Boris Leithäuser

Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.

Diagnostic value of magnetocardiography in coronary artery disease and cardiac arrhythmias: A review of clinical data

Despite the availability of several advanced non-invasive diagnostic tests such as echocardiography and magnetic resonance imaging, electrocardiography (ECG) remains as the most widely used diagnostic technique in clinical cardiology. ECG detects electrical potentials that are generated by cardiac electrical activity. In addition to electrical potentials, the same electrical activity of the heart also induces magnetic fields. These extremely weak cardiac magnetic signals are detected by a non-invasive, contactless technique called magnetocardiography (MCG), which has been evaluated in a number of clinical studies for its usefulness in diagnosing heart diseases. We reviewed the basic principles, history and clinical data on the diagnostic role of MCG in coronary artery disease and cardiac arrhythmias.

Dobutamine stress magnetocardiography for the detection of significant coronary artery stenoses - a prospective study in comparison with simultaneous 12-lead electrocardiography.

BACKGROUND Exercise electrocardiography is an imperfect test for the detection of coronary artery disease (CAD). Magnetocardiography detects cardiac electrical disturbances associated with myocardial ischemia. We prospectively investigated the accuracy of high-dose dobutamine stress magnetocardiography (DS-MCG) and simultaneous electrocardiography (DS-ECG) for the detection of significant CAD. METHODS 100 patients with an intermediate pre-test probability for CAD underwent DS-MCG using a multichannel magnetometer prior to invasive coronary angiography. Patients were examined at rest and during a standard dobutamine-atropine scheme. Significant reduction of epicardial current strength/density during stress, reconstructed from the magnetic field map and superposed on a virtual heart model indicates myocardial ischemia. A 12-lead DS-ECG was recorded simultaneously. Significant coronary artery stenosis was defined as > or = 70% of lumen reduction. RESULTS Without beta-blocker all 100 patients reached the targeted heart rate. The image quality of DS-MCG and DS-ECG was sufficient for analysis in all patients. In 19 patients CAD was ruled out angiographically. Thirty two or seven patients revealed coronary artery stenoses of 30-49% or of 50-69%, respectively. In 42 patients we found significant stenoses of > or = 70%. In 41 of these patients DS-MCG revealed myocardial ischemia. The sensitivity of DS-MCG and DS-ECG for the detection of significant coronary artery stenosis was 97.6% and 26.2%, the specificity of DS-MCG and DS-ECG 82.8% and 82.8%, respectively. CONCLUSIONS DS-MCG can be performed with a standard dobutamine/atropine stress protocol. DS-MCG yields a significantly higher accuracy for the detection of significant coronary artery stenosis than DS-ECG.

Correlation between postischemic vasodilation of the arteria brachialis and of the postischemic hyperemia in the adjacent microvascular bed

BACKGROUND Endothelial cells secrete different mediators depending on biochemical and/or biophysical conditions, which can lead to vasodilation or vasoconstriction, respectively. Impaired endothelial responsiveness to specific vasodilator stimuli has been used as a surrogate marker of cardiovascular risk. Multiple methods allow testing endothelial responses in both microvessels and conduit arteries, but it is still unclear whether there is a relationship in endothelial function between these two different vascular beds. MATERIAL AND METHODS In order to examine, whether such macrocirculatory data might correlate with data obtained in the supplied microvessels, a parallel investigation in the brachial artery (BA) and the supplied nailfold capillaries was performed. The duration and amplitude of the postischemic hyperemia (stasis in the vasculature of the left arm using a blood pressure cuff for 3 minutes) were measured (ultrasound technique) and simultaneously the amplitude and duration of the postischemic hyperemia in ipsilateral nailfold capillaries (intravital capillaroscopy). RESULTS There was absolutely no correlation between the duration (n = 153, r = 0.076, p = 0.3493) of the diameter increase in the BA and in ipsilateral nailfold capillaries. CONCLUSION The regulation of the cutaneous microcirculation did not follow diameter changes of the conduit artery (BA) but seems to be dominated by the precapillary arterioles.

Capillary bleeding under oral anticoagulation

BACKGROUND Oral anticoagulants are routinely used for prevention of thromboembolism in cardiac, arterial or venous diseases. Hemorrhages are serious treatment complications, frequently occurring under long-term and/or high-dose regiments. From animal experiments it is known that coumarin-type anticoagulants may cause capillary dilatation and increased permeability, red blood cell extravasation and punctate bleeding. Controlled human trials are lacking. METHODS 31 patients under oral anticoagulation were examined by video capillary microscopy. 52 patients with comparable diseases and treatment but without oral anticoagulation served as controls. Nailfold capillaries of four fingers of each hand were examined and analyzed off-line according to the following criteria: (1) numbers of capillaries investigated, (2) numbers of capillary bleedings, and (3) bleeding incidence (bleedings per 100 capillaries). RESULTS In 23 out of 31 patients (74.2%) capillary bleedings were observed. The bleeding incidence ranged from 0.33 to 4.29 per 100 capillaries. In contrast, only 4 out of 52 controls were detected with capillary bleedings (2.1%, p<0.001). The bleeding incidence was 0.34-2.41. In patients on anticoagulation there was no correlation between the number of capillary bleedings and the INR or Quick values. During a two year follow-up of patients on oral anticoagulation no significant difference was found in terms of clinically obvious bleedings in patients with or without capillary bleedings. CONCLUSION This study shows that capillary bleedings can be demonstrated in patients on oral anticoagulation. Bleedings occur independent of the INR-value. Thus, other factors than the vitamin-k-dependent coagulation effect seem to be causal for the damage of microvessels. Further, the evidence of capillary bleedings is not a prognostic indicator for future hemorrhage.

Influence of xantinole nicotinic acid on cutaneous microcirculation in patients with coronary artery disease and hyperlipoproteinemia

Xantinole nicotinic acid (NA) dose dependently lowers plasma levels of atherogenic lipoproteins and increases blood flow through vasodilation. The aim of this study was to evaluate the effect of NA on cutaneous microcirculation in patients with coronary artery disease and hyperlipidemia. In this open pilot study, five men and three women (74.2+/-9.1 yrs; 81.4+/-7.9 kg; 171.6+/-7.0 cm) with angiographically proven coronary artery disease and hyperlipidemia were included. Nailfold capillary microscopy was used for measurements of erythrocyte velocities at rest and after three minutes of ischemia, before and one hour after intake of 1000 mg of NA. The blood pressure (120+/-12/73+/-8 mmHg vs. 113+/-10/72+/-5 mmHg; p=0.19/0.83) and the heart rate (72+/-8/min vs. 70+/-7/min; p=0.38) remained unchanged. The mean capillary red blood cell velocity at rest (v(RBC); 0.27+/-0.23 mm/s vs. 0.32+/-0.18 mm/s; p=0.089) and the time to maximal post ischemia erythrocyte velocity (t(peak); 21.0+/-7.9 s vs. 24.3+/-15.5 s; p=0.49) did not change. The maximal post ischemic erythrocyte velocity (v(maxRBC); 0.93+/-0.33 mm/s vs. 1.19+/-0.19 mm/s; p=0.0096) raised slightly but significantly, the duration of post-ischemia hyperemia (DpH; 101+/-16 s vs. 127+/-15 s; p=0.0005) increased markedly. One patient reported about flush in the whole body. The administration of 1000 mg of NA resulted in a significant improvement of the cutaneous microcirculation in patients with coronary artery disease and hyperlipidemia.

Rheological and hemostasiological aspects of thrombus formation in the left atrial appendage in atrial fibrillation? A new strategy for prevention of cardioembolic stroke

Atrial fibrillation (AF), as the most common cardiac rhythm disturbance, gains in importance not only for the persons affected, but also for health care and social economy due to thromboembolic events, of which stroke is the most serious, disabling, and life threatening one. Cardiac embolism is due to thrombus formation mainly in the left atrial appendage (LAA). The pathophysiology leading to increased thrombogenicity is complex and requires a remodelling of the LAA structure, decreased LAA blood flow, activation of inflammatory processes, deviations of the hemostatic/fibrinolytic system, and activation/dysfunction of endothelial/endocardial cells. Altogether, a prothrombotic state proposed by Virchow more than 150 years ago. The presence of a LAA thrombus, therefore, is a result of a dynamic process of clot formation and lysis. A comprehensive understanding of this pathophysiology is helpful to optimize the management of patients at high risk of cardioembolic stroke. Especially those with contraindications for oral anticoagulation are in a need of an alternative approach that is not associated with a long-term risk of hemorrhage and other attendant circumstances. The reasonable alternative may be the exclusion of the LAA cavity from circulation by either surgical or percutaneous catheter-based procedures.

Sublingual application of liquid nitrendipine does not result in critical hypotension in healthy volunteers under phosphodiesterase-5 inhibition.

INTRODUCTION The introduction of phosphodiesterase-5 inhibitors as sildenafil, tadalafil, or vardenafil, has tremendously improved the treatment of erectile dysfunction. Patients with the common comorbidity of cardiovascular disease and erectile dysfunction, however, are at risk for critical hypotension in case of self-treatment of cardiac angina with nitrates after the intake of a phosphodiesterase-5 inhibitor. METHODS We evaluated the safety of 5 mg sublingual nitrendipine after pre-treatment of 8 healthy male volunteers (42.1+/-9.6 yrs) with 20 mg tadalafil. Randomly four different protocols were compared using six hours blood pressure recordings: (1) baseline, (2) 20 mg tadalafil, (3) 5 mg nitrendipine, and (4) 20 mg tadalafil+5 mg nitrendipine. RESULTS The blood pressure was not significantly affected by tadalafil. Nitrendipine lowered the systolic blood pressure significantly by -1.91 mmHg (p=0.0079). The co-medication of 20 mg tadalafil+5 mg nitrendipine lowered the blood pressure significantly by -2.86 mmHg (p<0.0001). There was no statistically significant difference between tadalafil and nitrendipine (p=0.598). Relevant hypotension (systolic blood pressure of <85 mmHg) was observed in none of the study individuals during the four protocols. CONCLUSIONS Sublingual nitrendipine seems to be safe for self-treatment of an anginal attack in patients with stable coronary artery disease, who have taken a phosphodiesterase-5 inhibitor. However, our findings on hemodynamic changes in apparently healthy volunteers have to be confirmed in patients with coronary artery disease.

Influence of acetylsalicylic acid (Aspirin) on cutaneous microcirculation

BACKGROUND The protective effect of acetylsalicylic acid (aspirin) in primary and secondary prophylaxis of cardiovascular events is attributed to the inhibition of platelet cyclooxygenase (COX). However, a recent animal study found a vasodilating and blood pressure lowering effect of aspirin independent of COX, but mediated by inhibition of the RhoA/Rho kinase signaling pathway. METHOD Prospective, randomized, double-blind, placebo-controlled cross-over study. In each instance 5 healthy volunteers received either aspirin 500 mg/d or placebo for 7 days. Capillary red blood cell velocity (vRBC) at rest and after postischemic hyperemia was determined on day 1 and 7 by means of nailfold capillary microscopy. RESULTS In the aspirin group after 7 days a significant increase of vRBC was found at rest and during hyperemia. In the placebo group vRBC did not change. The finding was confirmed by the cross-over design of the study. CONCLUSION Aspirin at a dosage of 500 mg/d has an impact on vasoregulation in the microcirculation. At present, the underlying mode of action in humans is unknown.

[Cardio-pulmonary vascular system. Three-dimensional quantitative evaluation by microcomputed tomography].

ZusammenfassungDie Mikrocomputertomographie (µCT) hat in den letzten Jahren zunehmende Bedeutung in der Grundlagenforschung gewonnen. Mit Hilfe kommerzieller µCT-Geräte steht heute ein neues, schnelles und zuverlässiges Verfahren zur kontinuierlichen nichtdestruktiven Darstellung und zur dreidimensionalen morphometrischen Analyse von Parenchym- und Gefäßstrukturen zur Verfügung. Die vorliegende Arbeit gibt einen Überblick über die technischen Grundlagen der µCT und über die Einsatzmöglichkeiten zur dreidimensional-quantitativen und funktionellen Analytik des kardiopulmonalen Gefäßsystems.AbstractIn recent years microcomputed tomography (µCT) has become more and more important in basic research. Now commercial µCT scanners are available. Thus, it is very likely that this new, accurate and promising method for three-dimensional and non-destructive quantitative evaluation of intact tissues including vessels will be applied more frequently. The review provides a survey of the basic technology of µCT and its current use for high resolution three-dimensional morphometric and functional analysis within the cardio-pulmonary vascular system.