Biomedical subjects
Publications and source records attributed to V Schächinger.
In a prospective observational study, 40 patients were treated with coronary stent grafts covered by a polytetrafluoroethylene membrane. These devices may be regarded as therapy of choice for acute coronary rupture; treatment of conventional in-stent restenosis was not associated with a favorable outcome, whereas the promising results in degenerated vein grafts warrant a randomized, controlled trial.
The vascular endothelium plays a key role in the control of vasomotor tone, local haemostasis and vascular wall proliferation processes. These responses are mediated by a variety of substances released from the endothelium in response to physiological stimuli, including prostacyclin, endothelin, and most importantly nitric oxide (NO). NO mediates vasodilation and furthermore inhibits platelet aggregation, expression of adhesion molecules for monocytes and adhesion of neutrophils, and it impairs growth of vascular smooth muscle cells. Risk factors for coronary atherosclerosis, such as hypercholesterolaemia, impair NO bioactivity, mainly due to an oxidative stress by superoxide radicals (O2-), which are able of rapidly inactivating endothelium-derived NO. Impaired NO bioactivity leads to unopposed paradoxical vasoconstriction of epicardial conductance vessels in response to physiological stimuli such as sympathetic activation as well as impaired vasodilator function of coronary resistance vessels. Therefore, endothelial dysfunction contributes to ischaemic manifestation of coronary artery disease. In addition, enhanced paradoxical vasoconstriction and a loss of endothelial antithrombotic activities might unfavourably modulate the course of acute coronary syndromes. Thus, the aim of therapeutic interventions is to increase NO bioavailability by either increasing NO production or decreasing O2- production in the endothelium. This goal can be reached, for example by ACE inhibitors, lipid-lowering drugs, increased shear-stress by physical exercise, oestrogens, and L-arginine, which have already been shown to improve endothelial vasodilator function. Nevertheless, it has to be determined whether ameliorated endothelial function will contribute to improved patients prognosis.
The vascular endothelium controls vasomotor tone by releasing a number of substances like nitric oxide (NO). NO has been shown to play a very important role, because it mediates vasodilation and furthermore inhibits platelet aggregation, expression of adhesion molecules for monocytes and adhesion of neutrophils and it impairs growth of vascular smooth muscle cells. An increased oxidative stress, decreasing the bioavailability of NO, is mainly responsible for a blunted endothelium dependent vasoreactivity. Risk factors for endothelial dysfunction are coronary artery disease, hypertension, hypercholesterolemia, smoking, and aging. Endothelial dysfunction in the presence of these risk factors might contribute to the occurrence of myocardial ischemia, aggravate acute coronary syndromes and accelerate progression of coronary artery disease. Amelioration of blunted endothelial function appears to be a major therapeutical goal to reduce ischemia and clinical events and might even retard progression of coronary artery disease.
The combination of morphological atherosclerotic alterations of coronary vessels and disturbance of coronary vasomotor control of epicardial and resistance vessels determines the amount of myocardial oxygen supply. The endothelium plays a crucial role for functional alterations of the coronary vessels in patients with early atherosclerosis or risk factors for coronary artery disease. A therapy which aims to ameliorate endothelium-dependent vasodilator capacity improves myocardial perfusion in patients with coronary artery disease. Thereby, even in patients with angiographically normal or minimally diseased coronary vessels who develop myocardial ischemia due to microvascular disease, symptomatic improvement might be achieved. Control of coronary vasomotor tone and proliferation processes within the vessel wall are both determined by the redox equilibrium of nitric oxide (NO) and superoxide radicals (O2-), induced by angiotensin II. Thus, vasomotor control and vessel wall proliferation is closely related to each other. Aim of a therapeutic intervention to enhance NO bioactivity is either to increase NO production in the endothelium or to decrease O2- production, which rapidly inactivates NO. NO bioactivity can be ameliorated by ACE-inhibitors, increase of shear stress on the endothelium by physical exercise, estrogens or L-arginine. For these therapies clinically an improvement of endothelial vasodilator function could be shown. In addition, improvement of endothelial vasodilator function can be achieved by a treatment which reduced oxidative stress in the vascular wall such as antioxidants and, especially, lipid lowering drugs. Endothelin-antagonists and angiotensin II receptor-blockers are promising to improve endothelial dysfunction. However, these therapies have to be validated. Most therapy strategies, which have shown to ameliorate endothelial dysfunction, are also able to improve prognosis of the patients. Whether endothelial dysfunction alone--without evidence of overt coronary atherosclerosis--is sufficient to justify a long-term therapy to improve prognosis, still has to be clarified.
BACKGROUND: Coronary stents are an effective treatment for selected coronary stenoses. However, thrombosis of the stented segment is a major adverse complication. Platelet aggregation has a key role in stent thrombosis. We investigated whether a polymorphism of platelet glycoprotein IIIa gene (PIA2) is associated with an increased risk of coronary stent thrombosis. METHODS: 318 consecutive patients were followed up for 30 days after coronary stent insertion. The primary endpoints were death, myocardial infarction, stent-vessel occlusion, and coronary artery bypass surgery. Gel electrophoresis of PCR products was used to identify the PIA1 and PIA2 alleles. The relative risk of stent occlusion was calculated from the odds ratio on logistic regression analysis. FINDINGS: 63 (19.8%) of patients had the PIA2 allele and 255 (80.2%) were homozygous for PIA1. Baseline clinical, angiographic, and procedural features did not differ between the groups with and without the PIA2 allele. Occlusion of the stent vessel occurred in five (1.9%) patients homozygous for PIA1 and six (9.5%) patients with PIA2 allele (odds ratio 5.26 [95% CI 1.55-17.85]). On multivariate regression analysis PIA1/A2 genotype was the only significant independent predictor of stent thrombosis. INTERPRETATION: Patients with the pIA2 allele have an increased risk of coronary stent thrombosis, which may warrant antiplatelet therapy with glycoprotein-IIb/IIIa inhibitors, although bleeding complications may also increase.
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Uncontrolled studies have suggested that intracoronary urokinase may be beneficial in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Therefore, 280 consecutive patients undergoing PTCA were prospectively randomized to receive a bolus injection of 12,500 U of heparin followed by a continuous intracoronary infusion via the guiding catheter of either 250 U heparin per minute or 250 U heparin plus 5,000 U urokinase per minute during the procedure. Procedural success rates (<50% final diameter stenosis by quantitative angiography and no major ischemic complications during in-hospital follow-up) were similar, with 87% in the heparin group (n=135) and 86% in the heparin plus urokinase group (n=127). Percent diameter stenosis after PTCA was 39 +/- 12% in the heparin group plus urokinase group (p=NS). There were no difference between groups with respect to PTCA-related acute vessels occlusion, angiographic evidence of intracoronary thrombus formation, creatine kinase increase after the procedure, Q-wave myocardial infarction, or emergency coronary artery bypass surgery. High-risk subgroup analysis revealed no beneficial effect of adjunctive intracoronary urokinase in patients with acute coronary insufficiency syndromes (n=86) or in stenoses with an irregular luminal contour (n=134). In addition, although risk stratification according to the criteria of the American College of Cardiology/American Heart Association Task Force classification proved to be very useful for the entire study population, no beneficial effect of intracoronary urokinase infusion was observed in any of the different risk groups. Thus, compared with heparin alone, adjunctive intracoronary urokinase therapy does not appear to have any beneficial effect upon procedural outcome or on type and frequency of acute complications during PTCA, even in subgroups of patients with high risk for thrombotic complications.
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The endothelium plays a crucial role in the regulation of coronary artery vasomotor tone by conducting stimuli from the blood into changes of vascular smooth muscle tone. Disturbance of this endothelial function might inadequately reduce myocardial oxygen supply, and, therefore, contribute to myocardial ischemia. Different risk factors for coronary artery disease are accompanied by a reduced bioactivity of vasorelaxing nitric oxide (NO), produced by the endothelium. In hypercholesterolemia, oxidized LDL and vascular wall macrophages induce an oxidative stress with increased production of superoxide anions, capable to inactivate NO. Therefore, NO-mediated vasorelaxation is blunted in epicardial arteries as well as in the microcirculation. In case of sympathetic stimulation, e.g. by physical exercise or cold exposure, the direct vasoconstrictor action of catecholamines on the vascular smooth muscle cells might dominate due to reduced bioactivity of NO. Especially, in the presence of coronary stenoses, myocardial ischemia might be aggravated. Although "exogenous" NO, derived from nitrates, also relaxes coronary vessels, these drugs are not able to simulate the physiological, demand-adjusted endothelial production of "endogenous" NO. In contrast, following a 6 months therapy with HMG-CoA-reductase inhibitors, impairment of endothelium-dependent vasorelaxation could be improved. In addition, ACE-inhibitors have been shown to ameliorate endothelium-mediated coronary vasodilator function. However, whether improved endothelium-dependent vasodilator function due to ACE-inhibitor or HMG-CoA-reductase inhibitor therapy relate to the improved coronary mortality observed with these drugs, remains to be determined.
BACKGROUND: Disturbances in vasomotor tone are closely linked to the development of atherosclerosis and play an integral part in the pathophysiology of myocardial ischemia in patients with coronary artery disease. Currently, evaluation of coronary vasomotor tone relies on assessment of luminal changes in response to vasoactive stimuli by quantitative angiography. Assessment of luminal changes, however, may be misleading because of the effects of geometric magnification induced by atherosclerotic wall thickening and differences in basal tone, which may obscure potential effects of vasoactive stimuli. METHODS AND RESULTS: Combining angiographic measurements of luminal changes with measurements of coronary wall architecture determined by intracoronary ultrasound, we calculated absolute coronary arterial vasomotor tone in 34 patients with angiographically normal or "minimally diseased" coronary arteries. Epicardial artery vasodilator capacity in response to intracoronary nitroglycerin decreased significantly with increasing atherosclerotic wall thickening. An inverse relation existed between local atherosclerotic plaque load and nitroglycerin-induced changes in vasomotor tone (r = -.65, P < .0001) regardless of potential systematically operative factors. At the same time, basal vasomotor tone significantly decreased with increasing local atherosclerotic wall thickening (r = -.38, P = .004). The vasomotor effects of acetylcholine, an endothelium-dependent vasodilator, were inversely related to wall thickening only in segments with very minor degrees of atherosclerosis, whereas no such relation was observed for epicardial artery segments with more advanced atherosclerotic wall thickening. In these segments, however, vasoreactivity to acetylcholine was closely correlated with basal vasomotor tone (r = -.62, P = .0002). CONCLUSIONS: Atherosclerosis is associated with impairment of the vasodilator response to both nitroglycerin and acetylcholine in epicardial arteries in vivo. Basal vasomotor tone appears to be the primary determinant of the altered coronary vasoreactivity in response to vasoactive stimuli.
BACKGROUND: Smoking is a primary risk factor for coronary and peripheral vascular disease. Because the endothelium is a principal target for the effects of risk factors early in the pathogenesis of atherosclerosis, we investigated whether long-term smoking is associated with impaired endothelial vasodilator function of epicardial conductance vessels regardless of the presence or absence of atherosclerotic lesions. METHODS AND RESULTS: Using quantitative coronary angiography, we measured epicardial artery diameter at baseline, after maximal increases in coronary blood flow that caused flow-mediated dilation (which is strictly endothelium dependent), and after intracoronary injection of nitroglycerin (an endothelium-independent dilator) in 96 patients. Endothelium-dependent, flow-mediated dilation was significantly (P < .0001) blunted in smokers (n = 46) compared with non-smokers (n = 50). The ratio of flow-dependent dilation to nitroglycerin-induced dilation was significantly (P < .001) lower in smokers (0.34 +/- 0.32) compared with nonsmokers (0.59 +/- 0.23), indicating that the blunted dilator response to increased blood flow was out of proportion to the mildly impaired dilator response to nitroglycerin in smokers. In the presence of angiographically visible atherosclerosis, flow-dependent dilation was essentially absent (3.0 +/- 6.5%) in smokers. Multivariate analysis revealed that luminal irregularities by angiography (P < .0001) and smoking (P < .001) were the only variables to be independently associated with a reduced flow-dependent dilator response of epicardial arteries. Intracoronary ultrasound demonstrated that flow-dependent dilation progressively decreased with increasing atherosclerotic plaque load (r = -.82, P < .0001; n = 24). However, over the entire range of wall thickening, segments from smokers exhibited a significantly (P < .01) impaired flow-dependent dilator response compared with those of nonsmokers. CONCLUSIONS: Long-term cigarette smoking is associated with impaired endothelium-dependent coronary vasodilation regardless of the presence or absence of coronary atherosclerotic lesions.
BACKGROUND: The release of endothelium-derived relaxing factors has been shown experimentally to be of pivotal importance for the maintenance of coronary blood flow during increased demand. In humans with coronary atherosclerosis, endothelial vasodilator dysfunction is not confined only to epicardial conductance vessels but may also extend into the coronary microcirculation. We therefore tested the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with myocardial ischemia during exercise in patients without hemodynamically significant epicardial artery stenoses. METHODS AND RESULTS: Coronary vasodilator function was assessed by subselective infusion of the endothelium-dependent dilator acetylcholine (0.036 to 3.6 micrograms/mL) and the endothelium-independent dilator papaverine (7 mg). Coronary blood flow responses were evaluated by intracoronary Doppler flow velocity recordings and quantitative angiography. Exercise-induced myocardial perfusion was determined by 201Tl single photon emission computed tomographic imaging. Thirteen patients had exercise-induced myocardial perfusion defects suggestive of myocardial ischemia, whereas 14 patients had normal thallium imaging during exercise. In patients with exercise-induced thallium perfusion defects, coronary blood flow responses to acetylcholine were significantly (P < .005) blunted compared with patients with normal thallium imaging during exercise. In contrast, coronary blood flow reserve to the endothelium-independent smooth muscle relaxant papaverine was similar in the two groups. Patients with exercise-induced thallium perfusion defects exhibited a significantly (P < .005) reduced (23.9 +/- 9.0% [mean +/- SD]) endothelium-mediated coronary vasodilator capacity compared with patients with normal thallium testing (56.2 +/- 27.8%). Epicardial artery vasoreactivity to acetylcholine did not differ between the two groups. CONCLUSIONS: Impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant epicardial artery lesions. Endothelial vasodilator dysfunction extending into the coronary microcirculation may thus contribute to the ischemic manifestations of coronary artery disease during times of increased myocardial demand.
BACKGROUND: The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation. METHODS AND RESULTS: By use of immunohistochemical techniques, we examined the presence of endothelin-1 in coronary atherosclerotic plaque tissue obtained by directional coronary atherectomy of primary lesions from 50 consecutive patients. The tissue specimens of 43 of 50 patients (86%) demonstrated endothelin-1-like immunoreactivity. Endothelin-1-like immunoreactivity preferentially localized to macrophage-rich areas, to hypercellular regions rich in microvessels, and to plaque areas with evidence of prior hemorrhage. Double-immunolabeling revealed that both macrophages (HAM56 positive) and intimal smooth muscle cells (alpha-actin positive) demonstrated cytoplasmic immunostaining for endothelin-1. Semiquantitative analysis of endothelin-1-like immunostaining revealed significantly (P < .005) higher staining grades in active (1.86 +/- 0.15, n = 40) compared with nonactive lesions (0.78 +/- 0.35, n = 10): endothelin-1 staining grades were significantly (P < .001) lower in patients with stable angina (0.69 +/- 0.19, n = 13) than in patients with crescendo angina (1.82 +/- 0.30, n = 11), with angina at rest (2.08 +/- 0.21, n = 12), or with angina after myocardial infarction (2.0 +/- 0.26, n = 14). CONCLUSIONS: Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1-like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque.
Percutaneous transluminal coronary angioplasty (PTCA) is increasingly extended to patients with complex stenosis morphology or acute coronary insufficiency syndromes. Especially these patients are at high risk to suffer thrombotic complications during PTCA. Thus an effective anticoagulant regimen is of great importance during PTCA. PTCA-induced damage of the arterial wall induces the formation of a platelet-rich thrombus. After adhesion of platelets to the arterial wall further platelet aggregation is stimulated mainly by activated thrombin, followed by fibrin formation stabilizing the growing thrombus. This article describes the pathophysiologic basis of coagulation and thrombus formation during PTCA and potential targets for a therapeutic intervention. The results of clinical studies regarding the currently available antithrombotic, antiplatelet, and thrombolytic therapies are described. Furthermore, the results are reported of clinical studies of newer anticoagulant strategies such as inhibition of the platelet glycoprotein receptor GP IIb/IIIa with monoclonal antibodies and direct inhibition of activated thrombin with hirudin analogues. At present an aggressive anticoagulant regimen with heparin is recommended during the PTCA procedure. Heparin should not be continued after the intervention unless a complication during the procedure has occurred. Already before PTCA patients should receive 100 mg aspirin daily. Thrombolytic therapy during PTCA has failed to demonstrate an improvement of clinical results. Thus its use should be limited to bail-out situations. First results with hirudin analogues and GP IIb/IIIa receptor antagonists are promising. Further studies are, however, warranted before a general use can be recommended.
Acute coronary syndromes are accompanied by exaggerated vasoconstriction. Since thrombin induces production of the potent vasoconstrictor endothelin-1, we used immunohistochemistry on coronary atherosclerotic specimens from 30 consecutive patients. Endothelin-1-like immunoreactivity was present in 5 of 9 (55%) lesions from patients with stable angina, in 6 of 7 (86%) from crescendo angina, and in all 14 from angina at rest. Endothelin-1 immunoreactivity was most common in areas with a positive Prussian-blue reaction indicative of previous intraplaque haemorrhage. Tissue endothelin-1-like immunoreactivity might contribute to the exaggerated coronary vasoconstriction.
The endothelium plays a major role in modulating vascular smooth muscle tone by synthesizing and metabolizing a number of vasoactive substances. Since the endothelium is both a target for and a mediator of vascular disease, functional alterations in coronary vascular reactivity due to endothelial dysfunction might play an important integral part in the clinical presentation of coronary artery disease. Recent advances in interventional techniques including intracoronary instrumentation by Doppler catheters to measure blood flow velocities and 2-D-ultrasound catheters to evaluate arterial wall architecture during coronary angiography provided the diagnostic tools to assess endothelial vasodilator function and its relation to atherosclerotic disease. The current weight of evidence suggests that disturbances of vasomotor function of epicardial conductance vessels are fundamental to the development of atherosclerosis, and impaired endothelial vasodilation is the predominant mechanism underlying inappropriate vasoconstriction in atherosclerosis. However, endothelial vasodilator dysfunction is not only confined to atherosclerotic epicardial vessels, but may also extend into the coronary microcirculation, which does not develop overt atherosclerotic lesions, but determines coronary blood flow in the absence of hemodynamically significant stenoses. The most important factors associated with impaired endothelium-mediated dilation of the coronary microcirculation are hypercholesterolemia and advanced age. With respect to the clinical presentation of coronary artery disease, endothelial vasodilator dysfunction appears to play a causative role for triggering myocardial ischemia in stable angina pectoris, to aggravate the sequelae of acute ischemic syndromes, and might be the primary underlying mechanism in some patients with syndrome X, whereas variant angina appears to be related to a hyperreactivity of the vascular smooth muscle layer. Thus, the assessment of endothelium-mediated modulation of coronary vasomotor tone in the clinical setting offers unique and important insights into mechanisms leading to ischemic manifestations of coronary artery disease.
BACKGROUND: Heparin needs the plasma protein antithrombin III to function as an inhibitor of thrombin, and local antithrombin III deficiency might therefore limit the antithrombotic effectiveness of heparin during percutaneous transluminal coronary angioplasty. METHODS AND RESULTS: In the present double-blind study, 615 consecutive patients undergoing percutaneous transluminal coronary angioplasty (PTCA), of a total of 713 stenoses, were prospectively randomized to receive a bolus injection of 15,000 U heparin followed by a continuous intracoronary infusion via the guiding catheter of either 250 U heparin per minute or 250 U heparin plus 25 U antithrombin III per minute during the procedure. Four clinical variables, 19 lesion-specific characteristics, and 16 procedure-related variables were evaluated. Procedural success was assessed by quantitative angiography; procedure-related ischemic complications were analyzed during in-hospital follow-up. Procedural success rates (< 50% final diameter stenosis and no major ischemic complication) were similar, with 85% in the heparin group (n = 324 patients) and 83% in the heparin+antithrombin III group (n = 291 patients). Percent diameter stenosis after PTCA was 39 +/- 18% in the heparin group and 40 +/- 20% in the heparin+antithrombin III group (NS). There were no differences between the two groups with respect to PTCA-related acute vessel occlusion, angiographic evidence of intracoronary thrombus formation, post-procedure creatine kinase increase, Q-wave myocardial infarction, or emergency coronary artery bypass surgery. High-risk subgroup analysis revealed no beneficial effect of adjunctive intracoronary antithrombin III in any of the analyzed subgroups. In addition, although risk stratification according to the criteria of the American College of Cardiology/American Heart Association Task Force classification proved to be very useful for the entire study population, no beneficial effect of intracoronary antithrombin III infusion was observed in any of the different risk groups. CONCLUSIONS: Compared with heparin alone, adjunctive intracoronary antithrombin III therapy does not appear to have any beneficial effect on procedural outcome as well as type and frequency of acute complications during PTCA even in subgroups of patients with a high risk for thrombotic complications. Thus, a local deficiency of antithrombin III does not play a major role for the failure of heparin to abolish thrombotic complications during PTCA.
Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L-arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium-derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)