Glycoprotein IIb/IIIa antagonists and low-molecular weight heparin in acute coronary syndromes.

The glycoprotein (GP) IIb/IIIa antagonists and the low-molecular weight heparins are the newest additions to the armamentarium of antiplatelet drugs for the treatment of acute coronary syndromes. They are extremely potent inhibitors of platelet aggregation and thrombin generation, respectively. There are currently three GP IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban) and two low-molecular weight heparins (dalteparin and enoxaparin) approved for use with acute coronary syndromes. Data continue to accumulate outlining the specific roles for these drugs in the treatment of patients with acute coronary syndromes. Clinical trials in patients with acute coronary syndromes have demonstrated that the GP IIb/IIIa antagonists and low-molecular weight heparins offer significant benefit with acceptable safety profiles. Future issues that need to be addressed include refinement of indications for administration and patient selection, comparison between existing agents, evaluation of newer agents, and optimization of dosing to maximize benefit and safety in the use of these powerful new classes of drugs.

Endothelial cell-conditioned medium downregulates smooth muscle contractile protein expression.

Smooth muscle cells (SMC) within atherosclerotic lesions proliferate and exhibit phenotypic modulation, but the contribution of vascular endothelium to this process is poorly understood. Our aim was to examine the effects of endothelial cell-conditioned medium (ECCM) on vascular SMC growth and differentiation. Rat aortic ECCM stimulated a ninefold increase in [3H]thymidine incorporation and downregulated smooth muscle-specific myosin heavy chain and alpha-actin synthesis in rat aortic SMC. These effects were not inhibited by antibodies to platelet-derived growth factor (PDGF)-BB or PDGF-AB or with a PDGF beta-receptor subunit. Treatment with PDGF-BB (at a concentration found in ECCM), PDGF-AA, basic fibroblast growth factor, endothelin-1, or transforming growth factor-beta did not reproduce these effects. The ECCM activities were sensitive to heat and trypsinization, were >30 kDa in molecular mass, and bound weakly to heparin-Sepharose. Our data indicate that cultured endothelial cells produce a factor(s) that downregulates contractile protein expression in SMC, which may contribute to SMC dedifferentiation and proliferation.

Molecular regulation of smooth muscle cell differentiation.

REGULATION OF SMOOTH MUSCLE CELL (SMC) GROWTH: Accelerated growth of SMC is known to play an integral role in atherosclerotic lesion formation as well as post-angioplasty restenosis, and is a characteristic feature in arteries of hypertensive patients and animals. There has thus been extensive interest in defining both positive and negative regulators of SMC growth, and many factors have been identified that may play a role in this process. REGULATION OF DIFFERENTIATED SMC: Despite clear evidence that the differentiated state of the intimal SMC is altered in atherosclerotic disease, and that this is likely to play a key role in lesion development, relatively little is known about the mechanisms and factors that regulate the differentiated state of SMC. Extrinsic factors (local environmental cues) make an important contribution to the regulation of the differentiated state of the vascular SMC. Molecular mechanisms control the expression of genes encoding for proteins such as smooth muscle alpha-actin and smooth muscle myosin heavy chain that are selective or specific for SMC, and which are required for the SMC principal differentiated function, contraction.

Myocardial contrast echocardiography demonstrates that collateral flow can preserve myocardial function beyond a chronically occluded coronary artery.

Myocardial contrast echocardiography, unlike coronary angiography, can define collateral perfusion. This study shows that collateral blood flow can preserve myocardial function beyond a chronically occluded coronary artery.

Nuclear proteins bind a cis-acting element in the smooth muscle alpha-actin promoter.

Identification of the regulators of smooth muscle cell (SMC) gene expression is critical to understanding SMC differentiation and alterations in SMC phenotype in vascular disease. Previous studies revealed positive transcriptional activity within the chicken smooth muscle (SM) alpha-actin promoter region from -209 to -257. In the present study, transient transfections of wild-type and mutant chicken SM alpha-actin promoter/reporter gene constructs into rat aortic SMC demonstrated that the positive transcriptional activity of this region was abolished with a two base pair mutation in a conserved sequence motif at -225 to -233 (TGTTTATC to TACTTATC). Electrophoretic mobility shift assays revealed that nuclear factors bound promoter fragments containing this sequence and that specific mutations in the TGTTTATC motif abolished nuclear factor binding. Studies thus provide evidence for binding of a nuclear factor to a positive cis-acting element within the SM alpha-actin promoter. Further characterization of this factor may contribute to a better understanding of the molecular mechanisms that regulate differentiation of SMC in vascular disease.

Elevated serum lipoprotein(a) is a risk factor for clinical recurrence after coronary balloon angioplasty.

BACKGROUND: Elevated lipoprotein (Lp) (a) concentrations are associated with coronary artery disease and myocardial infarction. Lp(a) is structurally related to proteins involved in lipid transport, fibrinolysis, coagulation, and cellular mitogenesis and is known to have important physiological interactions with the coagulation and fibrinolytic systems. Because these processes may be important to arterial healing after balloon injury, we hypothesized that elevated Lp(a) concentrations may be associated with recurrence of symptoms and restenosis after balloon angioplasty. METHODS AND RESULTS: We assessed 240 consecutive patients undergoing coronary balloon angioplasty with measurements of Lp(a), total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A-I, and apolipoprotein B-100 concentrations from fresh specimens. Patients were evaluated 4 to 6 months after angioplasty for clinical recurrence by repeat angiography if angina had returned or by maximal exercise treadmill testing with thallium imaging if patients remained asymptomatic. Ninety-seven patients (40%) had clinical recurrence; 143 (60%) did not. Patients with recurrence had significantly greater Lp(a) concentrations compared with those without (median, 29 versus 14; P < .0001). Each patient quintile stratified by increasing Lp(a) concentrations had incrementally greater recurrence rates ranging from 27% (lowest quintile) to 60% (highest quintile). By multivariate logistic regression analysis, Lp(a) concentration was the only predictor of recurrence (P < .0001). A subset of frozen, stored serum samples showed a significant decrease in measured Lp(a) concentration over time (mean, 605 days; P < .01). CONCLUSIONS: An elevated Lp(a) concentration was a risk factor for clinical recurrence after percutaneous transluminal balloon coronary angioplasty. Other lipid levels or clinical characteristics were not significantly associated with recurrence. When serum was frozen and stored for a prolonged period, Lp(a) concentration decreased over time.

Binding of the rat liver 7-8 S dexamethasone receptor to deoxyribonucleic acid.

The 7-8 S form of the [3H]dexamethasone (9 alpha-fluoro-11 beta,17,21-trihydroxy-16 alpha-methylpregna-1,4-diene-3, 20-dione) receptor from rat liver cytosol can be converted to the 3-4 S form by RNase treatment or high salt, suggesting a salt-sensitive association between the receptor protein and RNA. In DNA-cellulose column assays, the gradient-purified 3-4 S form bound DNA more efficiently than the 7-8 S form, though the 7-8 S form was also capable of binding to DNA-cellulose to a significant extent. Activated 7-8 S dexamethasone receptor could be released from its association with soluble DNA by treatment with DNase I. Sucrose gradient analysis showed that the released receptor sedimented as the 7-8 S form and was sensitive to RNase treatment, which induced a conversion to the 3-4 S form. Activated RNase-generated 3-4 S receptor again displayed a higher degree of binding to soluble DNA and was recovered in the 3-4 S form following DNase extraction. The fact that the 3-4 S form bound immobilized or soluble DNA more efficiently suggests that the associated RNA of the 7-8 S form interferes directly or indirectly with the receptor association with DNA. The observation that the receptor binds to DNA in its 7-8 S form suggests that the receptor complex is capable of binding RNA and DNA concurrently.

Motivation in hearing aid acceptance.

Patient case histories are presented in an attempt to pinpoint possible motivational factors affecting the acceptance of a hearing aid. Personality profiles were constructed on three representative patients through the use of an in-depth interview as well as three personality scales: the 16PF Multiphasic Personality Scale; the Crowne-Marlowe Social Desirability Scale; and the Attitude Toward Disabled Persons Scale. The very preliminary results indicate at least some face validity to the assertion that unsuccessful hearing aid wearers are measurably different from successful wearers and that these differences may be used to predict success of failure for future patients.