Impaired glucose tolerance-a new risk factor?
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Glucose Intolerance↗
Biomedical subjects
Christoph Bode
Publications and source records attributed to Christoph Bode.
Distinct roles of ligand affinity and cytoskeletal anchorage in alphaIIbbeta3 (GP IIb/IIIa)-mediated cell aggregation and adhesion.
Platelet integrin alphaIIbbeta3 (GP IIb/IIla) is functionally modulated by changes in ligand affinity or in cytoskeletal anchorage. CHO cells transfected with wild-type/mutated alphaIIbbeta3 allow the dissection of the relative contributions of the two regulatory mechanisms in alphaIIbbeta3-mediated adhesion and aggregation. Mutations included a truncation of the cytoplasmic domain of the beta-subunit, resulting in a loss of cytoskeletal anchorage of alphaIIbbeta3, and a VGFFK-deletion of the alpha-subunit, resulting in a permanent high affinity state. alphaIIbbeta3-mediated cell aggregation is dependent on the high affinity state but only partially on the cytoskeletal anchorage of alphaIIbbeta3. In contrast, alphaIIbbeta3-mediated cell adhesion is dependent on the cytoskeletal anchorage but only partially on the high affinity state of alphaIIbbeta3. Thus, the functional evaluation of mutated alphaIIbbeta3 implies a differential role of affinity state and cytoskeletal anchorage for alphaIIbbeta3-mediated cell adhesion and aggregation.
Animals↗
Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones.
Adipose tissue produces substantial amounts of plasminogen activator inhibitor type-1 (PAI-1), an established cardiovascular risk factor. This study evaluated PAI-1 expression in human adipose tissue in response to thiazolidinediones, insulin sensitising drugs activating peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Troglitazone, rosiglitazone, and ciglitazone significantly reduced PAI-1 protein expression in human preadipocytes under basal conditions and after stimulation of the cells with TGF-beta. Pioglitazone had no effect. In human adipocytes all four thiazolidinediones significantly attenuated PAI-1 expression. Signalling appeared to be mediated via PPAR-gamma and effects reflected, at least in part, changes in transcription. Accordingly, patients with insulin resistance may benefit from treatment with thiazolidinediones with respect to diminution of PAI-1 expression in adipose tissue and consequent potential reduction of cardiovascular risk.
Adipocytes↗
Fibrin-targeted direct factor Xa inhibition: construction and characterization of a recombinant factor Xa inhibitor composed of an anti-fibrin single-chain antibody and tick anticoagulant peptide.
We investigated whether the direct fXa inhibitor tick anticoagulant peptide (TAP) can be N-terminally coupled to a clot-targeting, single-chain antibody specific for fibrin (scFv(59D8)). Due to its unique position at the convergence point of the intrinsic and extrinsic pathways early in the coagulation cascade, factor Xa (fXa) represents an attractive therapeutic target. In contrast to indirect inhibitors, direct fXa inhibitors effectively inhibit clot-bound and prothrombinase-associated fXa. Targeting of direct fXa inhibitors to clots promises to enhance local anticoagulative potency and to reduce systemic anticoagulation which potentially results in less bleeding complications.TAP is a highly potent fXa inhibitor. Since its N-terminus is essential for anti-fXa activity, it was a challenging question, whether TAP will be active as a N-terminally coupled fusion molecule. Two step affinity chromatography with Ni(2+) and beta(15-22)-peptide of human fibrin results in a pure 36 kDa protein, which was tested for its targeting function and anti-fXa activity. The recombinant fusion did not destroy the function of the fusion partners. Antibody binding function was on a par with the parent molecule. TAP activity was partially reduced, arguing that a free N-terminus is not required for anti-fXa activity, but is important for maximal potency. In human whole blood clots, scFv(59D8)-TAP revealed anticoagulative properties at concentrations (200 to 500 nM) where non-targeted TAP did not reveal anticoagulative activity at all. In summary, scFv(59D8)-TAP constitutes a promising new anticoagulant with fibrin-targeted factor Xa inhibition. The production in E. coli and the established purification methods are a solid basis for a modern, large scale production at low cost and reproducible activity.
Amino Acid Sequence↗
Pharmacotherapy in cardiovascular diseases and vascular interventions.
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Anticoagulants↗
Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice.
Monocyte chemoattractant protein 1 (MCP-1) has been shown to be effective for the stimulation of collateral artery formation in small and large animal models. The availability of a genetic knockout mouse enables evaluation of the importance of the role of MCP-1 in the natural course of collateral artery growth. In a total of 21 MCP-1 -/- as well as 13 of the appropriate genetic background controls ([129Sv/J X C57BI/6J]F1), a femoral artery ligation was performed. Subsequently, a polyethylene catheter, connected to an osmotic minipump, was inserted retrogradely into the occluded femoral artery with the tip pointing upstream. Using this technique, PBS (MCP-1 -/-: n = 13 and C57BI/6J: n = 13) or MCP-1 (JE; MCP-1 -/-: n = 8) was delivered intra-arterially. Seven days after ligation, determination of hind limb flow was assessed by controlled tissue perfusion using differently labeled fluorescent microspheres. MCP-1 -/- mice exhibited a reduction of hind limb flow of 32.9 +/- 9.2% of the unligated hind limb, compared with 55.4 +/- 6.8% in C57BI/6J mice (p<0.01). MCP-1 -/- mice that underwent a subsequent 'rescue' treatment with MCP-1 showed a restoration of flow to a level of 47.4 +/- 9.8% (p = NS compared with PBS-treated C57BI/6J). Specific immunohistochemical staining for monocytes (MOMA-2: MCP-1 -/-, n = 5 and C57BI/6J, n = 5) showed a reduced number of monocytes around developing collateral arteries in the MCP-1 -/- mice. In conclusion, our data show that the absence of MCP-1 causes a strong reduction in flow restoration after femoral artery occlusion, coinciding with a reduced monocyte attraction, emphasizing the central role of this chemokine in the multifactorial process of collateral artery formation.
Animals↗
Reversibility versus persistence of GPIIb/IIIa blocker-induced conformational change of GPIIb/IIIa (alphaIIbbeta3, CD41/CD61).
Clinically used GPIIb/IIIa blockers are ligand mimetics, and thereby their binding can induce conformational changes of the platelet integrin GPIIb/IIIa. Since the reversibility of these conformational changes may be an important determinant of potential adverse effects of GPIIb/IIIa blockers, we produced a new monoclonal antibody (anti-LIBS-mAb), and by using its binding properties, we investigated the conformational changes of GPIIb/IIIa during the binding and especially the dissociation of GPIIb/IIIa blockers. Production of monoclonal antibody (mAb) clones was performed using purified GPIIb/IIIa in a high affinity conformation and using activated platelets. Clone anti-LIBS-145-mAb was chosen, since it allowed the sensitive probing of eptifibatide-induced conformational changes of GPIIb/IIIa. On resting and activated platelets and on GPIIb/IIIa-expressing Chinese hamster ovary cells, anti-LIBS-145-mAb binding returned to background binding after dissociation of eptifibatide, indicating a complete reversibility of the eptifibatide-induced conformational change. Furthermore, with the mixing of eptifibatide-preincubated and nonincubated cells, a fast reversibility could be demonstrated. However, when fibrinogen was present in a physiological concentration, the GPIIb/IIIa blocker-induced conformation was partially retained after the dissociation of eptifibatide and to the same extent binding of fibrinogen and the activation-specific mAb Pac-1 was induced. In conclusion, a fast reversibility of the conformational change of GPIIb/IIIa after dissociation of GPIIb/IIIa blockers could be demonstrated as an intrinsic property of the GPIIb/IIIa receptor. This mechanism prevents general platelet aggregation after dissociation of ligand mimetic GPIIb/IIIa blockers. Nevertheless, in the presence of fibrinogen this reversibility is not complete, which may explain some of the side effects of GPIIb/IIIa blockers, especially those of the oral GPIIb/IIIa blockers.
Animals↗
New three-dimensional echocardiographic system using digital radiofrequency data--visualization and quantitative analysis of aortic valve dynamics with high resolution: methods, feasibility, and initial clinical experience.
BACKGROUND: Common 3D systems have only limited spatial and temporal resolution (frame rate of 25 Hz). Thin structures such as cardiac valves are not imaged exactly; rapid movement patterns cannot be precisely recorded. The objective of the present project was to achieve radiofrequency (RF) data transmission to the 3D workstation to improve image resolution. METHODS AND RESULTS: A commercially available echocardiographic system (5-MHz transesophageal echocardiography probe) with an integrated raw data interface enables transmission of RF data (up to 40 megabytes per second). A 3D data set may contain up to 3 gigabytes, so that all of the high-resolution ultrasound information of the 2D image is available. Frame rates of up to 168 Hz result in temporal resolution 6 times that of standard 3D systems. The applicability of the system and the image quality were tested in 10 patients. The structure of the aortic valve and the dynamic changes were depicted by volume rendering. The changes in the orifice areas were measured in frame-by-frame planimetry. The mean number of frames recorded per cardiac cycle was 122+/-16. The improved structural resolution enabled a detailed imaging of the morphology of the aortic cusps. The rapid systolic movement patterns were recorded with up to 51 frames. The high number of frames enabled creation of precise area-time diagrams. Thus, the individual phases of aortic valve movement (rapid opening, slow valve closing, and rapid valve closing) could be analyzed quantitatively. CONCLUSIONS: A 3D system based on RF data enables high-resolution imaging of cardiac movement patterns. This offers new perspectives for qualitative and quantitative analyses, especially of cardiac valves.
Aortic Valve↗
Arteriogenesis - is this terminology necessary?
The role of the collateral circulation has been controversially discussed over many decades. With the availability of purified growth factors such as the fibroblast growth factors several studies provided data, that the growth of collateral arteries, termed arteriogenesis, is not limited to its natural timecourse. When applied in experimental models FGF in particular led to a significant increase in collateral conductance upon arterial occlusion. Thus the proliferation of preexisting bypassing arterioles could be enhanced therapeutically. The purpose of this review is to discuss the physiological importance of different kinds of vascular growth (e.g. vasculogenesis, angiogenesis, arteriogenesis) to enhance blood flow to ischemic limbs or the heart. It is outlined that large conductance arteries rather than capillary networks are needed to compensate for perfusion deficits due to atherosclerotic stenosis or occlusion.
Animals↗
Pacemaker therapy in very elderly patients: long-term survival and prognostic parameters.
BACKGROUND: Permanent pacing is the therapy of choice for treating severe and/or symptomatic bradyarrhythmia. However, augmented life expectancy and increasing health care expenditures have led to questions concerning the routine use of electrotherapy in very elderly patients. This study is aimed at assessing data on the actual number, characteristics, and survival of patients requiring pacing therapy at age > or =80 years. METHODS: Between 1971 and 2000, 1588 patients aged > or =80 years completed a standardized 6- to 12-month follow-up after pacemaker (PM) implantation, resulting in a total of 5244 patient years. Kaplan-Meier analyses were computed to visualize survival differences in various subgroups and implantation periods. RESULTS: Today, patients aged > or =80 years account for 32% of all PM implantations. An increasing 5-year survival after PM implantation to the current rate of 66% was found, compared to 37% and 47% in the previous decades. Based on a mean survival time of 8 years, clinical symptoms can be effectively treated with costs of < or =500 dollars per patient per year. Prognostic parameters were the decade of implantation (relative risk [RR] 0.80, CI 0.67-0.96, P < or =.02), a history of presyncope (RR 0.73, CI 0.57-0.95, P < or =.02), and male sex (RR 1.20, CI 1.04-1.40, P < or =.02). However, none of these parameters can be recommended for estimating outcome or for guiding device selection. CONCLUSIONS: Patients aged > or =80 years account for an increasing portion of PM implantations. Considering the remaining life expectancy of 8 years in these patients, PM therapy is a clinically and economically effective therapeutic option to control bradyarrhythmia-related symptoms.
Aged↗
Advanced heart failure requiring three devices for survival.
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Defibrillators, Implantable↗
Invasive and non-invasive evaluation of spontaneous arteriogenesis in a novel porcine model for peripheral arterial obstructive disease.
Our current knowledge regarding the efficacy of factors stimulating collateral artery growth in the peripheral circulation primarily stems from models in small animals. However, experimental models in large sized animals are a prerequisite for extrapolation of growth factor therapy to patients with peripheral atherosclerotic obstructive disease. Therefore, we have developed a novel porcine femoral artery ligation model using non-invasive and invasive evaluation techniques. In 12 young farm pigs and nine older minipigs, a ligation of the superficial femoral artery was performed. Using an intra-arterial catheter, phosphate buffered saline (PBS) was administered with a first-pass over the collateral vascular bed. Directly after ligation as well as after 2 weeks of continuous infusion of PBS, perfusion of the leg was measured using various flow and pressure parameters. Using a pump driven extracorporal system, collateral conductance was determined under maximal vasodilatation. Conductance decreased after acute ligation to similar levels in both young farm pigs as well as the older minipigs (both 9.3% of normal perfusion) and recovered after 2 weeks to a higher value in farm pigs compared with minipigs (22.4 vs. 12.7% of normal; P<0.05). Angiography using both X-ray and magnetic resonance imaging was performed to visualize the formed collateral arteries. To the best of our knowledge this is the first in vivo pig model for hemodynamic assessment of growth of collateral arteries in the peripheral circulation, that is suitable for evaluation of arteriogenic effects of growth factors or genes.
Angiography↗
In vivo analysis of aortic valve dynamics by transesophageal 3-dimensional echocardiography with high temporal resolution.
OBJECTIVES: Knowledge of aortic valve function has been obtained from experimental studies. The aim of the present study was to investigate characteristics of aortic valve motion in humans. METHODS: Fifty-six patients were studied: 19 with normal valve and good systolic left ventricular function (Group NL), 12 with normal valve and reduced left ventricular function (Group CMP), and 25 with aortic stenosis and good left ventricular function (Group AS). The frame rate was doubled (50 Hz) compared with previous 3-dimensional systems. A mean of 38 +/- 9 images were acquired per cardiac cycle, with 14 +/- 4 images during the systole. The changes in shape and orifice area were analyzed over time. RESULTS: With normal valves, valve movement proceeded in 3 phases: rapid opening, slow closing, rapid closing. Stenotic valves showed a slower opening and closing movement. The times to maximum opening in Groups NL, CMP, AS were 76 +/- 30, 88 +/- 18 (P =.06), and 130 +/- 29 (P <.01) ms, respectively. It was inversely correlated to the maximum orifice area (r = -0.59, P <.001). The opening velocities in Groups NL, CMP, AS were 42 +/- 23, 28 +/- 9 (P <.05), and 5 +/- 2 (P <.001) cm(2)/s, respectively. There was a close correlation between the opening velocity and the maximum orifice area (r = 0.87, P <.001). Slow valve closings occurred at a velocity of 8.0 +/- 5.2, 5.3 +/- 2.0 (P =.21), 2.8 +/- 1.1 (P <.01) cm(2)/s, respectively, and rapid closings in Groups NL and CMP at 50 +/- 23, 29 +/- 8 (P <.01) cm(2)/s. The results show good agreement with experimental data. CONCLUSION: Rapid aortic valve movement can be recorded by 3-dimensional echocardiography and analyzed quantitatively. Time and velocity indices of valve dynamics are influenced by valvular and myocardial factors. A comparable in vivo analysis is not possible with any other imaging procedure.
Aortic Valve↗
Beat-to-beat assessment of QT/RR interval ratio in severe heart failure and overt myocardial ischemia: a measure of electrical integrity in diseased hearts.
The study was designed to assess the beat-to-beat variation of ventricular repolarization in patients with myocardial ischemia, hear failure, and in normal subjects. Autonomic tone may alter the dynamic QT/RR interval relation and thus may be involved in ventricular arrhythmia development, especially in the diseased heart. The study included 145 patients (age 16-86 years) with CHF (LVEF < or = 0.30) or unstable angina pectoris (LVEF > 0.60). The control group consisted of healthy volunteers giving physiological baseline measures for the evaluated parameters: cycle length, QT interval, and QT/RR interval ratio during three time periods. In patients with myocardial ischemia (LVEF > 0.60) and healthy subjects the QT/RR interval ratio did not reveal significant differences between both groups (QT/RR(CAD) = 0.36 +/- 0.77 vs QT/RR(controls) = 0.28 +/- 0.83; NS). In sharp contrast, in patients with severe heart failure, RR dependent instantaneous variation of the QT interval was almost missing and regression line analysis disclosed a QT/RR interval slope substantially enhanced by 196% (compared to normal subjects) and 131% (compared to CAD patients; P < 0.05) with a complete loss of circadian modulation (QT/RR(CHF) = 0.83 +/- 0.71 vs QT/RR(CAD) = 0.36 +/- 0.77 vs QT/RR(controls) = 0.28 +/- 0.83; P < 0.05). Beat-to-beat QT interval assessment provides a dynamic parameter of physiological and altered repolarization in defined study groups. Compared to other groups (preserved LVEF), patients with left ventricular impairment exhibited a significantly increased sensitivity of repolarization to cycle length (enhanced QT/RR interval ratio) and a blunted circadian modulation of the QT interval. This is consistent with concept that increased repolarization disparity may be deleterious being a potential pathophysiological basis for enhanced arrhythmic risk.
Adolescent↗
A technical approach to optimized atrial recognition in the ICD: the intrathoracic six-channel farfield ECG.
Present-day ICD systems offer the possibility to reconstruct an intrathoracic 6-lead ECG (IT-ECG), using the defibrillator coils in the right ventricle and superior vena cava and the left-laterally positioned ICD as electrodes according to Einthoven and Goldberger. The aim of this study was to assess the feasibility of (1). automated P wave recognition in the IT-ECG without an additional atrial electrode as the basis of AV synchronous ventricular pacing (VDD) and for improved differentiation between supraventricular tachyarrhythmias and, (2). the automated detection of pacing evoked atrial potentials (EAP) in dual chamber ICDs as the basis for atrial "autocapture"pacing systems. In 27 patients during ICD implanation intraoperatively, the IT-ECG was digitally recorded. A recently established algorithm for automatic P wave and EAP detection correctly identified 1663/1672 (99.5%) P waves (oversensing rate 0.6%) and 543/554 (98.0%) EAP (no oversensing). During subthreshold atrial stimulation, 405/412 (98.3%) P waves were correctly identified (oversensing due to pacemaker spikes, n = 421, without subsequent EAP, 1.9%,n = 8). During stimulated ventricular tachycardia in 26/27 patients retrograde P wave or AV dissociation were identified. The 6-lead IT-ECG, easily implementable in ICD systems, is a diagnostic tool providing reliable information about atrial activation, serving as a basis for VDD pacing in single chamber ICD systems, allowing reliable EAP recognition that enables atrial "autocapture"pacing in dual chamber ICDs, and improves the differentiation between supraventricular and ventricular tachycardia.
Atrial Function↗
Three-dimensional echocardiographic determination of cardiac output at rest and under dobutamine stress: comparison with thermodilution measurements in the ischemic pig model.
Determination of cardiac output is a potentially important clinical application of three-dimensional (3-D) echocardiography since it could replace invasive measurements with the Swan-Ganz-catheter. To date, there are no studies available to determine whether cardiac output measured by thermodilution can be predicted reliably under changing hemodynamic conditions. Fifteen pigs with ischemic myocardium were examined under four hemodynamic conditions at rest and under pharmacological stress with 5, 10, and 20 microg/kg/min dobutamine. The 3-D datasets were recorded by means of transesophageal echocardiography. The endocardial definition was enhanced by administering the contrast agent FS069 (Optison). Cardiac output was calculated as the product of stroke volume (end-diastolic - end-systolic volume) and heart rate. The invasive measurements were performed with a continuous thermodilution system. In general, there was moderate correlation between 3-D echocardiography and thermodilution(r = 0.72, P < 0.001). At rest, the 3-D echocardiographic measurements were slightly but significantly lower than the invasive measurements (mean difference 0.6 +/- 0.5L/min,P < 0.001). Under stress with 5, 10, and 20 microg/kg/min dobutamine, there was a marked increase in the deviation (1.3 +/- 0.5L/min,P < 0.001; 1.6 +/- 0.7 L/min,P < 0.001; and 2.1 +/- 1.1L/min,P < 0.001, respectively). The deviation was based on two factors: (1). Under stress, the decreasing number of frames per cardiac cycle acquired with 3-D echocardiography led to imprecise recording of end-diastolic and end-systolic volumes, and thus to an underestimation of cardiac output. At least 30 frames per cardiac cycle are needed to eliminate this effect. (2). There is a systematic difference between 3-D echocardiographic and invasive measurements, which is independent of the imaging rate. This is based on an overestimation of the true values by thermodilution. In conclusion, cardiac output can be determined correctly by 3-D echocardiography for normal heart rates at rest. At elevated heart rates, the temporal resolution of 3-D systems currently available is not adequate for reliable determination. In performing and evaluating future clinical comparative studies, the systematic difference between 3-D echocardiography and thermodilution, based on overestimation by thermodilution, must be taken into account.
Animals↗
Abciximab, eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates.
Platelet GPIIb/IIIa antagonists are not only used to prevent platelet aggregation, but also in combination with thrombolytic agents for the treatment of coronary thrombi. Recent data indicate a potential of abciximab alone to dissolve thrombi in vivo. We investigated the potential of abciximab, eptifibatide, and tirofiban to dissolve platelet aggregates in vitro. Adenosine diphosphate (ADP)-induced platelet aggregation could be reversed in a concentration-dependent manner by all three GPIIb/IIIa antagonists when added after the aggregation curve reached half-maximal aggregation. The concentrations chosen are comparable with in vivo plasma concentrations in clinical applications. Disaggregation reached a maximum degree of 72.4% using 0.5 microg/ml tirofiban, 91.5% using 3.75 microg/ml eptifibatide, and 48.4% using 50 microg/ml abciximab (P < 0.05, respectively). A potential fibrinolytic activity of the GPIIb/IIIa antagonists was ruled out by preincubation with aprotinin or by a plasma clot assay. A stable model Chinese hamster ovary (CHO) cell line expressing the activated form of GPIIb/IIIa was used to confirm the disaggregation capacity of GPIIb/IIIa antagonists found in platelets. Not only abciximab, but also eptifibatide and tirofiban have the potential to disaggregate newly formed platelet clusters in vitro. Because enzyme-dependent fibrinolysis does not appear to be involved, competitive removal of fibrinogen by the receptor antagonists is the most likely mechanism.
Abciximab↗
Construction and in vitro testing of a novel fab-hirudin-based fusion protein that targets fibrin and inhibits thrombin in a factor xa-dependent manner.
Fibrin targeting of the thrombin inhibitor hirudin via chemical coupling is effective in vitro and in vivo. However, since chemical coupling has limitations, a recombinant approach was taken to improve the fibrin-targeting ability of hirudin. Additionally, to activate hirudin selectively at the target area and thereby limit side effects in an in vivo setting, the authors aimed to construct an inactive precursor molecule that is converted into an active thrombin inhibitor only upon cleavage by factor Xa. Using PCR, the coding region for hirudin was fused to parts of the genomic DNA of the IgG heavy chain that was cloned from the antifibrin antibody-producing hybridoma cell line 59D8. Additionally, a factor Xa recognition site was introduced between the antibody and the hirudin sequence. The fusion construct was then transfected into a heavy-chain loss variant of the hybridoma cell line 59D8. After selection of stable hybridoma clones, the expressed fusion protein was evaluated for its molecular size (57 kd) and its binding ability to the fibrin-specific peptide Bbeta 15-22. The cleavage of the fusion protein by factor Xa was demonstrated by HPLC. The recombinant anticoagulant revealed antithrombin activity only after cleavage by factor Xa. Thus, the newly designed hirudin fusion protein revealed the anticipated functions in vitro. Further experiments are needed to prove whether this precursor anticoagulant allows a highly clot-specific and efficient thrombin inhibition in vivo.
Antibodies, Monoclonal↗