Biomedical subjects

H Tillmanns

Publications and source records attributed to H Tillmanns.

At least 55 records · Page 3Linked to original sources

PubMed1999

Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives.

The association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke. We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-kappaB and its inhibitor molecule IkappaBalpha. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-kappaB. Experiments on cultured monocytes/macrophages demonstrated enhanced IkappaBalpha degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression. This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.

Adolescent↗

PubMed1998

[Disorders of microcirculation in coronary heart disease].

Disturbances of microcirculation in coronary artery disease can be seen in the presence of critical stenosis of epicardial coronary arteries, as a result of endothelial dysfunction in the absence of significant stenosis or during recovery of ischaemic myocardium after successful angioplasty of stenosed or occluded coronary arteries. Diagnostic methods are morphologic/morphometric analyses, measurement of the global coronary reserve, measurement of the regional coronary microcirculation (scintigraphy, positron emission tomography) and laboratory analysis of haemorheological alterations (plasma, erythrocytes, leucocytes). After successful angioplasty, normalisation of glutamate extraction rate takes three to six months. In patients with unstable angina, changes in plasma viscosity, erythrocyte aggregation and neutrophil activation occur. Neutrophils are activated after successful angioplasty in acute myocardial infarction and even after elective angioplasty (when measured in the coronary sinus). Therapeutic improvements of disturbed microvascular flow can be obtained by increasing perfusion pressure (by revascularisation, nitrates, calcium antagonists, physical training), by improving the fluidity of the blood and by reducing the extravascular component of coronary vascular resistance (by antihypertensive treatment).

Angina Pectoris↗

PubMed1998

ACE I/D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals.

BACKGROUND: Presence of the D allele or homozygosity for the deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism has been discussed as potent risk factor for coronary artery disease (CAD) and myocardial infarction (MI). METHODS AND RESULTS: In 2267 male Caucasians the relation of the ACE I/D gene polymorphism to CAD and MI were investigated. An association of the D allele to CAD was detected in younger subjects (e.g. < 61.7 years, mean value), but not in older patients (e.g. > or = 61.7 years). Additional exclusion of individuals with other cardiovascular risk factors (e.g. high BMI) produced an even stronger association of the D allele to CAD. In contrast, a relation of this polymorphism to non-fatal MI was only observed in older subjects; additional limitation to individuals without cardiovascular risk factors (e.g. BMI and/or diabetes) yielded a further enhancement of this association to MI. In younger subjects (e.g. < 61.7 years) the gene polymorphism was not related to non-fatal MI even after exclusion of additional risk factors. CONCLUSIONS: The present large case-control study strengthens the assumption of an association of the ACE D allele with the risk of ischemic heart disease.

Adult↗

PubMed1998

Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction.

The Del allele of the apolipoprotein B (apoB) signal peptide (SP) insertion/deletion (Ins/Del) polymorphism has been shown to be associated with elevated plasma levels of apoB, cholesterol and low density lipoprotein. It was the aim of the present study to analyse the relation of this gene variation to the risk of coronary artery disease (CAD) and of myocardial infarction (MI) in a population of 2259 male Caucasians, whose coronary anatomy was defined by means of coronary angiography. ApoB SP DelDel genotypes had significantly higher apoB plasma concentrations than InsIns homozygotes (P = 0.0001) and InsDel heterozygotes (P = 0.002); however, the apoB plasma levels of InsIns and InsDel genotypes were essentially the same (P = 0.54). Similar observations were made with respect to ApoB SP genotype-dependent cholesterol plasma concentrations. Since the apoB plasma level was not only associated with the apoB SP Ins/Del gene variation but also to the extent of coronary artery disease (P <0.0001), individuals with an InsIns genotype and without CAD had the lowest and subjects with a DelDel genotype and triple vessel disease the highest apoB plasma levels (P <0.0001). An association of the apoB SP Ins/Del gene variation with CAD was not detected, neither in the total population nor in low risk groups. In contrast, the gene variation was associated with MI (P <0.05). An Odds ratio of 1.18 (95% CI, 1.01-1.39) associated with the Del allele was detected in the total sample (P <0.02). In a subpopulation of individuals with low plasma triglyceride levels ( <154 mg/dl; mean value) and an DD genotype of the angiotensin I-converting enzyme insertion/deletion gene polymorphism an Odds ratio of 2.01 (1.42-3.05) was calculated (P <0.001). The present study presents evidence for a statistically significant difference in the development of MI between genotype classes of the apoB SP Ins/Del gene polymorphism.

Alleles↗

PubMed1998

Long-term follow-up after direct percutaneous transluminal coronary angioplasty for acute myocardial infarction.

OBJECTIVES: The purpose of this study was to analyze long-term follow-up information over several years from consecutive, unselected patients treated with direct percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (MI). BACKGROUND: Direct PTCA is often used in patients with acute MI. Short-term results are favorable. However, there is less information available on long-term observations over several years in these patients. METHODS: A total of 416 consecutive and unselected patients with acute MI underwent direct PTCA. Survival of the acute infarct phase was 94.2%; the remaining 392 patients--the study population-were discharged and followed for 3.3+/-1.4 years. Mortality as well as cardiac events and reinterventions are reported. Clinical variables assessed at the time of discharge are submitted to statistical analysis to detect potential risk factors. RESULTS: Total cumulative mortality in the first year was 10% for the entire group and 6% for patients not presenting in cardiogenic shock. Mortality after discharge was 4.6% in the first year and dropped to <4% per year thereafter. Reinterventions after discharge were required in 16% in the first year and in <4% per year in years 2 to 4. Poor left ventricular ejection fraction (<35%), three-vessel disease and advanced age (> or =75 years) were long-term risk factors for total mortality after direct PTCA. CONCLUSIONS: The clinical benefit of direct PTCA for acute MI is maintained during follow-up with respect to mortality. However, reinterventions for restenosis or de novo stenosis are often required (10% to 20%). Although few in number (<10%), patients with severely impaired left ventricular function continue to have a poor prognosis.

Adult↗

PubMed1998

Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases.

AIM: There is evidence that interaction between angiotensin II type 1 receptor A1166C gene polymorphism and angiotensin I-converting enzyme Insertion/Deletion gene variation might have an effect on the risk of myocardial infarction. The study was carried out in a population of 2244 male Caucasians, whose coronary anatomy was defined by means of coronary angiography. We analysed the relationship, on the risk of ischaemic heart disease, of angiotensin II type 1 receptor A1166C gene variation, not only to myocardial infarction but also to coronary artery disease, and its potential interaction with angiotensin I-converting enzyme Insertion/Deletion gene polymorphism. METHODS AND RESULTS: No association was detected between angiotensin II type 1 receptor A1166C gene polymorphism and coronary artery disease. Similarly, there was no link to myocardial infarction, either in the total population or in low risk groups. In addition, most importantly, we found no interaction between angiotensin II type 1 receptor A1166C gene variation and angiotensin I-converting Insertion/Deletion polymorphism, either in connection with the risk of coronary artery disease or myocardial infarction. CONCLUSION: This angiotensin II type 1 receptor A1166C gene variation is not associated with any detectable increase in risk of ischaemic heart disease. The findings of the present study do not suggest that, as regards risk of coronary artery disease and myocardial infarction, there is interaction between gene polymorphism and angiotensin I-converting enzyme Insertion/Deletion gene variation.

Aged↗

PubMed1998

Comparison of in vitro cardiovascular function with in vivo echocardiographic assessment after long-term administration of cyclosporine to rats.

Clinical reports indicate that cyclosporine is able to induce heart failure without rejection after heart transplantation. This supposition is supported by ex vivo animal studies, yet ex vivo studies do not account for the potential of counter-regulatory mechanisms, and the clinical observations seem rare in comparison with the number of patients treated with cyclosporine. We hypothesized that cyclosporine administration to rats would fail to exhibit any effect on myocardial contractility in vivo notwithstanding a negative influence ex vivo. Transthoracic echocardiographic examinations (two-dimensional targeted M-mode tracings) were done in a blinded fashion before and after 1-week treatment of rats (10 or 20 mg/kg/day cyclosporine i.p. vs. vehicle). After excision of the hearts, contractility and changes in coronary tone were determined ex vivo during flow-constant perfusion. Neither cyclosporine nor vehicle treatment resulted in changes of echocardiographic parameters (left ventricular diameter, fractional shortening). The heart rate was significantly increased in the high-dose cyclosporine group. This group showed a significant 38% reduction of contractility during the subsequent perfusion ex vivo, whereas low-dose cyclosporine or vehicle had no effect on myocardial performance. Vasoconstriction did not account for this impairment, because coronary tone was unaltered. Cyclosporine, given in doses used in animal studies, impairs myocardial contractility ex vivo but fails to exhibit any effect on myocardial performance in vivo, possibly because of an increase in sympathetic tone. Considering that the denervated transplanted heart in humans is even sensitized to adrenergic stimuli, our finding makes unlikely a clinical contribution of cyclosporine to failure after orthotopic heart transplantation.

Animals↗

PubMed1998

Association of the platelet glycoprotein IIIa PlA1/A2 gene polymorphism to coronary artery disease but not to nonfatal myocardial infarction in low risk patients.

BACKGROUND: The platelet membrane glycoprotein IIb/IIIa functions as a receptor for fibrinogen and von Willebrand factor during platelet aggregation. In a small case-control study, evidence has been presented that the PlA2 allele of the platelet glycoprotein GPIIIa PlA/A2 gene polymorphism might be an independent risk factor for acute myocardial infarction (MI). METHODS AND RESULTS: We explored the association of the PlA1A2 to the severity of coronary artery disease (CAD), as assessed angiographically in 2252 male individuals, and to myocardial infarction (MI). The severity of coronary heart disease (CHD) was also estimated by calculating a CHD score according to Gensini. The PlA genotype was determined by allele specific restriction digestion. Relation of the PlA2 allele to CAD: In the total population, the frequency of the PlA2 allele was not associated to the presence or to the extent of CAD. Also the CHD scores of PlA1/PlA2 genotypes were essentially the same. However, after exclusion of individuals with high BMI (> or =26.9 kg/m2) and/or low apoAI (< 1.43 g/l) PlA2PlA2 carriers had clearly higher CHD scores than PlA1PlA1 genotypes: PlA1PlA2 heterozygotes had intermediate values (p <0.05). After division of the study population into one group of individuals without any angiographic signs of CAD (CHD score = 0) and into another group of patients with severe CAD (CHD score (> or = 120), a strong association of the PlA2 allele with severe CAD was also found in the same low risk groups: e.g. exclusion of persons with high BMI and low apoAI resulted in an Odds ratio of 5.37 (1.46-19.7) (p <0.02). Relation of the PlA2 allele to MI: No association was found between PlA1/PlA2 genotypes and risk of MI neither in the total population nor in low risk subgroups. CONCLUSIONS: Whereas no difference in the distribution of allele and genotype frequencies between controls and survivors of MI could be detected, the PlA2 allele is associated with CHD in low risk patients.

Aged↗

PubMed1997

Cyclosporin A inhibits monocyte tissue factor activation in cardiac transplant recipients.

BACKGROUND: Fibrin deposition and thrombosis have been implicated in both allograft rejection and vasculopathy after cardiac transplantation. Because monocytes play a pivotal role in the pathophysiology of intravascular coagulation activation through their ability to synthesize tissue factor (TF), we asked (1) whether monocyte TF activation occurs in cardiac transplant recipients and (2) whether monocyte TF expression is affected by treatment with cyclosporin A (CsA). METHODS AND RESULTS: We measured levels of TF activity in peripheral blood mononuclear cells and highly purified monocytes/macrophages from 10 consecutive cardiac transplant recipients and 10 healthy control subjects. TF activity generated by both unstimulated and endotoxin-stimulated cells was significantly higher in transplant recipients than in control subjects (P<.05). Increased monocyte TF expression in transplant recipients was shown to be adversely affected by treatment with CsA: TF induction was markedly reduced by CsA serum concentrations reaching peak CsA drug levels. Inhibition of TF induction in the presence of high CsA blood concentrations was also observed when stimulation of cells was performed with interferon-gamma or interleukin-1beta. As shown by reverse transcription-polymerase chain reaction and electrophoretic mobility shift assay, respectively, treatment with CsA leads to decreased TF mRNA expression and reduced activation of the NF-kappaB transcription factor, which is known to contribute to the induction of the TF promotor in human monocytes. CONCLUSIONS: This study demonstrates that TF activation, occurring in mononuclear cells of cardiac transplant recipients, is inhibited by treatment with CsA. Inhibition of monocyte TF induction by CsA may contribute to its successful use in cardiac transplant medicine and might be useful in managing further settings of vascular pathology also known to involve TF expression and NF-kappaB activation.

Adult↗

PubMed1997

[New studies, new trends: directional coronary atherectomy].

Despite theoretical advantages of Directional Coronary Atherectomy (DCA) vs. PTCA, the first two controlled studies comparing both methods, the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT), and the Canadian Coronary Atherectomy Trial (CCAT), showed no clinical benefit of DCA, A second generation of trials, the Optimal Atherectomy Restenosis Study (OARS) and the Balloon versus Optimal Atherectomy Trial (BOAT), designed to optimize DCA with the use of 7F devices and adjunctive PTCA revealed lower angiographic restenosis rates compared to CAVEAT. In addition, the preliminary follow-up results of BOAT, presented by Donald S. Baim in Birmingham in August 1996, showed a 20% reduction of angiographic restenosis after DCA compared to PTCA. There was no association between post-procedure CK-MB elevation in the DCA group and late mortality. These results may further expand the application of DCA to clinical routine, whereas this procedure still has specific indications like treatment of ostial and bifurcation lesions and atherectomy in future may be the treatment of choice for restenosis in coronary stents.

Angioplasty, Balloon, Coronary↗

PubMed1997

[Early and long-term results of direct PTCA in patients with acute myocardial infarct].

A review of the literature suggests that direct PTCA for acute myocardial infarction is indicated and feasible in 90-95% of unselected, consecutive patients; direct PTCA is reported to be successful in > 90% of procedures. This results in a hospital mortality of 3-7% for unselected patients and a 4% re-infarction rate. A recent meta-analysis of direct PTCA vs i.v. thrombolysis in patients with acute infarction demonstrates a lower mortality after PTCA (4.4% vs 6.5%, p = 0.02) as well as lower mortality/re-infarction rate (7.2% vs 11.9%, p < 0.001). Mortality in the 1st year after discharge is < 5% with about half of the fatalities being due to cardiac causes. Patients presenting with or developing cardiogenic shock in the acute infarct phase experience a 20-50% acute mortality. Mortality rests at < 10% in these patients in the first year after discharge. In conclusion, (1) direct PTCA is feasible without additional risks in patients with acute myocardial infarction, (2) angiographic and clinical success rates of direct PTCA are favorable and superior to i.v. thrombolysis in the hands of expert operators, and (3) referral to an institution providing the option of immediate, direct PTCA must be considered in the patient with acute infarction but contraindication(s) to i.v. thrombolysis.

Angioplasty, Balloon, Coronary↗

PubMed1997

[Current aspects of thrombolytic therapy in unstable angina pectoris].

In the last years, several studies addressed the role of the different antithrombotic therapeutics in unstable angina pectoris. Acetylsalicylic acid still is the standard treatment reducing the rate of death and myocardial infarction by 50% in the first six months. Ticlopidin has no clinical effect in the first six days and therefore is not suited for treatment in the acute phase. Unfractionated heparin has an additional favourable effect when added to aspirin. Low molecular weight-heparin is at least as effective as UF-heparin. Direct thrombin-inhibitors (hirudin, hirudin-analoga) seem to be comparable to UF-heparin. Plasminogen-activators should not be given in unstable angina, as they show a tendency to worsen the clinical outcome. GP IIb/IIIa-antagonists (antibodies, synthetic antagonists) significantly improve the clinical effects of aspirin. When combined with a reduced dose of heparin, their favourable effect remains unchanged, while bleeding complications are reduced to a minimum.

Angina, Unstable↗

PubMed1997

Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart.

We investigated the potential of inhibition of elastase, a granulocyte-derived proteolytic enzyme, in ameliorating the effects of myocardial stunning caused by repetitive ischaemia (RI) and myocardial infarction (MI) for the first time in an in situ, perfused, rat heart model. The effects of the elastase-inhibitors Elafin (EL, 10 mg/kg/h) and ICI 200,880 (ICI,5 mg/kg/h) on myocardial blood flow (MBF, H2 clearance), regional myocardial function (FT, pulsed doppler) and neutrophil extravasation (myocardial myeloperoxidase activity, MPO) were investigated in RI (5x10 min ligature of the anterior descending ramus (LAD), 5x20 min reperfusion) and MI (50 min LAD ligature, 60 min reperfusion). Under control conditions, MBF and FT were significantly reduced and MPO was significantly increased after RI (n=8) and MI (n=8) in the ischaemic area compared with baseline. Pretreatment with EL (n=7) or ICI (n=7) did not improve MBF significantly and did not influence the successive attenuation of peak values of reactive hyperaemia. However, both EL and ICI significantly improved FT and significantly reduced MPO after RI and MI compared with control conditions. Additionally, both the area at risk and MI size were reduced significantly by both inhibitors. These results demonstrate that elastase inhibitors significantly improve the reduction of FT both in myocardial stunning and in myocardial infarction in the rat without significant improvement of MBF. It is concluded that elastase inhibitors exert a cardioprotective effect against reperfusion injury, probably by inhibition of leukocyte extravasation as indicated by the decrease in MPO activity.

Animals↗

PubMed1997

The expression of angiotensin-I converting enzyme in human atherosclerotic plaques is not related to the deletion/insertion polymorphism but to the risk of restenosis after coronary interventions.

Plasma and tissue concentrations of the angiotensin-I converting enzyme (ACE) have been shown to be associated with the ACE insertion/deletion (I/D) polymorphism. The purpose of this study was to examine the relation of ACE levels in atherosclerotic plaques to the ACE I/D polymorphism and to restenosis after balloon angioplasty and directional atherectomy (DCA). The study included 104 patients who underwent DCA and received angiographic follow-up at 12 to 18 months. The amount of ACE protein in various morphologically defined plaque components (fibrous, atheromatous, and complicated lesions) of the atherectomy specimens was determined by qualitative and semiquantitative immunohistochemistry. ACE levels were related to the ACE genotype, to plaque morphology and to the risk of restenosis. Sequential staining revealed that pathologic ACE overexpression of the atherosclerotic lesions occurred in intimal smooth muscle cells, fibrocytes/fibroblasts and macrophage/foam cells. The ACE content of the whole plaques and of the single plaque components was not associated with the I/D polymorphism, but with restenosis after coronary interventions. In addition, ACE levels in the atherosclerotic lesions correlated with the severity of vessel wall damage. The ACE phenotype might serve as an indicator for the risk of restenosis after coronary interventions.

Angioplasty, Balloon, Coronary↗

PubMed1997

Effect of bradykinin B2-receptor antagonism on post-ischemic coronary reperfusion.

Isolated rabbit hearts in a modified Langendorff preparation were used to study the role of bradykinin B2-receptor antagonism on recovery from cardiac ischemia. The experiments were performed to clarify a potential risk of administrating BK-receptor antagonists in patients with coronary heart disease and patients undergoing heart surgery. The hearts were perfused in an open system at a constant pressure of 70 mm Hg and at a constant temperature of 37 degrees C with Krebs-Henseleit-buffer solution containing 6.5% HAES (hydroxyethyl-amylopectin) and 10 mmol Na-pyruvate/l. The perfusate was equilibrated to a PO2 of about 500-600 mm Hg. After a steady state period of 30 min, coronary perfusion was stopped for 30 min and the hearts were subsequently reperfused for further 30 min. Pretreatment with the B2-receptor antagonist, CP-0127, significantly increased (p < 0.001) the coronary vascular resistance during reperfusion from 31.9 +/- 2.1 to 59.0 +/- 6.5 mm Hg/ml/min/10 g wt and decreased the left ventricular pressure amplitude to 44.0 +/- 15.2% (p < 0.005) of it's baseline. When ischemia was combined with hyperkalaemic cardioplegia, CP-0127 did not influence coronary vascular resistance, but depressed, only to a minor degree, left ventricular pressure amplitude to 65.1 +/- 15.4% (p < 0.005) during reperfusion. Arrhythmias during reperfusion with cardiac arrest occurred only in 2 hearts with B2-receptor inhibition when ischemia was not combined with cardioplegia. Dependent on the initial functional status of the heart B2-receptor inhibition impaired recovery from acute coronary ischemia by increasing the coronary vascular resistance and depressing the myocardial function and therefore may constitute a risk in patients undergoing heart surgery and extracorporeal circulation.

Analysis of Variance↗

PubMed1997

Inappropriate management of self-terminating ventricular arrhythmias by implantable cardioverter defibrillators despite a specific reconfirmation algorithm: a report of two cases.

Algorithms that attempt to reconfirm the presence of an arrhythmia prior to definite treatment have been implemented in ICDs to prevent inappropriate shock therapy due to self-terminating ventricular arrhythmias. Nevertheless, in two patients, clinically inappropriate shocks were delivered after spontaneous conversion of the arrhythmia despite the use of a specific reconfirmation algorithm. Reconfirmation criteria were met due to a premature ventricular complex causing a short cycle in the first patient and a long postextrasystolic pause in the second patient. To avoid inappropriate shock therapy due to self-terminating ventricular arrhythmias, further improvement of detection algorithms is required.

Algorithms↗

PubMed1997

Adaptation of myocardial blood flow to increased metabolic demand is not dependent on endothelial vasodilators in the rat heart.

OBJECTIVE: To investigate the role of endothelial vasodilating factors in adaptation of myocardial blood flow to increased metabolic demands. DESIGN: Alterations in the effects of endothelium dependent (acetylcholine) and independent (sodium nitroprusside) vasodilators and the beta 1 receptor agonist dobutamine were studied after inhibition of endothelium derived relaxing factor (EDRF) with L-NG-nitro-arginine methyl ester (L-NAME), prostanoid synthesis with indomethacin, and ATP sensitive potassium channels with glibenclamide. EXPERIMENTAL ANIMALS: Female Wistar rats, in situ perfused heart. MAIN OUTCOME MEASURES: Myocardial blood flow (H2 clearance); systolic fractional thickening (pulsed Doppler); mean arterial blood pressure. RESULTS: L-NAME reduced myocardial blood flow by 58 (12)% (mean (SD), P < 0.001) and systolic thickening fraction (FT) by 36 (9)% (P < 0.05). These effects were significantly reversed by administration of L-arginine but not D-arginine. Pretreatment with L-NAME inhibited the increase in myocardial blood flow caused by acetylcholine (control: +42 (9)%; L-NAME: -29 (7)%, P < 0.001) but did not affect the increase in myocardial blood flow caused by sodium nitroprusside (control: +44 (5)%; L-NAME: +34 (10)%, NS). Pretreatment with L-NAME did not change the effect of dobutamine on myocardial blood flow (+61 (3)%) and FT (+32 (8)%) compared with baseline values (P < 0.001). Neither pretreatment with indomethacin nor with glibenclamide reduced the dobutamine induced increase in myocardial blood flow. CONCLUSIONS: Inhibition of EDRF, prostanoid synthesis, and ATP sensitive potassium channels did not reduce the vasodilator reserve during increased metabolic demands induced by beta 1 adrenergic stimulation. Therefore, adaptation of myocardial blood flow to increased metabolic demands is independent of endothelial relaxing factors in the rat heart.

Acetylcholine↗

PubMed1997

Positive association of the beta fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction.

BACKGROUND: Fibrinogen has been demonstrated to be an independent risk factor of cardiovascular disease. The absence of the HaeIII cutting site (H2 allele) of an H1/H2 gene variation in the promoter region of the beta fibrinogen gene was associated with increased levels of fibrinogen. METHODS AND RESULTS: In the present study, the effects of the H1/H2 gene variation not only on plasma fibrinogen concentrations but also on coronary artery disease (CAD) and myocardial infarction (MI) were investigated in 923 individuals who underwent coronary angiography for diagnostic purposes. Relation of the H1/H2 genotype to fibrinogen plasma levels: A strong association was observed between the H1/H2 gene variation and fibrinogen levels. The differences in fibrinogen plasma levels between H2H2 and H1H1 homozygotes were almost threefold more pronounced within subjects with clinical chemical signs of an acute phase reaction (CRP > or = 7.5 mg/l) than within a subgroup of subjects without these signs (CRP < 7.5 mg/l) (median of CRP distribution: 7.5 mg/l). In 207 patients who underwent aortocoronary bypass surgery plasma fibrinogen levels were almost identical directly after surgery. Two days after operation fibrinogen increased to clearly higher levels in H2H2 homozygotes than in H1H2 and H1H1 genotypes, whereas almost the same maximal increases in fibrinogen concentrations were reached 3-4 days after surgery in all individuals. Relation of the H1/H2 genotype to CAD and MI. Whereas in the total population the plasma fibrinogen concentrations were strongly associated with smoking, CAD and MI, an association of the H1/H2 gene variation to CAD and MI was not detected. However, mean age at first MI of H2H2 individuals (62.9 years) was clearly higher than of H1H2 genotypes (56.9 years) and of H1H1 subjects (56.4 years). In addition, in a subgroup of individuals with a higher risk of MI by either high apoB and/or low apoA1 plasma levels the portion of MI patients was clearly smaller within H2H2 homozygotes than within H1H2 or H1H1 genotypes, although-also in these high risk groups-mean age at first MI of H2H2 individuals were higher than of the other two genotypes. CONCLUSIONS: Obviously, the H2 allele of the fibrinogen H1/H2 genotype does not only influence basal fibrinogen concentrations, but particularly also the extent of fibrinogen level increase during acute phase reaction. Whereas the fibrinogen plasma level is positively associated with coronary artery disease and myocardial infarction, the H2 allele-although exhibiting an association with elevated fibrinogen levels-was not positively associated with CAD and MI.

Acute-Phase Reaction↗