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Biomedical subjects

H Darius

Publications and source records attributed to H Darius.

At least 19 recordsLinked to original sources
PubMed2007

[Metabolic syndrome and peripheral arterial occlusive disease as indicators for increased cardiovascular risk].

BACKGROUND AND AIMS: The usefulness of the metabolic syndrome (MetS) or a low ankle brachial index (ABI), respectively, to identify patients with high risk for cardiovascular events has repeatedly been postulated. However, robust data on the prevalence and prognosis of such patients are missing in the primary care setting. PATIENTS AND METHODS: In the prospective, non-interventional "German epidemiological trial on Ankle Brachial Index (getABI) at total of 6880 unselected patients > or = 65 years were observed by their General Practitioners over 3 years. Death and cardiovascular events were recorded. The definition of MetS was similar to the one of NCEP ATP III (National Cholesterol Education Program--Adult Treatment Panel III). ABI (ratio of the systolic blood pressures measured at the distal part of the calf and at the upper arm) was measured with Doppler sonography. Peripheral arterial disease (PAD) was defined as ABI <0.9 or peripheral revascularization/amputation owing to PAD. Survival analyses were conducted with a Cox proportional hazard model. Hazard rate ratios (HRR, 95 % confidence intervals, CI) were multvariate adjusted. RESULTS: The observation time for the total cohort was more than 20,000 patient years (PY). Cardiovascular mortality in patients with MetS (n = 3040, 44 %) compared to patients without MetS (n = 3795; 55 %) was doubled (8.5 vs. 4.0 per 1,000 PY; HRR: 2.0; CI 1.3 - 2.9). Concomitant presence of MetS and PAD (n = 651; 9.5 %) increased the mortality risk compared to patients without both conditions (n = 3194; 46.4 %) drastically (21.1 vs. 3.0 per 1000 PY; HRR: 5.7; CI: 3.5 - 9.4). Similar significant risk increases also were noted for all-cause mortality or a combined endpoint of mortality and vascular morbidity. Further, in lower ABI categories cardiovascular event rates increased. CONCLUSIONS: Patients with MetS carry a substantially increased risk of premature death, especially cardiovascular death, and therefore require intensive treatment of their risk factors. This holds especially true if concomitant PAD is present.

Aged↗
PubMed2005

[Primary prevention of coronary heart disease with aspirin].

According to meta-analysis and the results of the two studies with the highest power, aspirin is effective in primary prevention of coronary heart disease. These beneficial effects, however, are at least partially out-weight by unwanted effects-such as intense gastrointestinal bleeding and hemorrhagic stroke. These side effects remain constant with increasing risk of coronary heart disease, whereas the protective effects increase. If an annual risk of coronary heart disease of < or =0.6% exists, aspirin is normally not indicated; for a risk of 0.7-1.4% the facts should be discussed with the patient. If a risk of > or =1.5% exists, aspirin should be given. Problems of aspirin therapy--such as "aspirin paradox" and "aspirin resistance"--have been documented for secondary prevention; they might, however, have likewise clinical implications in primary prevention.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

High prevalence of peripheral arterial disease and low treatment rates in elderly primary care patients with diabetes.

Representative data on peripheral arterial disease (PAD) in community-based office practice are scarce while at the same time of high interest. Thus, we aimed to determine the prevalence of peripheral arterial disease (PAD), comorbidity of atherothrombotic manifestations, and treatment intensity among elderly diabetic patients in primary care. In this monitored cross-sectional study, 344 general practitioners throughout Germany determined the ankle-brachial index (ABI) of 6880 consecutive, unselected patients aged 65 years or older with bilateral Doppler ultrasound measurements. PAD was defined according to the recent American Heart Association guidelines (using the higher of the 2 systolic ankle pressures: ABI < 0.9) or peripheral revascularisation, or amputation because of PAD. Coronary events (CAD) and cerebrovascular events (CVD) were taken from the patient's history without additional diagnostic measures. Diabetes was defined according to the clinical diagnosis of the physician and/or HbA1c > or = 6.5 % and/or intake of oral antidiabetic medication and/or application of insulin. 1.743 patients were classified as diabetics: the median disease duration was 6 years (1st; 3rd quartile: 2; 11), median HbA1c 6.6 % (5.9; 7.3), mean age 72.5 +/- 5.4 years, and 51.4 % were females. Diabetics had in comparison with non-diabetics a higher prevalence of PAD defined as ABI < 0.9 (26.3 % vs. 15.3 %, univariate odds ratio 2.0 [95 % confidence interval: 1.7; 2.3]), intermittent claudication (5.1 % vs. 2.1 %, OR: 2.5 [1.9; 3.4]), known CAD (16.1 % vs. 10.6 %, OR: 1.6 [1.4; 1.9]), and known CVD (6.8 % vs. 4.8 %; OR: 1.4 [1.2; 1.8]). 57.4 % of the diabetics with previously known PAD (as only atherothrombotic manifestation) received antiplatelet therapy (vs. 75.1 % with CAD and/or CVD only). The ABI was suitable as screening measure in the primary care setting. In elderly diabetics in comparison to non-diabetics, the prevalence of PAD was very high. Despite the known benefits of antiplatelet therapy, PAD patients were less intensively treated than patients with CAD or CVD.

Aged↗
PubMed2003

Are elevated homocysteine plasma levels related to peripheral arterial disease? Results from a cross-sectional study of 6880 primary care patients.

BACKGROUND: It is still unclear whether the strength of the association between elevated plasma homocysteine (HC) levels and peripheral arterial disease (PAD), coronary artery disease (CAD) and cerebrovascular disease (CVD) is similar. METHODS: Fasting homocysteine plasma levels were measured in 6880 unselected primary care patients aged 65 years or older. Presence of PAD was determined with the ankle brachial index, and both CAD and CVD were recorded according to patient history. RESULTS: Median homocysteine levels in the total sample (58.0% females, mean age 72.5 years, mean body mass index 27.3 kg m-2) differed between patients with and without PAD: 15.2 micro mol L-1 (95% confidence interval [CI] 14.8; 15.7, vs. 13.9 micro mol L-1 (CI: 13.8; 14.1; P < 0.001). Peripheral arterial disease prevalence moderately increased from 13.0% in the lowest HC quintile to 24.3% in the highest quintile (crude odds ratio [OR], 2.1 [CI: 1.7; 2.6]). The frequency of atherothrombotic manifestations in the patients' history increased nearly linearly across the homocysteine quintiles in the univariate analysis. However, the association diminished substantially after adjusting for known interfering variables: the ORs between the HC highest fifth vs. lowest fifth (adjusted for age, gender, smoking status, diabetes, hypertension lipid disorders, and estimated glomerular filtration rate levels) for PAD decreased to 1.4, for CAD to 1.0 (NS), and for CVD to 1.1. (NS). CONCLUSIONS: Elevated HC is only slightly more related to PAD than to CAD and CVD. After adjustment for known risk factors, the effect size is small, and an association can no longer be observed between homocysteine and CAD and CVD.

Age Distribution↗
PubMed2002

[New developments in anticoagulation therapy for Ione atrial fibrillation].

Lone atrial fibrillation is a major health problem for elderly patients with cardiovascular risk factors as hypertension, congestive heart failure or previous myocardial infarction. The increased stroke rate of these patients is significantly reduced by oral anticoagulation (target: INR 2-3) and less effective by acetylsalicylic acid at a dose of 325 mg/d. As an alternative to the vitamin K-antagonistic anticoagulants currently the SPORTIF trial program is performed investigating the safety and efficacy of the oral direct thrombin inhibitor ximelagatran. Recent data derived from a dose-finding study and its open label continuous follow-up period are very encouraging with regard to the low incidence of bleeding complications and ximelagatran's clinical efficacy for the prevention of thromboembolic events. Large confirmatory trials engaging about 3000 patients each are under way in Europe as an open-label trial and the United Staates as a double blind trial. Results are being expected for the end of year 2002. These data will clarify the role of ximelagatran for the prevention of thromboembolic events in patients with lone atrial fibrillation and may give us an insight into a new standard drug regimen for stroke prevention in high risk patients.

Anticoagulants↗
PubMed2001

Application of C1-esterase inhibitor during reperfusion of ischemic myocardium: dose-related beneficial versus detrimental effects.

BACKGROUND: Complement activation during reperfusion of ischemic myocardium augments myocardial injury, and complement inhibition with C1-esterase inhibitor (C1-INH) at the time of reperfusion exerts marked cardioprotective effects in experimental studies. Application of C1-INH in newborns, however, was recently reported to have dangerous and even lethal side effects. This study addresses the essential role of dosage in studies using C1-INH. METHODS AND RESULTS: Cardioprotection by C1-INH was examined in a pig model with 60 minutes of coronary occlusion followed by 120 minutes of reperfusion. C1-INH was administered intravenously 5 to 10 minutes before coronary reperfusion without heparin at a dose of 40, 100, and 200 IU/kg body wt. Compared with the NaCl controls, C1-INH 40 IU/kg reduced myocardial injury (44.1+/-13.8% versus 76.7+/-4.6% necrosis of area at risk, P</=0.05) and significantly suppressed local C3a and C5a generation. Myocardial protection was accompanied by reduced plasma concentrations of creatine kinase and troponin T. In contrast, no beneficial effects were observed when 100 IU/kg C1-INH was used. Furthermore, application of 200 IU/kg C1-INH provoked severe side effects and coagulation disorders. CONCLUSIONS: When applied at the correct dose, C1-INH significantly protects ischemic tissue from reperfusion damage. However, overly high doses (>/=100 IU/kg) of C1-INH will provoke detrimental side effects, probably via its procoagulatory action.

Anaphylatoxins↗
PubMed2001

Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

Animals↗
PubMed2001

Oral glycoprotein IIb/IIa antagonists for unstable angina--is there still a chance for the oral substances?

The intravenous glycoprotein IIb/IIIa antagonists abciximab, tirofiban and eptifibatide are well accepted for the therapy of patients with unstable angina and/or as concomitant medication during coronary interventions. Despite the fact that these drugs are not used in all patients presenting with unstable angina during coronary interventions, the scientific evidence is overwhelming including the substantial reduction in mortality 3 years after utilisation of abciximab for coronary interventions in patients with unstable angina. In addition to these two indications, intravenous glycoprotein IIb/IIIa antagonists are currently being investigated for use in patients undergoing carotid artery interventions, peripheral arterial interventions and stroke, as well as adjunct therapy in patients undergoing fibrinolytic therapy during acute myocardial infarction. In contrast, the large trials being performed in patients with unstable angina and following coronary interventions using oral glycoprotein IIb/IIIa antagonists have been very disappointing. There were only minor therapeutic effects detectable, resulting in a slight reduction in ischemic cardiac events in some investigations, however, in all studies, there was a slight trend towards an increased mortality in the glycoprotein IIb/IIIa receptor-antagonist-treated group of patients. In meta-analysis, an approximately 35% relative increase in mortality has been calculated for patients being treated long term with the oral glycoprotein antagonists. The reason for this therapeutic failure is still unknown, however, the limited bioavailability of these drugs, together with our still very limited knowledge about the regulation of the platelet fibrinogen receptor, may be partially responsible for this therapeutic failure. Other compounds with improved pharmacokinetic properties are currently in clinical development.

Administration, Oral↗
PubMed2001

[Does early high dosage dipyridamole in prevention of secondary stroke induce cardiac events?].

In a post hoc analysis of the European Stroke Prevention Study 2 (ESPS2), we investigated whether dipyridamole given as antiplatelet drug in patients with TIA or stroke increases the risk of cardiac events. ESPS2 was a secondary prevention trial including 6602 patients with TIA or stroke. Patients were randomized into one of four treatment arms: 2 x 25 mg acetylsalicylic acid (ASA), 2 x 200 mg slow release dipyridamole (DP), the combination of DP and ASA and placebo. DP did not result in a higher number of cardiac events, e.g., angina pectoris, myocardial infarction or death. The combination of ASA plus DP was superior to either drug alone in the prevention of strokes.

Administration, Oral↗
PubMed2001

Diagnosis of culture-negative endocarditis: the role of the Duke criteria and the impact of transesophageal echocardiography.

BACKGROUND: The Duke criteria have been shown to be more sensitive than the von Reyn criteria in the diagnosis of culture-positive endocarditis but to date have not been fully validated for culture-negative endocarditis (CNE). The aim of this study was (1) to compare the diagnostic accuracy of the Duke criteria versus clinical judgment and the von Reyn criteria in CNE and (2) to assess the diagnostic impact of transesophageal echocardiography (TEE) on the Duke criteria in CNE. METHODS: The study group consisted of 49 patients with suspected CNE in whom the presence (n = 32) or absence (n = 17) of endocarditis was confirmed by surgery, autopsy, or both. All patients underwent transthoracic echocardiography (TTE) and TEE. They were classified into a Duke category initially with TTE data only, and then the Duke categories were reevaluated with the additional TEE data. RESULTS: The Duke criteria demonstrated a significantly higher sensitivity (72%) than the von Reyn criteria (28%; P =.0008) and a higher specificity (100%) than clinical judgment (76%; P =.02). No major differences were noted between sensitivities of the Duke criteria and clinical judgement. TEE significantly augmented the capacity to diagnose CNE by Duke criteria versus TTE (P <.05). CONCLUSIONS: The Duke criteria are of high diagnostic validity for the conduction of clinical studies on CNE. They have the potential to affect clinical decision-making, based on the higher specificity versus clinical judgment. TEE appears to be crucial for the diagnosis of CNE when the Duke criteria are applied. The diagnostic differentiation between CNE, sclerotic valve degeneration, and nonbacterial thrombotic endocarditis remains a challenge.

Adult↗
PubMed2001

Substantial reduction of platelet adhesion by heparin-coated stents.

Although optimized antiplatelet medication has improved the clinical outcome after coronary stenting, vessel occlusion and restenosis still remain a relevant clinical problem. Platelets play a key role in this process. Therefore, the authors compared the platelet adhesion on different stent surface modifications (electropolished without coating or coated with carbon, carbon and additional heparin, silicon carbide, or heparin alone) to investigate their role in reducing platelet adhesion. All stents and additional stainless steel plates were incubated in heparinized whole blood with radiolabeled platelets. After washing the stents and plates four times, radioactivity caused by the adhesion of radiolabeled platelets was measured. The adhesion of radiolabeled platelets, compared to uncoated, electropolished stents, was reduced through silicon carbide coating to 58.6%, by carbon coating with additional heparin to 32.9%, and heparin coating alone to 7.7%. Stent coating with heparin is the most effective among the examined coatings in reducing platelet adhesion in vitro.

Anticoagulants↗
PubMed2001

Involvement of PKC and NF-kappaB in nitric oxide induced apoptosis in human coronary artery smooth muscle cells.

Apoptosis of vascular smooth muscle cells is critically involved in progression of atherosclerosis and may prevent intimal hyperplasia in restenosis and vascular remodeling. Nitric oxide (NO) is known to induce apoptosis, but the signaling pathways still remain unclear. We investigated p53 accumulation, protein kinase C (PKC) activation and nuclear transcription factor (NF-kappaB) binding activity as possible signaling mechanisms of NO-induced apoptosis. Apoptosis was induced dose-dependently with the NO-donors sodiumnitroprusside (SNP: 232+/-48%) and SIN-1 (241+/-90% of actinomycin D induced apoptosis; means +/- SEM, *p< or =0.05 vs. control) in HSMC. Inhibition of PKC significantly attenuated NO-induced apoptosis. Staurosporine reduced SIN-1/SNP-mediated DNA fragmentation by 55.3+/-13.8% and 38.3+/-13.9% respectively. Comparable results were obtained for calphostin C. However, NO-mediated induction of apoptosis was not preceded by p53 accumulation. SNP decreased NF-kappaB binding activity in HSMC. These results suggest that induction of apoptosis by exogenous NO in HSMC is not dependent on p53 accumulation but involves protein kinase C signaling and regulation of NF-kappaB binding activity. This opens a new therapeutical approach in preventing restenosis after angioplasty.

Apoptosis↗
PubMed2001

Spontaneous echo contrast caused by platelet and leukocyte aggregates?

BACKGROUND AND PURPOSE: Spontaneous echocardiographic contrast (SEC) is correlated to clinical thromboembolic events. We sought to determine the origin of SEC by utilizing direct analysis of left atrial blood. METHODS: We examined the blood of 13 patients with and 19 without SEC. Blood samples were taken from the femoral vein and artery and from the right and left atria after transseptal puncture. Samples were incubated with fluorescence-labeled antibodies directed against the platelet (CD41a-PE, CD42b-PE, and CD62p-FITC) and leukocyte membrane epitopes (CD45-APC and CD14-FITC). The expressed epitopes were analyzed by dual laser flow cytometry immediately after blood withdrawal. RESULTS: In the peripheral blood of both groups, more activation and aggregation were found in the venous blood than in the arterial blood (CD41a, P=0.007; CD14neutro, P=0.017; and leukocyte-platelet aggregates [LTAg], P=0.002). In patients without SEC, the degree of activation and aggregation of the cardiac samples closely resembled the results of the peripheral samples. The degree of activation and aggregation was significantly higher in the right atrium than in the left atrium (LTAg, P<0.01; leukocyte activation, P<0.01; CD41a, P<0.01; CD62p, P<0.02). In contrast, in patients with SEC the parameters of platelet and leukocyte activation as well as LTAg was significantly higher in the left atrium than in the right atrium of the same patient (all P<0.01). A correlation between the amount of SEC and platelet-monocyte aggregates could be found (r=0.92, P<0.0001). CONCLUSIONS: The hypothesis that platelet aggregates are involved in the pathogenesis of SEC is supported by the fact that platelets in the left atrium of patients with SEC showed more activation.

Adult↗
PubMed2001

Anticoagulation: the present and future.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Administration, Oral↗
PubMed2001

Cardiac safety in the European Stroke Prevention Study 2 (ESPS2).

The second European Stroke Prevention Study investigated the prevention of stroke and/or death in 6602 patients with transient ischaemic attack or stroke with aspirin (25 mg b.d.), dipyridamole (400 mg b.d.), the combination of aspirin and dipyridamole or placebo. This post hoc analysis investigated cardiac events in patients with coronary heart disease or myocardial infarction (MI) at entry. Dipyridamole did not result in a higher number of cardiac events, e.g. angina pectoris, MI, or death from all causes. The combination of aspirin plus dipyridamole was superior to either drug alone in the prevention of stroke.

Angina Pectoris↗