Background—Recent data suggest that inhaled NO can inhibit platelet aggregation. This study inves... more Background—Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation. Methods and Results—In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO 2 mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced
Atrial fibrillation (AF), the most common significant cardiac arrhythmia, increases the risk of s... more Atrial fibrillation (AF), the most common significant cardiac arrhythmia, increases the risk of stroke, particularly in the elderly. Warfarin is effective in reducing stroke risk but is burdensome to patients and is difficult to control. Rivaroxaban is an oral direct factor Xa inhibitor in advanced development as an alternative to warfarin for the prevention and treatment of thromboembolic disorders. ROCKET AF is a randomized, double-blind, double-dummy, event-driven trial, which aims to establish the noninferiority of rivaroxaban compared with warfarin in patients with nonvalvular AF who have a history of stroke or at least 2 additional independent risk factors for future stroke. Patients are randomly assigned to receive rivaroxaban, 20 mg once daily (od), or dose-adjusted warfarin titrated to a target international normalized ratio (INR) of 2.5 (range 2.0-3.0, inclusive) using point-of-care INR devices to receive true or sham INR values, depending on the study drug allocation. The primary efficacy end point is a composite of all-cause stroke and noncentral nervous system systemic embolism. The primary safety end point is the composite of major and clinically relevant nonmajor bleeding events. Over 14,000 patients have been randomized at 1,100 sites across 45 countries, and will be followed until 405 primary outcome events are observed. The ROCKET AF study will determine the efficacy and safety of rivaroxaban as an alternative to warfarin for the prevention of thromboembolism in patients with AF.
In the current study on human hibernating myocardium (HHM), we tested the hypothesis that increas... more In the current study on human hibernating myocardium (HHM), we tested the hypothesis that increased glycolysis might exert a positive effect during a supply-demand balance situation by augmentation of myocardial energy formation. In 14 patients HHM was preoperatively detected by clinical methods and validated by the recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were
Objective: complications of coronary stenting include thrombotic reocclusion and restenosis. In t... more Objective: complications of coronary stenting include thrombotic reocclusion and restenosis. In this study anticoagulation by the warfarin analogue phenprocoumon in combination with aspirin was compared to treatment with ticlopidine and aspirin. Hemostatic markers for thrombosis were measured in a subset of patients.Design: non-elective implantation of 322 Palmaz-Schatz coronary stents was performed in 293 patients. Treatment with either phenprocoumon (163 patients) or ticlopidine (130 patients) was administered in addition to aspirin. Postprocedural complications were analyzed and laboratory parameters of hemostasis were determined. All data were reviewed in a retrospective data analysis.Results: complete stent occlusion occurred in 17 patients (5.8%) within the first 15 days. Out of these 17 patients 15 were treated with phenprocoumon (9.2%) and two with ticlopidine (1.5%), (P=0.05). Post-procedural complications in the two groups were the following: groin aneurysm 25.8 vs 7.7% (P=0.0001), bleeding complications 11 vs 2.3% (P=0.008) and post-stenting myocardial infarction 8.6 vs 1.5% (P=0.0173). Parameters of thrombin activation and hemostasis were measured in 16 patients of the phenprocoumon group with five stent occlusions and 11 non-occlusive stents. Patients with stent occlusion had elevated levels of trothrombin fragments F1+2 (4.8±2.8 nmol/l) compared to patients with patent stents (0.8±0.4 nmol/l; P=0.03). Levels of thrombin-antithrombin TAT (22.2±13.7 μg/l vs 2.5± 0.5 μg/l; P<0.004), and fibrinogen (617.5±101.3 mg/dl vs 441.4±47.0 mg/dl; P=0.003) were increased in patients with stent occlusion. Patients with and without stent occlusion had elevated plasminogen activator inhibitor-1 (PAI-1) levels (mean 46.2±20.5 ng/ml) without significant difference between the two groups.Conclusion: post-stenting treatment with the platelet antagonist ticlopedine prevents acute and subacute stent occlusion more efficiently and is associated with fewer side effects compared to anticoagulation with phenprocoumon. F1+2 and TAT are useful markers for stent thrombosis but are not suitable for the prediction of stent occlusion. Fibrinogen, however, appears to be a risk factor for coronary stent occlusion.
Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary interventi... more Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with ...
Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion ... more Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/-) mice and wildtypes (WT). In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24%) in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized...
European heart journal cardiovascular Imaging, Jan 10, 2015
Recently, transcatheter aortic valve replacement (TAVR) has evolved as the standard treatment in ... more Recently, transcatheter aortic valve replacement (TAVR) has evolved as the standard treatment in patients with inoperable aortic valve stenosis. According to TAVR guidelines, body computed tomography (CT) is recommended for pre-procedural planning. Due to the advanced age of these patients, multiple radiological potentially malignant incidental findings (pmIFs) appear in this cohort. It is unknown how pmIFs influence the decision by the heart team to intervene and the mortality. We evaluated in a retrospective single-centre observational study 414 participants screened for TAVR with dual-source CT between October 2010 and December 2012. pmIFs are common and appeared in 18.7% of all patients screened for TAVR. The decision to intervene by TAVR or surgical aortic valve replacement (SAVR) was made by an interdisciplinary heart team and the role of pmIF in decision-making and time to treatment with TAVR or SAVR was analysed, retrospectively. The appearance of a pmIF vs. no pmIF did not ...
To compare the long-term clinical safety between two drug-eluting stents with different healing c... more To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥ 3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT u...
Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation o... more Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E- deficient (apoE/) mice and whether it affects the systemic development of atherosclerosis. A total of 78 apoE/ mice were treated with local infusion of low-dose MCP-1 (1 g/kg
Journal of The American College of Cardiology, 2004
ObjectivesThe aim of the present study was to objectify the loss of myocytes and the mechanism by... more ObjectivesThe aim of the present study was to objectify the loss of myocytes and the mechanism by which myocytes die in human hibernating myocardium (HHM).
Objective: Bone Morphogenetic Protein-4 (BMP-4) and Extracellular-Signal Regulated Kinases (ERK) ... more Objective: Bone Morphogenetic Protein-4 (BMP-4) and Extracellular-Signal Regulated Kinases (ERK) play crucial roles in vascular diseases. Here, we demonstrate that BMP-4 not only signals through the classical Smad cascade but also activates ERK phosphorylation as an alternative pathway in human umbilical vein endothelial cells (HUVEC) and that Smad and ERK pathways communicate through signal crosstalk. Methods: HUVECs were treated with
Arteriosclerosis Thrombosis and Vascular Biology, 2007
Integrins are attractive therapeutic targets. Inhibition of integrin alphaIIb beta3 effectively b... more Integrins are attractive therapeutic targets. Inhibition of integrin alphaIIb beta3 effectively blocks platelet aggregation. However, limitations with intravenous alphaIIb beta3 antagonists and failure of oral alphaIIb beta3 antagonists prompted doubts on the current concept of ligand-mimetic integrin blockade. Evaluating P-selectin expression on platelets by flow cytometry, we report a mechanism of paradoxical platelet activation by ligand-mimetic alphaIIb beta3 antagonists and define three requirements: (1) Induction of ligand-bound conformation of alphaIIb beta3, (2) receptor clustering, (3) prestimulation of platelets. Conformational change is inducible by clinically used ligand-mimetic alphaIIb beta3 antagonists, RGD-peptides, and anti-LIBS antibodies. In a mechanistic experimental model, clustering is achieved by crosslinking integrins via antibodies, and preactivation is induced by low-dose ADP. Finally, we demonstrate that platelet adhesion on collagen represents an in vivo correlate of platelet prestimulation and receptor clustering, in which the presence of ligand-mimetic alphaIIb beta3 antagonists results in platelet activation as detected by P-selectin, CD63, and CD40L expression as well as by measuring Ca2+-signaling. Blockade of the ADP receptor P2Y12 by AR-C69931MX and clopidogrel inhibits alphaIIb beta3 antagonist-induced platelet activation. These findings can explain limitations of ligand-mimetic anti-alphaIIb beta3 therapy. They describe potential benefits of concomitant ADP receptor blockade and support a shift in drug development from ligand-mimetic toward allosteric or activation-specific integrin antagonists.
Background—Recent data suggest that inhaled NO can inhibit platelet aggregation. This study inves... more Background—Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation. Methods and Results—In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO 2 mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced
Atrial fibrillation (AF), the most common significant cardiac arrhythmia, increases the risk of s... more Atrial fibrillation (AF), the most common significant cardiac arrhythmia, increases the risk of stroke, particularly in the elderly. Warfarin is effective in reducing stroke risk but is burdensome to patients and is difficult to control. Rivaroxaban is an oral direct factor Xa inhibitor in advanced development as an alternative to warfarin for the prevention and treatment of thromboembolic disorders. ROCKET AF is a randomized, double-blind, double-dummy, event-driven trial, which aims to establish the noninferiority of rivaroxaban compared with warfarin in patients with nonvalvular AF who have a history of stroke or at least 2 additional independent risk factors for future stroke. Patients are randomly assigned to receive rivaroxaban, 20 mg once daily (od), or dose-adjusted warfarin titrated to a target international normalized ratio (INR) of 2.5 (range 2.0-3.0, inclusive) using point-of-care INR devices to receive true or sham INR values, depending on the study drug allocation. The primary efficacy end point is a composite of all-cause stroke and noncentral nervous system systemic embolism. The primary safety end point is the composite of major and clinically relevant nonmajor bleeding events. Over 14,000 patients have been randomized at 1,100 sites across 45 countries, and will be followed until 405 primary outcome events are observed. The ROCKET AF study will determine the efficacy and safety of rivaroxaban as an alternative to warfarin for the prevention of thromboembolism in patients with AF.
In the current study on human hibernating myocardium (HHM), we tested the hypothesis that increas... more In the current study on human hibernating myocardium (HHM), we tested the hypothesis that increased glycolysis might exert a positive effect during a supply-demand balance situation by augmentation of myocardial energy formation. In 14 patients HHM was preoperatively detected by clinical methods and validated by the recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were
Objective: complications of coronary stenting include thrombotic reocclusion and restenosis. In t... more Objective: complications of coronary stenting include thrombotic reocclusion and restenosis. In this study anticoagulation by the warfarin analogue phenprocoumon in combination with aspirin was compared to treatment with ticlopidine and aspirin. Hemostatic markers for thrombosis were measured in a subset of patients.Design: non-elective implantation of 322 Palmaz-Schatz coronary stents was performed in 293 patients. Treatment with either phenprocoumon (163 patients) or ticlopidine (130 patients) was administered in addition to aspirin. Postprocedural complications were analyzed and laboratory parameters of hemostasis were determined. All data were reviewed in a retrospective data analysis.Results: complete stent occlusion occurred in 17 patients (5.8%) within the first 15 days. Out of these 17 patients 15 were treated with phenprocoumon (9.2%) and two with ticlopidine (1.5%), (P=0.05). Post-procedural complications in the two groups were the following: groin aneurysm 25.8 vs 7.7% (P=0.0001), bleeding complications 11 vs 2.3% (P=0.008) and post-stenting myocardial infarction 8.6 vs 1.5% (P=0.0173). Parameters of thrombin activation and hemostasis were measured in 16 patients of the phenprocoumon group with five stent occlusions and 11 non-occlusive stents. Patients with stent occlusion had elevated levels of trothrombin fragments F1+2 (4.8±2.8 nmol/l) compared to patients with patent stents (0.8±0.4 nmol/l; P=0.03). Levels of thrombin-antithrombin TAT (22.2±13.7 μg/l vs 2.5± 0.5 μg/l; P<0.004), and fibrinogen (617.5±101.3 mg/dl vs 441.4±47.0 mg/dl; P=0.003) were increased in patients with stent occlusion. Patients with and without stent occlusion had elevated plasminogen activator inhibitor-1 (PAI-1) levels (mean 46.2±20.5 ng/ml) without significant difference between the two groups.Conclusion: post-stenting treatment with the platelet antagonist ticlopedine prevents acute and subacute stent occlusion more efficiently and is associated with fewer side effects compared to anticoagulation with phenprocoumon. F1+2 and TAT are useful markers for stent thrombosis but are not suitable for the prediction of stent occlusion. Fibrinogen, however, appears to be a risk factor for coronary stent occlusion.
Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary interventi... more Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with ...
Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion ... more Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/-) mice and wildtypes (WT). In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24%) in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized...
European heart journal cardiovascular Imaging, Jan 10, 2015
Recently, transcatheter aortic valve replacement (TAVR) has evolved as the standard treatment in ... more Recently, transcatheter aortic valve replacement (TAVR) has evolved as the standard treatment in patients with inoperable aortic valve stenosis. According to TAVR guidelines, body computed tomography (CT) is recommended for pre-procedural planning. Due to the advanced age of these patients, multiple radiological potentially malignant incidental findings (pmIFs) appear in this cohort. It is unknown how pmIFs influence the decision by the heart team to intervene and the mortality. We evaluated in a retrospective single-centre observational study 414 participants screened for TAVR with dual-source CT between October 2010 and December 2012. pmIFs are common and appeared in 18.7% of all patients screened for TAVR. The decision to intervene by TAVR or surgical aortic valve replacement (SAVR) was made by an interdisciplinary heart team and the role of pmIF in decision-making and time to treatment with TAVR or SAVR was analysed, retrospectively. The appearance of a pmIF vs. no pmIF did not ...
To compare the long-term clinical safety between two drug-eluting stents with different healing c... more To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥ 3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT u...
Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation o... more Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E- deficient (apoE/) mice and whether it affects the systemic development of atherosclerosis. A total of 78 apoE/ mice were treated with local infusion of low-dose MCP-1 (1 g/kg
Journal of The American College of Cardiology, 2004
ObjectivesThe aim of the present study was to objectify the loss of myocytes and the mechanism by... more ObjectivesThe aim of the present study was to objectify the loss of myocytes and the mechanism by which myocytes die in human hibernating myocardium (HHM).
Objective: Bone Morphogenetic Protein-4 (BMP-4) and Extracellular-Signal Regulated Kinases (ERK) ... more Objective: Bone Morphogenetic Protein-4 (BMP-4) and Extracellular-Signal Regulated Kinases (ERK) play crucial roles in vascular diseases. Here, we demonstrate that BMP-4 not only signals through the classical Smad cascade but also activates ERK phosphorylation as an alternative pathway in human umbilical vein endothelial cells (HUVEC) and that Smad and ERK pathways communicate through signal crosstalk. Methods: HUVECs were treated with
Arteriosclerosis Thrombosis and Vascular Biology, 2007
Integrins are attractive therapeutic targets. Inhibition of integrin alphaIIb beta3 effectively b... more Integrins are attractive therapeutic targets. Inhibition of integrin alphaIIb beta3 effectively blocks platelet aggregation. However, limitations with intravenous alphaIIb beta3 antagonists and failure of oral alphaIIb beta3 antagonists prompted doubts on the current concept of ligand-mimetic integrin blockade. Evaluating P-selectin expression on platelets by flow cytometry, we report a mechanism of paradoxical platelet activation by ligand-mimetic alphaIIb beta3 antagonists and define three requirements: (1) Induction of ligand-bound conformation of alphaIIb beta3, (2) receptor clustering, (3) prestimulation of platelets. Conformational change is inducible by clinically used ligand-mimetic alphaIIb beta3 antagonists, RGD-peptides, and anti-LIBS antibodies. In a mechanistic experimental model, clustering is achieved by crosslinking integrins via antibodies, and preactivation is induced by low-dose ADP. Finally, we demonstrate that platelet adhesion on collagen represents an in vivo correlate of platelet prestimulation and receptor clustering, in which the presence of ligand-mimetic alphaIIb beta3 antagonists results in platelet activation as detected by P-selectin, CD63, and CD40L expression as well as by measuring Ca2+-signaling. Blockade of the ADP receptor P2Y12 by AR-C69931MX and clopidogrel inhibits alphaIIb beta3 antagonist-induced platelet activation. These findings can explain limitations of ligand-mimetic anti-alphaIIb beta3 therapy. They describe potential benefits of concomitant ADP receptor blockade and support a shift in drug development from ligand-mimetic toward allosteric or activation-specific integrin antagonists.
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Papers by Christoph Bode