at least 10 years.
Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides.
Authors: Mayer E J , Newman B , Quesenberry C P , Friedman G D , Selby J V
Published: June 2012

BACKGROUND

The relation between alcohol intake and insulin levels may explain, in part, the reported associations of alcohol with cardiovascular disease risk factors, including high-density lipoprotein (HDL) cholesterol, triglycerides, blood pressure, and glucose levels, each of which has been recognized as a component of the insulin resistance syndrome.

METHODS AND RESULTS

Subjects included nondiabetic participants of the Kaiser Permanente Women Twins Study (1989 through 1990). Usual alcohol intake was assessed as part of a food frequency questionnaire. For women from twin pairs in which both twins drank (n = 338), an increment of 12 g of alcohol per day (about one drink) was associated with an 8% lower 2-hour post-glucose-load insulin (P < .01) in a multiple regression analysis for twin data, adjusted for age, body mass index, waist-to-hip ratio, total caloric intake, and family history of diabetes. With genetic influences removed by matched analysis of the subset of 98 monozygotic twin pairs, an intrapair difference of 12 g of alcohol per day was associated with a 12.4% intrapair decrement in postload insulin (P < .01). Inverse associations were also seen for fasting insulin. Alcohol consumption was inversely associated with postload glucose but not with fasting glucose in unmatched (P = .05) and matched (P = .005) analyses. A significant positive association of alcohol intake with high-density lipoprotein cholesterol and an inverse relation of alcohol intake with triglycerides were each independent of insulin levels (P < or = .02 in the matched models). Neither systolic nor diastolic blood pressures were related to alcohol consumption in this sample, perhaps because of the rather low level of alcohol intake in the study population (median, 4 g/d).

CONCLUSIONS

Within the range of light to moderate drinking habits, alcohol consumption was inversely related to fasting and postload insulin levels. This relation did not explain associations of alcohol intake with lipid levels and may instead reflect an additional mechanism by which moderate alcohol consumption impacts cardiovascular disease risk.
Impact of regional ventricular function, geometry, and dobutamine stress on quantitative 99mTc-sestamibi defect size.
Authors: Sinusas A J , Shi Q , Vitols P J , Fetterman R C , Maniawski P , Zaret B L , Wackers F J
Published: June 2012

BACKGROUND

Serial myocardial perfusion imaging with 99mTc-sestamibi (MIBI) was used to evaluate infarct risk area and salvage after thrombolysis. The purpose of this investigation was to determine whether changes in MIBI defect size observed after reperfusion may result in part from distortion of regional and global left ventricular geometry.

METHODS AND RESULTS

Twenty-five open-chest dogs were subjected to either 15 minutes (groups 1A and 1B) or 3 hours (group 2) of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion. MIBI was injected before occlusion (group 1A) or during occlusion (groups 1B and 2), and serial ECG-gated planar imaging was performed. Dobutamine was infused after 3 hours of reperfusion (groups 1B and 2) to transiently alter left ventricular size and function. Perfusion defect magnitude (DM) and extent (DE) were serially quantified with circumferential profile analysis of end-systolic (ES), end-diastolic (ED), and summed images. Flow was assessed with radiolabeled microspheres and correlated with myocardial MIBI activity. Myocardial thickening was assessed in the risk area with sonomicrometers. In group 1A dogs, ischemic dyskinesis produced large artifactual quantitative MIBI defects on ES images (DM, 9.3 +/- 1.3; DE, 27.8 +/- 6.0) that were significantly smaller on ED images (DM, 4.5 +/- 0.9, P < .05; DE, 4.4 +/- 2.3, P < .05). In addition, DM and DE correlated inversely with myocardial thickening on ES images (DM, r = -.84; DE, r = -.78) and summed images (DM, r = -.72; DE, r = -.61) but not ED images (DM, r = -.12; DE, r = -.15). An index of defect reduction derived from summed images correlated well with thickening fraction in stunned dogs (group 1B, r = .89) but poorly in infarcted dogs (group 2, r = .41) subjected to dobutamine stress.

CONCLUSIONS

99mTc-MIBI defect size may be affected by alteration of left ventricular geometry. Changes in regional function may confound analysis of risk area and myocardial salvage with serial 99mTc-MIBI imaging and may also affect defect size during pharmacological stress with dobutamine. Dobutamine 99mTc-MIBI imaging may be useful for distinguishing viable and nonviable myocardium.
Circadian variation of sudden cardiac death reflects age-related variability in ventricular fibrillation.
Authors: Arntz H R , Willich S N , Oeff M , Brüggemann T , Stern R , Heinzmann A , Matenaer B , Schröder R
Published: June 2012

BACKGROUND

Previous studies report a morning peak in the occurrence of out-of-hospital sudden cardiac death but lack detailed information on underlying arrhythmias. We used the documentation system of the semiautomated defibrillators used by emergency medical technicians to investigate the circadian pattern of defined arrhythmias and the influence of demographic patient characteristics on this pattern.

METHODS AND RESULTS

From December 1988 to December 1990, 703 consecutive patients (63% men; age, 67 +/- 17 years) with sudden cardiac death were registered in the Klinikum Steglitz area of the Berlin emergency care system. Determination of time of day of the event was based on the arrival time of the rescue squad. A marked circadian variation (P < .0001) in the occurrence of sudden cardiac death was observed with a primary morning peak (6 AM to noon) and a secondary afternoon peak (3 to 7 PM). The subgroup of 294 patients with ventricular fibrillation as initially documented arrhythmia showed a similar circadian variation (P < .0001). In significant contrast (P < .01), patients with asystole (n = 260) or pulseless bradyarrhythmias (n = 149) were more evenly distributed during the daytime with a primary night trough. Multivariate logistic regression analysis revealed that the circadian pattern of ventricular fibrillation was similar in both gender groups but tended to differ with regard to age: patients older than 65 years demonstrated a monophasic distribution, whereas patients aged 65 years or less had a biphasic distribution with peaks in the morning and in the afternoon.

CONCLUSIONS

The circadian pattern of sudden cardiac death reflects primarily a circadian variation in onset of ventricular fibrillation. The different circadian patterns of ventricular fibrillation, pulseless bradyarrhythmias, and asystole suggest different pathophysiological mechanisms of causation of death. The age dependence of the pattern of ventricular fibrillation may indicate different underlying external or endogenous triggers.
Myocardial force-frequency defect in mitral regurgitation heart failure is reversed by forskolin.
Authors: Mulieri L A , Leavitt B J , Martin B J , Haeberle J R , Alpert N R
Published: June 2012

BACKGROUND

Postoperative ejection phase parameters and patient survival rates for mitral valve replacement surgery are considerably lower than for similar aortic valve surgery. While chordal transection probably is the major contributor to the lowered values, there is also evidence for decreased preoperative myocardial contractile reserve in mitral regurgitation patients. This study characterizes abnormalities in the force-frequency relation that may underlie impaired function of myocardium isolated from mitral regurgitation patients with New York Heart Association class II-III heart failure.

METHODS AND RESULTS

Left ventricular epicardial myocardium was obtained by surgical biopsy during mitral valve replacement surgery in patients with mitral regurgitation heart failure (left ventricular ejection fraction, 0.64 +/- 0.05) and during coronary artery bypass surgery in patients with normal ventricular function. The steady-state twitch tension versus frequency relation was measured in myocardial strip preparations (37 degree C, 12 to 228 min-1) in the absence and presence of forskolin. Relative to normal function, peak isometric twitch tension in mitral regurgitation is depressed by 50% (P < .02) and 74% (P < .003) at contraction frequencies of 60 min-1 and 168 min-1, respectively. The slope of the tension-frequency curve is blunted and its peak is shifted to a lower frequency (mitral regurgitation: 134 min-1; normal function: 173 min-1; P < .02). The myosin heavy chain concentration did not differ between mitral regurgitation and normal function strips (53 +/- 4 versus 54 +/- 4 nmol/g blotted wt). Forskolin (0.5 mumol/L) completely reversed the tension depression, blunting, and the lowered peak frequency in the mitral regurgitation preparations.

CONCLUSIONS

Preoperatively, myocardial tension generation in mitral regurgitation patients is severely depressed, and the force-frequency curve is blunted and has a negative slope in the exercise range of heart rates. The reversal of these defects by forskolin suggests that abnormal excitation-contraction coupling may underlie the decreased contractile reserve in mitral regurgitation patients.
Increased aortic impedance precedes peripheral vasoconstriction at the early stage of ventricular failure in the paced canine model.
Authors: Eaton G M , Cody R J , Binkley P F
Published: June 2012

BACKGROUND

Aortic input impedance is altered in patients with congestive heart failure. However, little is known about whether this vascular response is an early change or a late manifestation of left ventricular dysfunction.

METHODS AND RESULTS

This investigation used a paced canine model of congestive heart failure to demonstrate that abnormal aortic input impedance does evolve in the setting of ventricular systolic dysfunction and to prospectively define the time course of change in aortic input impedance and conduit vessel compliance. Studies were performed in closed-chest conditioned beagles aged 1 to 2 years that underwent hemodynamic evaluation at baseline and after induction of left ventricular dysfunction by rapid ventricular pacing. Within 48 hours of the onset of rapid ventricular pacing, we observed mild left ventricular systolic dysfunction with an echocardiographically derived left ventricular ejection fraction of 37% (p < .001 compared with baseline) measured during interruption of rapid ventricular pacing. Concomitant with this reduction in left ventricular systolic function, the aortic input impedance spectrum was shifted above baseline in all dogs studied. Characteristic impedance of the aorta significantly increased from 121 +/- 65 dynes.s/cm5 to 186 +/- 114 dynes.s/cm5 (P < .02), and a significant increase in the first modulus of impedance from 137 +/- 43 dynes.s/cm5 to 228 +/- 139 dynes.s/cm5 was observed (P < .05). Although characteristic aortic impedance increased by 50%, there was at this point no change in peripheral vascular resistance. Therefore, these abnormalities in aortic input impedance are representative of an early vascular change that evolves in response to ventricular systolic dysfunction.

CONCLUSIONS

Considering the early appearance of these findings, the resultant impaired power transfer and reduced conduit vessel compliance likely contribute to the progression of abnormal myocardial energetics and systolic dysfunction characteristic of ventricular failure.
Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation.
Authors: Rimar S , Gillis C N
Published: June 2012

BACKGROUND

Inhaled nitric oxide gas selectively decreases pulmonary artery pressure without affecting systemic arterial pressure. To determine if the selective pulmonary vasodilating effect of inhaled nitric oxide gas is due to inactivation by hemoglobin, we studied the ability of whole blood to inhibit the vasodilator activity of effluent from isolated lungs exposed to inhaled nitric oxide.

METHODS AND RESULTS

The effluent from ventilated, Krebs-perfused rabbit lungs was passed directly over 3- to 4-mm rabbit aortic rings. Inhaled nitric oxide (150 ppm for 3 minutes) reduced pulmonary perfusion pressure, elevated by a continuous infusion of U46619, by 35 +/- 7% (mean +/- SEM, n = 5). Lung effluent from this series of experiments caused 40 +/- 13% relaxation of phenylephrine-preconstricted aortic rings. When blood was added to the combined lung/ring perfusion cascade (final hemoglobin concentration, 1 g/dL), inhaled nitric oxide again significantly reduced pulmonary perfusion pressure, but the effluent now failed to relax the aortic rings (30 +/- 6% [control] versus 1.5 +/- 1% [blood]). Both reduction in pulmonary perfusion pressure and relaxation of the rings during nitric oxide exposure were unchanged from control values after discontinuing the blood infusion.

CONCLUSIONS

The presence of hemoglobin, even in extremely small amounts, restricts the vasodilating effect of inhaled nitric oxide gas to the pulmonary circulation.
Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs.
Authors: Lerman A , Webster M W , Chesebro J H , Edwards W D , Wei C M , Fuster V , Burnett J C
Published: June 2012

BACKGROUND

Hypercholesterolemia is characterized by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. This abnormality may be due to reduced synthesis of endothelium-derived relaxing factor and/or enhanced synthesis and release of an endothelium-derived contracting factor. Endothelin is an endothelium-derived vasoconstrictor and mitogenic peptide that is present in normal plasma, and its circulating concentrations are elevated in disease states that are characterized by abnormal endothelium-dependent relaxation to acetylcholine. The current studies were designed to test the hypotheses that experimental hypercholesterolemia results in elevation of plasma and tissue endothelin immunoreactivity and that the abnormal acetylcholine-evoked coronary vasoconstriction in the hypercholesterolemic animals is associated with further elevation of plasma endothelin.

METHODS AND RESULTS

Plasma concentrations and molecular forms of endothelin immunoreactivity were determined following 2% cholesterol diet for 4 months in pigs and during intracoronary acetylcholine administration. Second, we assessed the presence of endothelin in the coronary vascular wall by using immunohistochemistry. Hypercholesterolemia elevated plasma endothelin concentration and enhanced coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increases plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction. The predominant molecular form of endothelin in hypercholesterolemia is the biological active endothelin-1.

CONCLUSIONS

This study suggests a role for endothelin as an early participant and a marker for the endothelial dysfunction in hypercholesterolemia as well as a participant in the atherogenic process.
Postextrasystolic potentiation. Do we really know what it means and how to use it?
Authors: Cooper M W
Published: June 2012

Postextrasystolic potentiation (PESP), the increase in contractility that follows an extrasystole, is an interesting phenomenon that has been known for almost 100 years. The literature on this effect is reviewed. It is found that there is significant evidence that the phenomenon is independent of muscle loading and represents a distinct property of the myocardium. Examination of the literature pertaining to the cause of the effect suggests that calcium shifts within the sarcoplasmic reticulum are responsible, although there are some conflicts with this conclusion. Regarding the utility of PESP as a diagnostic test of latent viability of ischemic myocardium, the literature review reveals contradictions and conflicts with several methodological problems of the experiments. Finally, concerning the utility of continuous PESP (paired-pacing) to augment ventricular function in the failing ventricle, the studies again are inconclusive and methodologically suspect. Conditions for the proper analysis of the PESP response are reported, and suggestions for future studies are introduced.
Pressure recovery in aortic valve stenosis.
Authors: Laskey W K , Kussmaul W G
Published: June 2012

BACKGROUND

Pressure recovery is the variable increase in lateral pressure downstream from a stenotic orifice. The magnitude and clinical significance of pressure recovery in aortic valve stenosis are poorly defined.

METHODS AND RESULTS

We obtained high-fidelity pressure and velocity recordings in 11 patients with isolated significant aortic valve stenosis at the time of diagnostic cardiac catheterization. Systematic catheter pullback from the left ventricular cavity revealed a consistent although variable subvalvular gradient. Further pullback across and distal to the region of the stenosed aortic valve revealed a consistent and progressive increase in the ascending aortic pressure. This increase in lateral pressure occurred pari passu with a diminution in amplitude of the velocity pulse. The extent of pressure recovery was directly related to systemic blood flow and transvalvular flow but inversely related to the Gorlin-derived aortic valve area.

CONCLUSIONS

These findings have potentially important implications for the hemodynamic evaluation of mild to moderately severe aortic valve stenosis. The extent of pressure recovery may be of additional utility in the assessment of aortic valve stenosis under varying physiological states.
Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia.
Authors: Page R L , Wilkinson W E , Clair W K , McCarthy E A , Pritchett E L
Published: June 2012

BACKGROUND

Paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia are recognized clinically when patients seek treatment for symptoms due to recurrent arrhythmias; atrial fibrillation also increases the risk of stroke. The frequency with which asymptomatic arrhythmias occur in patients with these arrhythmias is unknown.

METHODS AND RESULTS

Twenty-two patients with paroxysmal atrial fibrillation (n = 8) or paroxysmal supraventricular tachycardia (n = 14) were studied for 29 days with two different ambulatory ECG-monitoring techniques to measure the relative frequency of asymptomatic and symptomatic arrhythmias. All class I antiarrhythmic drugs, calcium channel blockers, beta-blockers, and digitalis were withheld. Sustained asymptomatic arrhythmia events (defined as lasting at least 30 seconds) were documented using continuous ambulatory ECG monitoring once weekly for a total of 5 of the 29 study days; symptomatic arrhythmia events were documented using transtelephonic ECG monitoring for all 29 days of the study. In the group of patients with paroxysmal atrial fibrillation, asymptomatic arrhythmia events occurred significantly more frequently than symptomatic arrhythmia events; the mean rates, expressed as events/100 d/patient (95% confidence interval), were 62.5 (40.4, 87.3) and 5.2 (2.7, 9.0) (P < .01); the ratio of the mean rates was 12.1 (5.8, 26.4). In contrast, in the group of patients with paroxysmal supraventricular tachycardia, asymptomatic arrhythmia events were significantly less frequent than symptomatic arrhythmia events; the mean rates were 0.0 (0.0, 5.3) and 7.4 (5.0, 10.6) (P = .02). The ratio of the mean rates was 0.0 (0.0, 0.8).

CONCLUSIONS

In a group of patients with paroxysmal atrial fibrillation, sustained asymptomatic atrial fibrillation occurs far more frequently than symptomatic atrial fibrillation. However, it is not known whether asymptomatic atrial fibrillation is a potential risk factor for stroke even when patients are not having symptomatic arrhythmias.
Pulmonary atresia with ventricular septal defect in adults.
Authors: Marelli A J , Perloff J K , Child J S , Laks H
Published: June 2012

BACKGROUND

Multistage surgery culminating in completed hemodynamic repair is now performed for pulmonary atresia with ventricular septal defect (PA-VSD). Justification for operation in patients with an adequate collateral pulmonary circulation is controversial. Data on natural adult survival are scant but are necessary to provide the rationale for multistage reconstructive procedures.

METHODS AND RESULTS

All cyanotic adults with PA-VSD in the UCLA Adult Congenital Heart Disease Center Registry from 1978 through 1992 formed the basis for this study. Registry data and echocardiographic, hemodynamic, and angiographic information were used to determine longevity, clinical course, and operative feasibility. Of 26 patients, 16 were unoperated when referred (group A), and 10 had been palliated before age 18 years (group B). Two thirds were 18 to 29 years old. Only 2 patients survived beyond age 40 years. Six died during follow-up at a mean age of 31 years (+/- 12.1 SD). Eight group A patients were in New York Heart Association class II, and 8 were in class III. Of the 26 group A and B patients, 20 had aortic regurgitation, which was moderate or severe in 10. Eight had cardiac failure. Of 11 group A patients who remained unoperated, 5 died. Twelve patients were considered eligible for surgery at > or = 18 years of age. Ten underwent completed hemodynamic repair with a mean post-operative right ventricular-to-left ventricular systolic pressure ratio of 0.45 (+/- 0.16 SD), and there were no early or late deaths.

CONCLUSIONS

Even when collateral blood flow permits adult survival, all such patients are symptomatic. Mean life expectancy without operation did not exceed three decades. Aortic regurgitation and cardiac failure are significant negative variables. Nearly half of unoperated adults died during follow-up. Staged hemodynamic repair can be performed with a low surgical risk in properly selected adults with PA/VSD.
Fast computed tomography detection of coronary calcification in the diagnosis of coronary artery disease. Comparison with angiography in patients < 50 years old.
Authors: Fallavollita J A , Brody A S , Bunnell I L , Kumar K , Canty J M
Published: June 2012

BACKGROUND

The predominant cause of coronary artery calcification is atherosclerosis. Although fast x-ray computed tomography (CT) has been demonstrated to be a sensitive technique to detect coronary calcification, the increasing prevalence of calcification with age has been associated with a low specificity for identifying obstructive atherosclerosis. We hypothesized that the specificity of this test would be improved in a younger patient population, making it more useful in the diagnosis of coronary artery disease.

METHODS AND RESULTS

We compared fast CT-detected calcification with coronary angiography in 106 patients under the age of 50 years. Nonenhanced fast CT scans consisting of 20 contiguous 3-mm tomograms of the proximal coronary arteries were obtained during a single breath hold. A positive scan was defined as 4 contiguous voxels (> or = 1 mm2) of density > 130 Hounsfield units in the region of the epicardial coronary arteries. Calcification detected by fast CT had an 85% sensitivity to predict patients with significant coronary artery disease (> or = 50% diameter stenosis), with a specificity of 45%. Although the sensitivity to detect multivessel disease was 94%, the sensitivity to detect single-vessel disease was 75%. Changing the threshold for defining a positive fast CT scan from 4 to 2 contiguous voxels produced a small improvement in sensitivity, to 88%, but reduced specificity to 36%.

CONCLUSIONS

Although the specificity to detect angiographically significant coronary disease with fast CT improves in a younger patient population, it continues to be relatively low. In contrast to older patient populations, a small but significant number of patients < 50 years old with angiographically significant coronary artery disease do not have coronary calcification demonstrated by fast CT. Thus, caution should be used in excluding significant coronary artery disease on the basis of a negative fast CT study.
Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist.
Authors: Mousa S A , Bozarth J M , Forsythe M S , Jackson S M , Leamy A , Diemer M M , Kapil R P , Knabb R M , Mayo M C , Pierce S K
Published: June 2012

BACKGROUND

Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus, we have identified a systemically active peptide analogue (DMP 728) of the arginine-glycine-aspartic acid (RGD) recognition sequence that mediates the binding of ligands such as fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptors. The goals of the present study were to determine the antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models.

METHODS AND RESULTS

DMP 728 demonstrated antiplatelet efficacy in vitro in inhibiting ADP-induced human platelet aggregation (IC50, 46 +/- 2 nmol/L) and fibrinogen binding to human platelets (IC50, 2.3 +/- 0.8 nmol/L) or purified human GPIIb/IIIa receptors (IC50, 0.6 +/- 0.1 nmol/L). DMP 728 demonstrated high affinity and specificity for human platelet GPIIb/IIIa over other adhesion molecules. In anesthetized mongrel dogs, DMP 728 at 0.001 to 1.0 mg/kg IV produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and in prolonging template bleeding time. DMP 728 effects on bleeding time prolongation were more rapidly reversible than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 0.01 mg/kg IV bolus. The antithrombotic efficacy of DMP 728 was examined in vitro and in vivo after IV administration at different doses in various models of arterial thrombosis. In the coronary artery Folts model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED50 of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions. Additionally, DMP 728 demonstrated 100% prevention of primary thrombosis and rethrombosis (P < .01) after treatment with different thrombolytics, including tissue plasminogen activator and streptokinase, in an electrolytically induced femoral artery thrombosis model in dogs.

CONCLUSIONS

Acute intravenous DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in different arterial thrombosis models. These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective antithrombotic agent in coronary and peripheral artery thromboembolic disorders.
Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease.
Authors: Nordt T K , Schneider D J , Sobel B E
Published: June 2012

BACKGROUND

Both vascular disease and elevated concentrations in plasma of plasminogen activator inhibitor type-1 (PAI-1) are prominent in patients with non-insulin-dependent diabetes mellitus (NIDDM). We and others have hypothesized that the increased PAI-1 may contribute to acceleration of atherosclerosis in this condition and in other states characterized by insulin resistance as well. Surprisingly, however, elevations of PAI-1 decrease when type II diabetic patients are treated with exogenous insulin, as do circulating concentrations of the precursor of insulin, proinsulin, in plasma. Accordingly, the increased PAI-1 in patients with NIDDM may reflect effects of precursors of insulin rather than or in addition to those of insulin itself. To assess this possibility directly, this study was performed to identify potential direct effects of proinsulin and proinsulin split products on synthesis of PAI-1 in liver cells, thought to be the major source of circulating PAI-1 in vivo.

METHODS AND RESULTS

Hep G2 cells (highly differentiated human hepatoma cells) were exposed to human proinsulin, des(31,32)proinsulin and des(64,65)proinsulin (split products of proinsulin), or C-peptide. Accumulation of PAI-1 in conditioned media increased in a time- and concentration-dependent fashion in response to the two des-intermediates [3.3-fold with des(31,32)proinsulin and 4.5-fold with des(64,65)proinsulin]. C-peptide elicited no increase. Stimulation was transduced at least in part by the insulin receptor as shown by inhibition of stimulation by insulin receptor antibodies, mediated at the level of PAI-1 gene expression as shown by the 2.2- to 2.9-fold increases in steady-state concentrations of PAI-1 mRNA, and indicative of newly synthesized protein as shown by results in metabolic labeling experiments.

CONCLUSIONS

Our results are consistent with the hypothesis that precursors of insulin (proinsulin and proinsulin split products), known to be present in relatively high concentrations in plasma in patients with NIDDM and conditions characterized by insulin resistance, may directly stimulate PAI-1 synthesis, thereby attenuating fibrinolysis and accelerating atherogenesis.
Heat-shock protein induction in rat hearts. A direct correlation between the amount of heat-shock protein induced and the degree of myocardial protection.
Authors: Hutter M M , Sievers R E , Barbosa V , Wolfe C L
Published: June 2012

BACKGROUND

Previous studies have demonstrated that heat-shock treatment results in the induction of 72-kD heat-shock protein (HSP72) and a reduction of infarct size after subsequent ischemia and reperfusion.

METHODS AND RESULTS

To test the hypothesis that the degree of protection from ischemic injury in heat-shocked rats correlates with the degree of prior HSP72 induction, rats pretreated with 40 degrees C, 41 degrees C, or 42 degrees C of whole-body hyperthermia followed by 24 hours of recovery and control rats (n = 6 in each group) were quantitatively assessed for the presence of myocardial HPS72 by optical densitometry of Western blots and a primary antibody that is specific for HSP72 and a tertiary antibody labeled with 125I. Although rats heat-shocked to 40 degrees C had no significant induction of myocardial HSP72, rats heat-shocked to 41 degrees C and 42 degrees C demonstrated progressively increased amounts of myocardial HSP72 compared with controls. Separate groups of rats heat-shocked to 40 degrees C (n = 16), 41 degrees C (n = 37), and 42 degrees C (n = 36) with 24 hours of recovery and controls (n = 26) were subjected to 35 minutes of left coronary artery occlusion and 120 minutes of reperfusion. Compared with control and 40 degrees C rats, there was progressive infarct size reduction, assessed by triphenyltetrazolium chloride staining, in rats that were heat-shocked to 41 degrees C and 42 degrees C. Furthermore, there was a direct correlation between the amount of HSP72 induced and the reduction in infarct size (r = .97, P = .037).

CONCLUSIONS

These results suggest that the improved salvage after heat-shock pretreatment may be related to the amount of HSP72 induced before prolonged ischemia and reperfusion.
Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.
Authors: van der Wal A C , Becker A E , van der Loos C M , Das P K
Published: June 2012

BACKGROUND

The study was designed to verify the concept of plaques "at risk" and whether inflammation could play a role in plaque rupture and thrombosis.

METHODS AND RESULTS

In 20 patients who had died of acute myocardial infarction, the thrombosed coronary artery was identified and the site of plaque rupture was traced in serial sections. The cellular characteristics of the fibrous cap at the immediate site of rupture were analyzed and compared with the adjacent cap tissue by use of monoclonal antibodies reactive with macrophages, T lymphocytes, and smooth muscle cells. A deep intimal rupture, extending into the lipid core, was encountered in 12 plaques, whereas 8 had superficial erosions only. Ten atherosclerotic plaques had a distinctly attenuated fibrous cap covering a large atheroma, 7 showed a thick fibrocellular cap overlying a lipid pool, and 3 showed a fibrocellular lesion without a clear lipid core. Macrophages, and to a lesser extent T lymphocytes, were the dominant cells at the immediate site of either rupture or superficial erosion in each instance. These sites, moreover, were always characterized by abundant expression of HLA-DR antigens on both inflammatory cells and adjacent smooth muscle cells, suggesting an active inflammatory reaction. In terms of overall cellular composition of the ruptured plaques, the dominant cell types were macrophages and T cells in 11, smooth muscle cells in 3, and mixtures of both in 6.

CONCLUSIONS

The underlying atherosclerotic plaque morphology in complicated coronary artery lesions causing acute myocardial infarction is heterogeneous with respect to both plaque architecture and cellular composition. However, the immediate site of plaque rupture or erosion is always marked by an inflammatory process. This suggests that inflammation plays a role in destabilizing the fibrous cap tissue and, thus, in enhancing the risk of coronary thrombosis.
Angiotensin-converting enzyme inhibition with fosinopril sodium in the prevention of restenosis after coronary angioplasty.
Authors: Desmet W , Vrolix M , De Scheerder I , Van Lierde J , Willems J L , Piessens J
Published: June 2012

BACKGROUND

Several angiotensin-converting enzyme inhibitors have antiproliferative effects in a rat model after carotid artery balloon injury.

METHODS AND RESULTS

We conducted a randomized, double-blind, placebo-controlled trial to assess the effect of fosinopril, a novel angiotensin-converting enzyme inhibitor, in restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received fosinopril or matched placebo 10 mg at least 18 hours before PTCA, 20 mg at least 4 hours before PTCA, and 40 mg daily for 6 months. In addition, all patients received aspirin. Coronary angiograms before PTCA and immediately after PTCA as well as at 6-month follow-up were quantitatively analyzed. A total of 509 patients were recruited. The final per-protocol population consisted of 153 fosinopril-treated and 151 placebo-treated patients. Restenosis rates according to the National Heart, Lung, and Blood Institute criterion 4 (loss of > or = 50% of the initial gain [primary end point]) were 45.7% and 40.7% in the fosinopril and control groups, respectively (not significant). The respective mean differences in minimal coronary luminal diameter between post-PTCA and follow-up angiograms were -0.59 +/- 0.71 mm and -0.51 +/- 0.67 mm (not significant). Clinical events during the 6-month follow-up period, analyzed on an on-treatment basis, were ranked according to the most serious event. The respective numbers in the fosinopril and the control groups were for death, 0 and 0; myocardial infarction, 0 and 0; coronary artery bypass graft surgery, 1 and 3; repeat PTCA, 35 and 35; recurrent signs of ischemia necessitating early repeat coronary angiography and managed medically, 6 and 7; and none of the above, 111 and 106. All these differences were significant.

CONCLUSIONS

Administration of fosinopril in a dose of 40 mg daily during 6 months after PTCA does not prevent restenosis and has no effect on overall clinical outcome.
Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited.
Authors: el-Tamimi H , Mansour M , Wargovich T J , Hill J A , Kerensky R A , Conti C R , Pepine C J
Published: June 2012

BACKGROUND

In patients with angiographically detectable atherosclerosis or in those with risk factors for coronary artery disease, intracoronary acetylcholine causes coronary constriction instead of endothelium-derived relaxing factor-mediated dilation. Therefore, it has been hypothesized that diffuse endothelial dysfunction precedes development of coronary atherosclerosis. We tested this hypothesis in a systematic investigation of the effects of ascending doses of acetylcholine on the diameters of nonstenotic segments of the left coronary artery in patients with advanced atherosclerosis and coronary risk factors.

METHODS AND RESULTS

Effects of intracoronary infusion of acetylcholine (10(-6) to 10(-4) mol/L) on diameters of proximal, middle, and distal nonstenotic segments of the left coronary artery were studied in 28 consecutive patients with chronic stable angina, positive exercise tests, and angiographic evidence of obstructive atherosclerosis (> or = 50% reduction in lumen diameter in at least one vessel). Two patterns of response to the maximal acetylcholine dose (10(-4) mol/L) were observed. In 21 patients (group 1), only constriction was observed in all left anterior descending and circumflex artery segments studied (16 +/- 3%, 19 +/- 4%, and 23 +/- 4%, respectively; P < .01 compared with control). In 7 other patients (group 2), both constriction and dilation were observed in adjacent segments of the same vessel; maximal acetylcholine dose caused constriction in 14 left anterior descending artery segments from a control diameter of 1.94 +/- 0.19 to 1.33 +/- 0.26 mm (37% reduction, P < .01) and dilation in 16 other segments from 1.63 +/- 0.22 to 1.93 +/- 0.21 mm (25% increase, P < .01). In the circumflex artery, this dose caused constriction in 16 segments from a control diameter of 1.88 +/- 0.14 to 1.33 +/- 0.17 mm (31% reduction, P < .01) and dilation in 12 segments from 1.37 +/- 0.12 to 1.71 +/- 0.09 mm (34% increase, P < .01).

CONCLUSIONS

In 25% of patients studied with advanced angiographic coronary atherosclerosis and coronary risk factors, coronary segments with acetylcholine-inducible dilatation are present. In these patients, the endothelium is not diffusely dysfunctional as currently believed but rather shows marked segmental heterogeneity in the response to acetylcholine reflecting degrees of endothelial dysfunction.
Trans-fatty acids intake and risk of myocardial infarction.
Authors: Ascherio A , Hennekens C H , Buring J E , Master C , Stampfer M J , Willett W C
Published: June 2012

BACKGROUND

Concern that trans-fatty acids formed in the partial hydrogenation of vegetable oils may increase the risk of coronary disease has existed for several decades, but direct evidence on this relation in humans is limited.

METHODS AND RESULTS

With a case-control design, we studied the association between intake of trans-fatty acids and a first acute myocardial infarction among 239 patients admitted to one of six hospitals in the Boston area and 282 population control subjects. Intake of trans-fatty acids was estimated using a previously validated food frequency questionnaire. After adjustment for age, sex, and energy intake, intake of trans-fatty acids was directly related to risk of myocardial infarction (relative risk for highest compared with lowest quintile, 2.44; 95% confidence interval, 1.42, 4.19; for trend P < .0001). This relation remained highly significant after adjustment for established coronary risk factors, multivitamin use, and intake of saturated fat, monounsaturated fat, linoleic acid, dietary cholesterol, vitamins E and C, carotene, and fiber. Intake of margarine--the major source of trans-isomers--was significantly associated with risk of myocardial infarction.

CONCLUSIONS

These data support the hypothesis that intake of partially hydrogenated vegetable oils may contribute to the risk of myocardial infarction.
Higher risk of cardiovascular mortality among lean hypertensive individuals in Tecumseh, Michigan.
Authors: Carman W J , Barrett-Connor E , Sowers M , Khaw K T
Published: June 2012

BACKGROUND

A cohort of 2181 men and women, aged 40 to 79 years, without evidence of coronary heart disease or cancer at entry to the Tecumseh Study was evaluated.

METHODS AND RESULTS

Subjects were defined as lean if their Metropolitan Life Insurance table relative weight was < 110 (n = 584) and as obese if their relative weight was > or = 120 (n = 1024). There were 688 subjects with hypertension at study entry (systolic blood pressure > or = 160, diastolic blood pressure > or = 95, or treated). The 29-year relative risk (RR) of mortality from ischemic heart disease (IHD) or cardiovascular disease (CVD) associated with systolic blood pressure level was significant for both lean and obese subjects. Among hypertensive subjects, the RR of fatal IHD for lean versus obese hypertensive subjects was 1.87 (95% confidence interval, 1.21 to 2.88) and the RR of fatal CVD was 1.56 (95% confidence interval, 1.10 to 2.20) using a Cox proportional-hazards model to adjust for the independent effects of age and traditional CVD risk factors. The findings are consistent with other studies in men showing lean hypertensive subjects to be at greater risk of IHD or CVD mortality than obese hypertensive subjects. A similar finding is now observed in women.

CONCLUSIONS

Associations do not prove causality or dictate management. Nevertheless, the unexplained higher mortality in lean versus obese hypertensive subjects has now been reported with sufficient frequency to suggest that the association is real (if unexplained). Determining the reasons for this association may improve targeted prevention and treatment strategies.
Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus.
Authors: Yamada T , Matsumori A , Sasayama S
Published: June 2012

BACKGROUND

Tumor necrosis factor-alpha (TNF-alpha) has been reported to have an antiviral effect in vitro; however, its in vivo effect remains to be clarified.

METHODS AND RESULTS

To investigate the role of TNF-alpha in viral myocarditis using a murine model induced by encephalomyocarditis virus (EMCV), we evaluated (1) plasma TNF-alpha levels by enzyme-linked immunosorbent assay (ELISA), (2) the effect of recombinant human TNF-alpha for its possible antiviral effect in vivo, and (3) the effect of anti-murine TNF-alpha monoclonal antibody (mAb) in vivo. Four-week-old DBA/2 mice were inoculated intraperitoneally with EMCV (day 0). Mice were injected intravenously daily with 1 microgram of TNF-alpha or 2 x 10(3) units of anti-TNF-alpha mAb starting on day -1, day 0, or day 1 until day 2 (TNF-alpha study) or day 4 (anti-TNF-alpha mAb study). A portion of the mice were killed on day 5 (protocol 1); their hearts were removed, and plaque assays were performed to demonstrate the myocardial virus content. The remaining mice were killed on day 14 (protocol 2); myocardial lesions were examined histopathologically in terms of severity, and their survival rates were determined. Plasma TNF-alpha concentration was elevated in the blood of infected mice compared with uninfected mice 3, 5, and 7 days after virus inoculation. The myocardial virus content was higher in the TNF-alpha-treated group than in the control group. Histopathological analysis revealed that myocardial necrosis and cellular infiltration were more prominent in the TNF-alpha group than in the control group. The anti-TNF-alpha mAb improved survival and myocardial lesions when its treatment was started 1 day before virus inoculation. However, it showed no therapeutic effect when administered simultaneously with the inoculation or on day 1.

CONCLUSIONS

TNF-alpha may play an important role in the very early stage of the immune response, and anti-TNF-alpha mAb may prevent the early pathway of acute viral myocarditis.