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Heparin-induced thrombocytopenia (HIT) is the most common drug-related thrombocytopenia. Thromboembolic complications occur in approximately 50% of patients with HIT and result in limb amputation and death in up to 20% and 30% respectively. Because patients with a history of HIT may require future intravenous anticoagulation but have a high-risk of thromboembolism if re-challenged with heparin, alternative therapies are necessary when further anticoagulation is indicated. The use of direct thrombin inhibitors in HIT patients who also require thrombolytic therapy offers unique challenges to anticoagulant monitoring and safety. We present a case of progressive ileofemoral deep venous thrombosis in a patient with a history of HIT in order to review the combined use of hirudin and thrombolysis in this setting.

Prostacyclin is an endothelially derived vasodilator and inhibitor of platelet aggregation. Despite its therapeutic potential for peripheral arterial disease, the short half-life and chemical instability are barriers to routine therapy. Accordingly, prostacyclin analogs are being evaluated in patients with peripheral arterial disease. State-of-the-art non-invasive ultrasonography allows for serial testing of the hemodynamic effects of vasoactive drugs. The safety, efficacy and hemodynamic effects of UT-15, a novel, long-acting prostacyclin analog, were studied in patients with severe intermittent claudication. A total of eight patients with stable severe intermittent claudication, Fontaine classes IIb-III, were admitted to the hospital for intravenous infusion of UT-15. A symptom-limited, dose-escalation protocol was instituted, beginning with placebo and then with increasing dosage at 60-min intervals, followed by a 2-h period of maintenance dose at the maximum well-tolerated infusion rate. The hemodynamic response in the lower limbs was assessed with serial ultrasonography, segmental arterial pressures and pulse volumes. Blood flow in the common femoral artery increased 29% (p = 0.003) by the end of the maintenance period and remained above baseline throughout the washout period (p = 0.044). Blood velocity in the lower limb increased in most of the peripheral arteries. These increases achieved statistical significance in the common femoral artery (p = 0.025) and anterior tibial artery (p = 0.019), and approached significance in the popliteal artery (p = 0.062). In two of four patients in whom blood flow was undetectable before the infusion, arterial blood flow at the ankle level became apparent on ultrasonography during maintenance infusion. UT-15 infusion improved the pulse volume recording (p = 0.016) but the ankle/brachial index did not change significantly. Common side effects at peak dose included headache and nausea. There were no serious adverse events attributable to UT-15 treatment. In most patients, the optimal infusion rate was 10-20 ng/kg per min. In conclusion, ultrasonography is a novel approach for assessing the hemodynamic response to vasoactive agents. UT-15 is well tolerated when given for up to 2 h and increases arterial blood flow and velocity in patients with severe intermittent claudication.

Risk factors for atherosclerosis should be identified and reduced in all patients who have peripheral arterial disease. Cessation of smoking, strict control of diabetes and hypertension, and aggressive reduction in low-density lipoprotein cholesterol level result in a slowdown of disease progression and a reduction in cardiovascular events. Unless contraindicated, all patients with peripheral arterial disease should receive antiplatelet therapy. New pharmacologic therapies are emerging, but supervised exercise rehabilitation is the most effective medical therapy to restore pain-free walking for patients with intermittent claudication. Patients with symptoms that limit their lifestyles may benefit from elective invasive revascularization. Symptoms consistent with limb-threatening ischemia (such as rest pain) or a foot ulcer that does not heal (especially in a patient with diabetes) requires immediate attention and possibly revascularization.

Background and Aim of the Study: Cardiac valve calcification is the predominant pathology in patients needing valve replacement. The aim of this study was to determine if aortic valve cells calcify spontaneously and, if so, to characterize the nodular complex and response to growth factors., Methods: Aortic valves were obtained from humans undergoing surgical valve replacement, and from female dogs. The valvular endothelium was removed and explants cultured in medium., Results: A population of valvular interstitial cells spontaneously formed distinct calcified nodules containing hydroxyapatite within two to three weeks in canine and within six weeks in human aortic valves. The nodules contained an inner ring of dead cells surrounded by an outer ring of living cells. Cells associated with nodules had osteoblast-like characteristics and stained positively for extracellular bone matrix proteins. Incubating canine cells with potential calcifying stimuli tested the stimulus for calcification. The rate of nodule formation was increased with transforming growth factor beta-1 (+25 nodules), 25-hydroxycholesterol (+9 nodules) and bone morphogenetic protein 2 (+4 nodules) as compared with vehicle control (+3 nodules) over 25 days., Conclusions: We identified a population of valvular interstitial cells with osteoblast-like characteristics that spontaneously form calcific nodules in cell culture. In addition, the rate of calcific nodule formation was increased with transforming growth factor beta-1 and 25-hydroxycholesterol. Further study of these 'calcifying valve cells' may yield a new in vitro model for testing therapy aimed at preventing calcific valve stenosis.

While the anticarcinogenic effects of tea in animal models have been reported by several groups, human epidemiological studies examining tea consumption and cancer prevention have produced equivocal results. The beneficial properties of tea to human health may be related to the antioxidant properties of tea components. However, little evidence has been provided that tea consumption can either increase the antioxidant capacity or decrease oxidative stress in humans. In the present study, the effects of tea treatment (green tea) on biomarkers of oxidative stress were investigated in smokers and nonsmokers in two volunteer study groups (one in China and the other in United States). Green tea consumption in both study groups decreased oxidative DNA damage (8-OHdG in white blood cells and urine), lipid peroxidation (MDA in urine), and free radical generation (2, 3-DHBA in urine) in smokers. Nonsmokers (US study group) also exhibited a decrease in overall oxidative stress.

We searched the medical literature for articles containing markers of cardiac ischemia and echocardiography in the evaluation of patients presenting to the emergency department to determine their combined clinical use. Several published articles indicate two-dimensional echocardiography is a useful and cost-effective imaging technique for the evaluation of patients with chest pain in the emergency department. New studies are emerging that evaluate ischemic markers in combination with echocardiography to assess patients presenting to the emergency department with chest pain. We searched the MEDLINE Database for English-language articles published from December 1980 to August 1998 using the key words troponin, echocardiography, myocardial infarction, and emergency. These key words were crossed referenced to determine publications in this area. Pertinent trials and reviews were selected from the database. There were six articles evaluating biochemical markers of ischemia and echocardiography to assess patients presenting with acute coronary syndromes in the emergency department. Very few studies combined the information obtained from novel ischemic markers and echocardiogram analysis to help delineate potential cardiac etiologies of acute coronary syndromes. However, the limited studies available indicate that echocardiography is both sensitive and specific for detecting acute myocardial infarction. The presence of regional wall motion abnormalities increases the chance of in-hospital complications and likelihood of developing congestive heart failure after admission for unstable angina. The combined use of troponin T levels and echocardiographic imaging was a more powerful predictor of adverse events than were isolated results. Myocardial scarring with ventricular wall thinning or aneurysm may allow for rapid diagnosis of 'occult' coronary artery disease in a patient presenting with chest pain who does not have a previous history of a cardiovascular event. Echocardiography may also help identify other cardiovascular causes of chest pain, such as aortic dissection, aortic stenosis, cardiac tamponade, pericarditis, and hypertrophic cardiomyopathy. The clinical use of combining ischemic markers of disease with echocardiographic imaging seems justified given their unique clinical advantages. Future clinical trials are needed to determine whether the combination of novel ischemic markers and echocardiography can provide for a more expedient and accurate diagnosis, resulting in improved patient care and a safe reduction in unnecessary hospitalization.

Stroke is the third leading cause of death in the USA and in the developed world. The beneficial role of cholesterol reduction in decreasing stroke has been uncertain. However, recent data indicate that statin treatment in patients with a history of myocardial infarction not only reduces the risk of a second myocardial infarction, coronary heart disease, revascularization procedures and death, but also significantly reduces the risk of stroke. However, the mechanism(s) by which statins reduce stroke remain uncertain. Thus, the therapeutic armamentarium for the reduction of stroke in secondary prevention now includes cholesterol reduction with statins.

We investigated the clinical utility of cardiac troponin T (TnT) and echocardiography in the emergency department to predict subsequent in-hospital diagnosis and adverse cardiac events. TnT is a cardiac-specific protein released during cell injury such as that following acute myocardial inFarction (MI). Unlike creatine kinase-MB isoenzymes, TnT is increased in a subset of patients with unstable angina, and these may be at higher risk for subsequent cardiac events. Echocardiography is a useful noninvasive imaging technique for the assessment of ischemic heart disease in acute care settings because of its mobility and rapid results. Serial TnT determinations and echocardiographic images were prospectively evaluated in 100 patients with chest discomfort and admitted to the hospital. Serum was obtained for CKMB and TnT on presentation to the emergency department and 4, 8, 16 and 24 hours later. TnT was considered increased when at values greater than 0.1 microg/L. Echocardiograms were recorded on videotape in the emergency department and images reviewed in a blinded fashion for wall-motion abnormalities. When available, current echocardiographic results were compared with previous results to determine whether a new wall-motion abnormality was present. Of the 100 patients (57 men, 43 women), TnT was increased in 21 of 21 with acute MI and 15 of 41 with unstable angina. One of the 38 patients with stable angina had an increased TnT value and died 5 months later of a noncardiac cause. Ninety percent of patients who sustained acute MI had a TnT increase detected within 4 hours of presentation. Fifteen of 18 patients with acute MI and 9 of 37 patients with unstable angina had a new wall-motion abnormality on echocardiography. The combination of TnT levels with echocardiography yielded a positive predictive value of 84% and a negative predictive value of 90% for adverse cardiac events in the follow-up population, which was more accurate than either test analyzed separately. TnT and echocardiography are useful tests in emergency department triage of unstable coronary syndromes. Both tests are predictive of discharge diagnosis and follow-up events. However, the combined utility of TnT levels and echocardiographic imaging is a more powerful predictor of adverse cardiac events than isolated results.

The non-enzymatic peroxidation product of arachidonic acid, 8-epi-PGF2alpha or 8-isoprostane (8-IP) was measured in H2O2-exposed cultured pulmonary artery endothelial cell (PAEC) monolayers using a commercially-available enzyme immunoassay kit. H2O2 (50 microM for 1-30 min) significantly increased 8-IP production in a time-dependent fashion. Treatment with higher H2O2 concentrations (100 or 250 microM) failed to further increase 8-IP generation. Determinations of thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) were not sufficiently sensitive to detect lipid peroxidation in PAEC exposed to 50 microM H2O2 for 15 min. 8-IP (100 pM-500 nM for 2 h) caused PAEC monolayer barrier dysfunction measured as the transmonolayer clearance of albumin without causing significant PAEC cytotoxicity (measured as intracellular lactate dehydrogenase release). This is the first report to provide evidence that 8-IP generated in H2O2-exposed PAEC contributes to oxidant-mediated alterations in monolayer barrier function at non-cytotoxic concentrations.

One of the most abundant F2 isoprostanes formed under pathological conditions is 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), a potent vasoconstrictor. The purpose of this study was to determine the signal transduction events initiated by 8-epi-PGF2 alpha-induced vasoconstriction. Isolated arterial rings from male Sprague-Dawley rats were suspended in tissue baths containing Krebs-Henseleit salt solution, stretched to optimal resting tension and stimulated. 8-epi-PGF2 alpha induced concentration-dependent contractions in pulmonary arteries (EC50: 7.7 +/- 2.1 microM; n = 3) and aortas (EC50: 0.9 +/- 0.1 microM; n = 4) which were blocked by the TXA2 receptor antagonists SQ29548, L657925 and L657926. The contractile response to 8-epi-PGF2 alpha was significantly (*p < 0.05; n = 4) diminished by: 1) indomethacin and ibuprofen; 2) Ca++ free media; 3) verapamil, a voltage gated Ca++ channel blocker; 4) flunarizine, a T-type Ca++ channel blocker; and 5) calphostin C, a protein kinase C inhibitor. These data suggest that the contractile response to 8-epi-PGF2 alpha is: 1) mediated via activation of TXA2 receptors; 2) partially dependent on the synthesis and release of other cyclooxygenase derived products; 3) dependent on an influx of extracellular Ca++ possibly via Ca++ channels; and 4) may be PKC dependent.

Objectives: We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF)., Background: The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown., Methods: In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment., Results: The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (+/- SD) plasma levels of TNF-alpha were 5.69 +/- 0.32 pg/ml, and those of IL-6 were 9.23 +/- 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event-CHF or death-occurred more commonly in patients with higher IL-6 levels., Conclusions: Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6.

Cardiac valve calcification often results in obstruction of blood flow, which eventually leads to valve replacement. The molecular mechanisms resulting in valve calcification are unknown. Collagen and specific bone matrix proteins are thought to provide the framework for ectopic tissue calcification. This investigation was performed to determine whether the bone matrix protein osteopontin was present in calcified human aortic valves. Proteins extracted from human aortic valve tissue were subjected to polyacrylamide gel electrophoresis followed by Western blotting, using polyclonal antibodies directed against osteopontin. Fresh frozen tissue sections were also screened for osteopontin and macrophages using immunohistochemical techniques. Osteopontin was present in both heavily and minimally calcified aortic valves and absent in noncalcified purely regurgitant or normal aortic valves by both radioimmunoassay (n = 16) and immunohistochemical techniques (n = 8). Osteopontin colocalized with valvular calcific deposits, and macrophages were identified in the vicinity of osteopontin. These results, in addition to showing that osteopontin is present in calcified human aortic valves, suggest that osteopontin is a regulatory protein in pathological calcification. Identification of the cells producing osteopontin in abnormal cardiac valves and of proximate stimuli for its secretion may lead to novel therapeutic strategies to prevent and/or reverse calcific valve disease.

Lipid peroxidation is thought to be an important event in the pathogenesis of atherosclerosis. It has been suggested that pentane, which can be formed during the oxidation of omega-6 fatty acids, is a marker of lipid peroxidation. Previous studies have reported elevated breath pentane and serum markers of lipid peroxidation in smokers. However, chromatographic separation of pentane from isoprene in virtually all of these studies was incomplete and the methods used did not resolve pentane into its isomers, n-pentane and isopentane. Additionally, most current methods are complicated, requiring trapping and concentrating steps to obtain adequate sensitivity prior to hydrocarbon analysis. The purpose of the current study was to develop a gas chromatographic system to analyze breath pentane, that addresses the above technical problems and that would provide a simple in vivo method for measuring lipid. n-Pentane and isopentane standards were easily separated from isoprene with a Al2O3/KCI capillary column contained in a portable gas chromatograph equipped with a photoionization detector. The analysis of repeated measures showed a low coefficient of variation for measurements of n-pentane (10%) and isopentane (9%). We measured breath pentane in 27 subjects (15 smokers, 12 non-smokers). There were no significant difference between the baseline and 4 week interval measurements of n-pentane for smokers both before and after cigarette smoking. The within-subject variability data showed that the assay is highly reproducible for both low and high pentane levels in smokers. Smokers were found to have higher levels of both n-pentane and isopentane than non-smokers (P < 0.001). In addition, smokers had further significant elevation of pentane levels 10 min after smoking (P < 0.001), which returned to baseline by 1 h. These studies demonstrate that measurement of breath pentane, using a gas chromatograph with a photoionization detector, is simple and reproducible. Additionally, these results suggest that pentane elevation associated with smoking is secondary to the oxidant effects of cigarette smoke and an important temporal relationship exists between cigarette smoking and breath sample analysis.

To investigate the mechanisms for intracellular signaling and increased vascular tone by 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), we measured mitogen-activated protein kinase (MAPK) activity and myosin regulatory light chain (LC20) phosphorylation in porcine carotid arteries incubated with 8-epi-PGF2 alpha or PGF2 alpha. With stimulation by either 8-epi-PGF2 alpha or PGF2 alpha. MAPK activity and the force of contraction rose in parallel and were maintained during the time of exposure to agonist (2 hours). LC20 phosphorylation levels rose and then partially declined during stimulation with either agonist. The effects of 8-epi-PGF2 alpha on contraction, MAPK activity, and myosin light chain phosphorylation were completely inhibited by the receptor antagonists, SQ-29548 and BMS-180291; the effects of PGF2 alpha were only partially inhibited by these compounds. Thus, intracellular signaling by 8-epi-PGF2 alpha in fully differentiated vascular smooth muscle, resulting in MAPK activation and increased myosin phosphorylation, is specifically mediated by an activation of thromboxane A2/prostaglandin endoperoxide receptors. Lipid peroxidation and 8-epi-PGF2 alpha production, resulting from such vascular pathological processes as atherosclerosis, lead to an activation of two intracellular signaling pathways in smooth muscle: one pathway results in the activation of MAPK, while the other results in myosin light chain phosphorylation.

We prospectively compared digital echocardiographic images, by a minimal digital-acquisition strategy, with videotape images to determine the diagnostic utility of digital imaging in patients admitted to the emergency department with chest pain. Digital acquisition has many potential advantages for evaluating echocardiographic images, especially in the acute-care setting. It is not yet known how much the imaging study can be condensed with digital technology and still provide the necessary information needed for clinical echocardiographic diagnosis. One hundred seventeen patients with diagnoses consisting of coronary artery disease, pericardial disease, and valvular disease were studied. Overall agreement between videotape and digital recordings with regard to normal versus abnormal wall motion was 94% (p < 0.001). The wall motion score index, a semiquantitative measure of global function, also correlated well (r = 0.94). Complete concordance was noted in all patients with aortic stenosis and pericardial effusion. Digital echocardiographic imaging, by a minimal-acquisition strategy, is an accurate summary of the complete echocardiographic examination and provides the relevant diagnostic data needed for the assessment of patients with chest pain in the emergency department.

We report the incidence, diagnosis, prevention, and treatment of peripheral vascular complications following coronary interventional procedures as reviewed in the English-language literature. Peripheral vascular complications include hematomas, pseudoaneurysms, arteriovenous fistulae, acute arterial occlusions, cholesterol emboli, and infections that occur with an overall incidence of 1.5-9%. Major predictors of such complications following coronary interventional procedures include advanced age, repeat percutaneous transluminal coronary angioplasty, female gender, and peripheral vascular disease. Minor predictors include level of anticoagulation, use of thrombolytic agents, elevated creatinine levels, low platelet counts, longer periods of anticoagulation, and use of increased sheath size. Ultrasound-guided compression repair of pseudoaneurysms and arteriovenous fistulae are discussed, as are newer methods of treatment such as hemostatic puncture closure devices. Anticipation and early recognition of possible peripheral vascular complications in conjunction with careful attention to the optimal activated clotting time for sheath removal following coronary interventional procedures may translate into fewer vascular complications as well as into shorter and less costly hospital stays.

We had the opportunity to study the clinical effects of granulocyte colony-stimulating factor in a heart transplant patient with a classic febrile neutropenic episode that was thought to be caused by immunosuppressive therapy. Administration of granulocyte colony-stimulating factor resulted in rapid recovery of his absolute neutrophil count, with resolution of fevers. Endomyocardial biopsy showed no pathologic evidence of worsened rejection. The use of hematopoietic cytokines after the organ allograft requires further study before it can be routinely advocated in this patient population.

Although much emphasis has been placed on the role of cholesterol and lipoproteins in atherosclerotic plaque formation, recent studies suggest that lipids have other vascular actions which may contribute to the pathogenesis of myocardial ischemia. These include deleterious effects of lipids on platelet and endothelial cell function, coagulation, fibrinolysis, and prostacyclin metabolism. The purpose of this report is to review recent data regarding the nonatherogenic effects of lipids and provide insight as to how lipid lowering might contribute to clinically important improvements in vascular biology.

Iron deficiency occurs when the body's iron stores are exhausted. The source of blood loss leading to iron deficiency must be identified in all cases. Anemia of chronic disease generally results from an infectious, inflammatory, or malignant process. However, in some reported cases, no such process could be identified. Differentiating iron deficiency anemia from anemia of chronic disease may be difficult because of similarities in presentation. Physicians need to be aware of special clinical considerations when these two types of anemia coexist. Ferrous sulfate therapy is the ideal form of iron replacement.

Recent evidence suggests that high-density lipoprotein (HDL) cholesterol has important vasoactive properties which may contribute to its beneficial effects on atherosclerotic coronary artery disease. The endothelium-dependent vasodilator acetylcholine has been used in a number of experimental studies to assess endothelial function. The relation between serum lipoproteins and acetylcholine-induced coronary vasoreactivity was investigated in patients (n = 27) undergoing elective coronary arteriography. Mean serum cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglyceride levels were 189 +/- 7 (4.84 +/- 0.18 mmol/liter), 134 +/- 6 (3.47 +/- 0.15 mmol/liter), 41 +/- 3 (1.06 +/- 0.08 mmol/liter) and 106 +/- 30 mg/dl (1.20 +/- 0.03 mmol/liter), respectively. After a baseline arteriogram, acetylcholine was infused into the left main coronary artery and percent change from baseline dimension was determined in 27 angiographically smooth coronary artery segments and in 14 arterial segments with evidence of mild atherosclerotic disease. Intact vascular smooth muscle function was then confirmed in all segments by dilation to intracoronary nitroglycerin. Acetylcholine produced significant vasoconstriction of both angiographically smooth (13 +/- 4%, p less than 0.05 vs baseline) and diseased (19 +/- 4%, p less than 0.05 vs baseline) coronary segments. A positive correlation was observed between HDL cholesterol and normal acetylcholine-induced coronary vasoreactivity in both angiographically smooth (r = 0.59, p less than 0.001) and diseased (r = 0.62, p less than 0.02) coronary segments. No significant correlation was observed, however, between total and low-density lipoprotein cholesterol, or between total cholesterol to HDL ratio and the response of coronary artery diameter to acetylcholine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Hospital records of 120 patients undergoing aortic valve replacement were retrospectively reviewed for risk factors associated with early aortic valve replacement. Patients were separated into four groups (rheumatic, congenital bicuspid, degenerative, and miscellaneous) based upon the morphologic etiology of aortic stenosis. Multiple regression analysis was performed using age at surgery as the dependent variable. Independent variables for the study were race, gender, systemic hypertension, total triglyceride level, total serum cholesterol level, tobacco smoking history, diabetes mellitus, and angiographic coronary artery disease. In the rheumatic valve group only race showed a statistically significant risk effect whereas in the congenital bicuspid valve group race, gender, and triglycerides were statistically correlated with age at surgery. In the degenerative valve group gender and smoking were found to be statistically significant risk factors. The establishment of aortic stenosis risk factors might be an indication for clinical trials of risk factor modification in patients with aortic stenosis.