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H Drexler

Publications and source records attributed to H Drexler.

At least 19 recordsLinked to original sources
PubMed2000

Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.

BACKGROUND: Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. METHODS AND RESULTS: Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT(1)) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT(1) receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. CONCLUSIONS: Ang II, AT(1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT(1) receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.

Angina, Unstable↗
PubMed2000

The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system : relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes.

BACKGROUND: Fas (APO-1/CD95) is a transmembrane receptor belonging to the tumor necrosis factor receptor superfamily. Cross-linking of Fas by Fas ligand (FasL), a tumor necrosis factor-alpha-related cytokine, promotes apoptosis and/or transcription factor activation in a highly cell-type-specific manner. The biological consequences of Fas activation in cardiomyocytes and the regulation of Fas and FasL abundance in the myocardium in vivo remain largely unknown. METHODS AND RESULTS: As shown by immunohistochemistry, Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. Moreover, FasL was constitutively expressed in the myocardium and in isolated cardiomyocytes, as revealed by reverse transcription polymerase chain reaction and Western blotting. Left ventricular abundance of Fas but not FasL was upregulated in a rat model of compensated volume-overload hypertrophy and was closely related to diastolic but not systolic wall stress as determined by MRI. Cardiomyocyte apoptosis was not enhanced in volume-overload hypertrophy despite the increased expression of Fas and the presence of FasL in the myocardium. Moreover, injection of mice with an agonistic anti-Fas antibody promoted hepatocyte but not cardiomyocyte apoptosis in vivo. Stimulation of isolated cardiomyocytes with recombinant FasL promoted an activation of the transcription factor AP-1 as shown by electrophoretic mobility shift assays but did not induce cell death. CONCLUSIONS: Fas and FasL are constitutively expressed in the myocardium and in cardiomyocytes. Myocardial expression of Fas is closely related to diastolic loading conditions in vivo. Signaling pathways emanating from Fas are coupled to an activation of the transcription factor AP-1 in cardiomyocytes.

Animals↗
PubMed2000

Myocardial "hybrid" revascularisation with minimally invasive direct coronary artery bypass grafting combined with coronary angioplasty: preliminary results of a multicentre study.

OBJECTIVE: To expand the benefits of the minimally invasive direct coronary artery bypass (MIDCAB) concept to patients with multivessel disease, a hybrid procedure combining surgical revascularisation of the left anterior descending artery with interventional procedures for additional coronary lesions has recently been introduced. Preliminary results in patients undergoing this hybrid procedure are presented. DESIGN AND PATIENTS: Since December 1996, 35 patients (29 male, 6 female, mean (SD) age 56.7 (17) years) underwent a hybrid revascularisation performed as a primary MIDCAB procedure for grafting of the left anterior descending artery with the left internal mammary artery, followed by staged angioplasty and stenting of additional coronary lesions. RESULTS: After MIDCAB grafting the postoperative course was uneventful in all patients. Coronary reangiography after a median of seven days revealed patent and functioning left internal mammary artery grafts in all patients. Applying subsequent percutaneous transluminal coronary angioplasty and occasional stenting (n = 14), a total of 47 lesions were treated successfully. Procedure related complications did not occur. All patients remained free from angina and no stress ECG changes were recorded. CONCLUSIONS: The preliminary results of this hybrid approach to myocardial revascularisation suggest that this is a safe and effective procedure for complete revascularisation in selected patients with multivessel disease. Elderly and reoperative patients with significant comorbidity may benefit especially from such hybrid procedures by avoiding cardiopulmonary bypass and mid sternotomy.

Adult↗
PubMed1999

Sodium-hydrogen exchange inhibition: novel strategy to prevent myocardial injury following ischemia and reperfusion.

Activation of Na+/H+ exchange and subsequent calcium overload in cardiac myocytes appear to play an important role in myocardial tissue injury following ischemia and reperfusion. Results of several in vitro studies in isolated myocytes and heart preparations and in vivo studies in pigs and rats have suggested that inhibition of Na+/H+ exchange is an effective means to prevent lethal reperfusion injury, arrhythmia, and improve myocardial contractile dysfunction. In patients with acute myocardial infarction (MI), any preventive agent is administered immediately before or shortly after reperfusion, rather than before the occurrence of coronary occlusion. The direct interventional approach to treating acute MI provides the opportunity to see if reperfusion has already occurred; if not, a protective agent prior to mechanical reperfusion by percutaneous transluminal coronary angioplasty (PTCA) can be administered to limit reperfusion injury. In a multicenter, randomized, placebo-controlled clinical trial, we tested the hypothesis that inhibition of Na+/H+ exchange with cariporide (HOE 642) could limit infarct size and improve myocardial function in patients with acute transmural MI treated with direct PTCA. Patients were randomized to receive placebo or cariporide given as a 40-mg intravenous bolus prior to reperfusion. Global and regional left ventricular function were analyzed via paired contrast left ventriculograms performed before direct PTCA and after 21 days. Myocardial enzymes (i.e., creatine kinase [CK], CK-MB, and lactate dehydrogenase) as markers for myocardial tissue injury were evaluated as well. The results of this pilot study suggested that the Na+/H+ exchange inhibition could be of benefit to prevent reperfusion injury in patients with acute anterior MI treated with direct angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1999

Endothelial dysfunction in human disease.

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.

Acetylcholine↗
PubMed1999

[Hybrid technique for myocardial revascularization: value of combined minimal invasive bypass technique (MIDCAB) with interventional therapy (PTCA)].

BACKGROUND: Minimally invasive direct coronary artery bypass (MIDCAB) grafting without cardiopulmonary bypass (CPB) through an anterolateral minithoracotomy has become a promising therapeutical option especially in multimorbid, elderly and reoperative patients with single vessel disease. However, this procedure precludes complete revascularization in multivessel disease because the minithoracotomy limits the surgical access either to anterior or lateral or posterior vessels of the beating heart. To expand the benefits of the MIDCAB concept to patients with multivessel disease, new interdisciplinary approaches have recently been introduced. METHODS: Since December 1996, 26 patients (21 male, 5 female, mean age 56.6 +/- 18.8 years) underwent a "hybrid" revascularization performed as a primary MIDCAB procedure for grafting of the left anterior descending artery (LAD) with the left internal mammary artery (LIMA) followed by staged angioplasty and stenting of additional coronary lesions. RESULTS: After MIDCAB grafting, the postoperative course was uneventful in all patients. Coronary re-angiography after a median of 7 days revealed patent and functioning LIMA grafts in all patients. Applying subsequent percutaneous transluminal coronary angioplasty (PTCA) and occasional stenting (n = 8), a total of 31 lesions were treated successfully. Procedure related complications did not occur. All patients remained angina-free and no stress electrocardiographic changes were recorded. CONCLUSION: Our preliminary results of a "hybrid" approach to myocardial revascularization suggest that this concept is a safe and effective approach of complete revascularization for selected patients with multivessel involvement. Especially elderly and reoperative patients with significant comorbidity may benefit from hybrid procedures avoiding cardiopulmonary bypass and midsternotomy.

Adult↗
PubMed1999

The renin-angiotensin system and experimental heart failure.

Experimental studies suggest that the renin-angiotensin system (RAS) and its primary effector peptide, angiotensin II (Ang II), are involved in the pathophysiology of cardiac hypertrophy and failure. All the components required for Ang II production are present in the heart, and cardiac Ang II formation appears to be regulated independent from the circulating RAS. In animal models and in patients with heart failure, the cardiac RAS is activated and, presumably, local Ang II formation is enhanced. Several cardiac cell types express Ang II type 1 (AT1) and/or type 2 (AT2)-receptors and represent potential targets for Ang II-mediated effects. In neonatal cardiac myocytes, Ang II induces a hypertrophic response via the AT1-receptor. Likewise, activation of the AT1-receptor triggers hypertrophy in terminally differentiated cardiac myocytes and in perfused heart preparations. In the neonatal system, Ang II appears to be a major autocrine/paracrine mediator of cardiac myocyte hypertrophy in response to passive mechanical stretch. By contrast, AT1-receptor activation apparently is not required to trigger load-induced hypertrophy in the adult cardiomyocyte. Recent studies suggest that the AT2-receptor opposes AT1-receptor-mediated growth signals in neonatal and in adult cardiac myocytes. Pharmacological studies have established that a blockade of the RAS at the level of the angiotensin-converting enzyme (ACE) or the AT1-receptor ameliorates the remodeling process of the heart and prolongs long-term survival in animal models of cardiac hypertrophy and failure. The therapeutic effects of ACE inhibitors and AT1-receptor antagonists clearly suggest an important role for the ACE-Ang II-AT1-receptor axis in the development of cardiac hypertrophy and failure. It must be kept in mind, however, that these drugs enhance AT2-receptor and B2-kinin receptor-dependent signaling pathways which may contribute significantly to the beneficial effects observed in vivo. Molecular and physiological analyses of transgenic mice with a cardiac-specific overexpression of the AT1 or AT2-receptor confirm that AT1 and AT2-receptor-dependent signaling cascades potently modulate cardiac myocyte function and growth. However, studies in AT1-receptor knockout mice demonstrate that cardiac hypertrophy in response to hemodynamic overload can occur independent from the AT1-receptor. In this paper, we review recent experimental evidence suggesting a critical role for the RAS in cardiac hypertrophy and failure with special emphasis on the putative role of Ang II and Ang II-receptor signaling in cardiac myocytes.

Angiotensin II↗
PubMed1999

Reciprocal changes in endothelial and inducible nitric oxide synthase expression following carotid angioplasty in the pig.

OBJECTIVE: Nitric oxide produced by nitric oxide synthase appears to have an important role in the regulation of arterial tone, platelet adhesion and smooth muscle cell proliferation. Our aim was to investigate the effects of balloon angioplasty on expression of endothelial NO synthase (cNOS) and inducible NO/synthase (iNOS) in the pig carotid artery and to relate any changes in expression to the processes of reendothelialisation and vascular repair. METHODS: Pigs were sacrificed at various time points to follow NOS expression in the neointima, media and regenerated endothelium. Immunocytochemical staining was used to localize cNOS and iNOS expression in the vessel wall. Relative amounts of cNOS were measured using quantitative in vitro alitoradiography. cNOS mRNA and iNOS mRNA was quantified by competitive PCR based on the sequenced cDNA of porcine cNOS and iNOS. RESULTS: Uninjured carotid arteries exhibited dense uniform luminal endothelial staining for cNOS. Balloon angioplasty caused denudation of cNOS immunoreactive cells and a marked reduction of cNOS gene expression but a complete recovery was noted by day 35. In normal uninjured carotid arteries no evidence of iNOS immunoreactivity was demonstrable but 24 h after injury, marked homogeneous iNOS immunoreactivity was detected in medial vascular smooth muscle cells. By 5 days, staining was evident in cells within the forming neointimal layer with no evidence of iNOS immunoreactivity in the media. iNOS immunoreactivity persisted in cells at the luminal surface at 7 days and iNOS gene expression appeared to be sustained in some animals with ruptured internal elastic lamina at 21 days. CONCLUSION: Balloon injury is associated with de-endothelialisation and a marked reduction in cNOS gene expression and activity. iNOS is induced throughout the arterial media within VSMC soon after balloon injury and persists for up to 21 days. These observations imply an important regulatory role for locally generated NO in the pathophysiological response to balloon injury.

Amino Acid Sequence↗
PubMed1999

Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both.

OBJECTIVES: The purpose of this study was to test the hypothesis that long-term supplementation with Vitamin E improves endothelium-dependent relaxation in hypercholesterolemia patients and/or chronic smoking, two risk factors that have been shown to be associated with increased radical formation. BACKGROUND: Experimental evidence suggests that oxidized low density lipoprotein (LDL) impairs endothelium-dependent relaxation, and vitamin E, a lipid-soluble antioxidant, reduces the oxidation of LDL. METHODS: Thirteen subjects with hypercholesterolemia, 14 smokers and 15 hypercholesterolemic smokers were enrolled in a double-blind, placebo-controlled study. After baseline measurements of plasma autoantibodies against oxidized LDL and assessment of endothelium-dependent relaxation using intra-arterial forearm infusions of acetylcholine, participants within each group were randomly assigned in a 1:2 fashion to receive either placebo or vitamin E for 4 months, when plasma levels of autoantibodies against oxidized LDL and vascular function were reassessed. RESULTS: Vitamin E significantly augmented endothelium-dependent relaxation in hypercholesterolemic smokers but not in patients with either hypercholesterolemia or chronic smoking. At baseline, hypercholesterolemic smokers had significantly higher autoantibody levels against oxidized LDL (compared with the other two groups), which were significantly reduced after 4 months of vitamin E supplementation. There was a significant relationship between improvement in acetylcholine-induced vasodilation and the change in autoantibody titer against oxidized LDL (r = -0.59; p = 0.002). CONCLUSIONS: Long-term vitamin E supplementation improves endothelium-dependent relaxation in forearm resistance vessels of hypercholesterolemic smokers, which are characterized by increased levels of autoantibodies against oxidized LDL. These findings may suggest that the beneficial effect of vitamin E is confined to subjects with increased exposure to oxidized LDL.

Acetylcholine↗
PubMed1999

Early angiographic results after revascularization by minimally invasive direct coronary artery bypass (MIDCAB).

OBJECTIVE: Anastomosing the left anterior descending artery (LAD) by use of the internal mammary artery (IMA) via an anterior minithoracotomy represents the most commonly performed minimally invasive direct coronary artery bypass (MIDCAB). However, little is known about angiographic results beyond patency rates. METHODS: Therefore, a retrospective analysis of 205 consecutive control angiographies was performed evaluating anastomototic patency as well as the angiographic morphology of the left IMA and the LAD. RESULTS: The overall anastomotic patency rate was 98.0%. As a result of incomplete IMA preparation (6-15 cm) large side branches (n = 4), or an IMA course under tension (n = 6) were occasionally observed. Despite a tension-free course, the IMA appeared fixed to the chest wall without functional compromise in 21 cases. A restrictive thrombus formation occurred once, IMA dissection was not seen. Two of the grafts developed spasms. A distal IMA stenosis >50% was seen in five cases. Stenosis of the anastomosis (>50%) itself was found once, as well as unexpected malinsertation to diagonal branches (n = 4). Compared with preoperative angiograms, de novo stenoses of the LAD were assessed proximal (14< or =50%, 2>50%) and distal (15< or =50%, 2>50%) to the anastomosis. Elevation of the LAD out of the vascular bed was an additional finding (n = 12) in a few cases. CONCLUSIONS: The overall patency of MIDCAB-LAD-grafting appears to be equivalent to conventional IMA grafting to the LAD. Particular angiographic findings, however, may be directly associated to the applied surgical technique.

Adult↗
PubMed1999

Noninvasive diagnosis in patients with undocumented tachycardias: value of the adenosine test to predict AV nodal reentrant tachycardia.

INTRODUCTION: Patients with symptoms suggestive of paroxysmal supraventricular tachycardia (PSVT) but no tachycardia documentation often undergo diagnostic electrophysiologic study. In dual AV node physiology with AV node reentrant tachycardia (AVNRT), the anterograde fast pathway is more sensitive than the slow pathway to the effects of adenosine. The purpose of the study was to test the hypothesis that adenosine can be used as a bedside test for the diagnosis of dual AV node physiology and hence for AVNRT. METHODS AND RESULTS: During electrophysiologic study, 37 patients without prior documentation but symptoms indicative for PSVT received incremental dosages of adenosine during sinus rhythm until second-degree or greater AV block was observed. Suggestive signs of dual AV node physiology on the surface ECG (sudden jump of PQ interval > or = 50 msec) were found in 13 (76%) of 17 patients with inducible AVNRT but in only 1 (5%) of the remaining patients (P < 0.01). In the AVNRT group, the maximal increase of the PQ interval between two beats was greater (88+/-45 msec) than in the remaining 20 patients (17+/-11 msec) (P < 0.01). CONCLUSION: Careful evaluation of surface ECG during administration of adenosine helps to identify patients prone to AVNRT. The adenosine test is a valuable noninvasive adjunct in patients with undocumented palpitations suggestive of PSVT.

Adenosine↗
PubMed1999

Efficacy of measures of hygiene in workers sensitised to acid anhydrides and the influence of selection bias on the results.

OBJECTIVES: Organic acid anhydrides are potential sensitisers and cause occupational airway diseases. In an intervention study the efficacy of measures of hygiene at the workplace and possible selection bias were investigated. METHODS: A first investigation with 110 workers exposed to hexahydrophthalic acid anhydride (HHPA) and methyltetrahydrophthalic acid anhydride (MTHPA) was carried out in July 1991. The results (skin prick test, specific serum IgE) showed that 20 people were sensitised, and in a challenge test the clinical relevance of the sensitisation was confirmed in six subjects. In December 1991, the hygiene conditions at the plant were improved. In November 1995 a second investigation of 84 people was performed (anamnesis, skin prick test, specific IgE, spirometry, and ambient and biological monitoring). The 27 people who had left the plant in the meantime were asked their reasons for leaving. RESULTS: The relative risk of people sensitised in 1991 of leaving the plant between 1991 and 1995 was 2.6 (95% confidence interval (95% CI) 1.4 to 4.9) compared with people without any sign of sensitisation. The percentage of people identified as sensitised in 1991, who were still working at the plant and came to the second investigation, was higher than for people without evidence of sensitisation (10/10 v 47/73; p < 0.05). In all the 10 sensitised people in 1991 the findings of the first investigation were confirmed in 1995. The rate of sensitisation in 1995 was 21%. None of the six people employed after 1991 showed evidence of sensitisation. Of the six people with clinically relevant sensitisation confirmed by a challenge test in 1991, five were still at their workplace. From 1991 they were only exposed to MTHPA at a reduced concentration (< 0.5-36 micrograms/m3 in 1995). All of them reported fewer symptoms than in 1991. No signs of bronchial obstruction were detected by spirometry at the workplace. CONCLUSIONS: In cross sectional studies there is a selection bias with a risk of underestimating the incidence of allergic diseases. The results further suggest that the improved hygiene conditions probably had a positive effect on the symptoms in sensitised people.

Adult↗