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Biomedical subjects

Michael Böhm

Publications and source records attributed to Michael Böhm.

At least 73 records · Page 4Linked to original sources
PubMed2004

Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice.

BACKGROUND: Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis. METHODS AND RESULTS: Apolipoprotein E-deficient (ApoE-/-) mice were crossed with AT1A receptor-deficient (AT1-/-) mice to obtain homozygous double-knockout animals (ApoE-/--AT1-/- mice). Wild-type (C57BL/6J), ApoE-/-, AT1-/-, and ApoE-/--AT1-/- mice were fed a high-cholesterol diet for 7 weeks. In contrast to wild-type and AT1-/- mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE-/- mice. In the age-matched ApoE-/--AT1-/- littermates, development of diet-induced endothelial dysfunction and atherosclerotic lesion formation was profoundly inhibited. Concomitantly, aortic release of superoxide radicals was increased 2-fold in ApoE-/- mice compared with wild-type animals, whereas aortic superoxide production was normalized in ApoE-/--AT1-/- mice (L-012 chemiluminescence). There were no significant differences in plasma cholesterol levels between ApoE-/- and ApoE-/--AT1-/- animals. Systolic blood pressure was significantly lower in ApoE-/--AT1-/- animals than in ApoE-/- mice (tail-cuff measurements). Oral treatment of ApoE-/- mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function. CONCLUSIONS: Genetic disruption of the AT1A receptor leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in ApoE-/- mice irrespective of blood pressure and plasma cholesterol levels. These results indicate a fundamental role of AT1 receptor activation in atherogenesis.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Carvedilol but not metoprolol reduces beta-adrenergic responsiveness after complete elimination from plasma in vivo.

BACKGROUND: Carvedilol but not metoprolol exhibits persistent binding to beta-adrenergic receptors (beta-ARs) even after washout in cell culture experiments. Here, we determined the significance of this phenomenon on human beta-ARs in vitro and in vivo. METHODS AND RESULTS: Experiments were conducted on human atrial trabeculae (n=8 to 10 per group). In the presence of metoprolol, isoproterenol potency was reduced compared with controls (P<0.001). In the presence of carvedilol, isoproterenol identified 2 distinct binding sites of high (36+/-6%; -8.8+/-0.4 log mol/L) and low affinity (-6.5+/-0.2 log mol/L). After beta-blocker washout, isoproterenol potency returned to control values in metoprolol-treated muscles, whereas in carvedilol-treated preparations, isoproterenol potency remained decreased (P<0.001 versus control). In vivo studies were performed in 9 individuals receiving metoprolol succinate (190 mg/d) or carvedilol (50 mg/d) for 11 days in a randomized crossover design. Dobutamine stress echocardiography (5 to 40 microg x kg(-1) x min(-1)) was performed before, during, and 44 hours after application of study medication. Beta-blocker medication reduced heart rate, heart rate-corrected velocity of circumferential fiber shortening, and cardiac output compared with baseline (P<0.02 to 0.0001). After withdrawal of metoprolol, all parameters returned to baseline values, whereas after carvedilol, all parameters remained reduced (P<0.05 to 0.001) despite complete plasma elimination of carvedilol. CONCLUSIONS: Carvedilol but not metoprolol inhibits the catecholamine response of the human heart beyond its plasma elimination. The persistent beta-blockade by carvedilol may be explained by binding of carvedilol to an allosteric site of beta-ARs.

Adrenergic alpha-Antagonists↗
PubMed2004

Effect of atorvastatin 80 mg on endothelial cell function (forearm blood flow) in patients with pretreatment serum low-density lipoprotein cholesterol levels <130 mg/dl.

The effect of 6-week treatment with 80 mg/day atorvastatin on vascular function in the forearm was investigated in 18 patients with mean pretreatment serum low-density lipoprotein cholesterol concentrations of 112 +/- 4 mg/dl in a double-blind, placebo-controlled, randomized study. Statin treatment improved hyperemic forearm blood flow and decreased serum markers of oxidative stress and inflammation.

Administration, Oral↗
PubMed2004

[From hypertension to heart failure-a pathophysiological continuum].

The heart failure syndrome is one the most common chronic diseases in western countries with poor prognosis. In view of the estimated aging of our society, it will gain further importance. Hypertension and/or myocardial infarction are the main causes of chronic heart failure, accounting for about three quarters of the cases. In hypertension, pressure overload of the heart leads to an increase in wall stress. This frequently results in cardiac hypertrophy, which is induced by the mechanical stress on the cardiomyocytes and the activation of neuroendocrine mechanisms, particularly the renin-angiotensin-aldosterone system and the sympathetic nervous system. Myocardial hypertrophy represents an independent risk factor for cardiovascular events and is a powerful predictor for the development of heart failure. The signal transduction pathways leading to the transition from compensated hypertrophy to heart failure are subject of intensive research. The knowledge of the maladaptive signaling pathways may be the basis for new therapeutic strategies in the prevention and management of heart failure.

Animals↗
PubMed2004

[Pathophysiology and differential diagnosis of dyspnea].

Dyspnea is the sensation of breathlessness, which is one of a few symptoms described as frightening and alarming. There are different hypotheses of pathophysiological mechanisms explaining a multitude of symptoms described by patients. Objective criteria for this commonly reported symptom do not exist. In general, one differentiates between dyspnea at rest and dyspnea on exertion. This article attempts to summarize the current understanding of dyspnea, explain the essential underlying pathophysiological mechanisms, discuss the broad differential diagnosis, and suggest diagnostic algorithms.

Algorithms↗
PubMed2004

[Polymorphonuclear neutrophils in myocardial ischemia and reperfusion injury. Influence of coronary intervention?].

UNLABELLED: Circulating polymorphonuclear neutrophils (PMNs) are known to contribute to the pathophysiology of myocardial ischemia and reperfusion injury. The present study was designed to examine whether the duration of ischemia in myocardial infarction, the type of coronary intervention (angioplasty vs. angioplasty plus stenting) and duration of the procedure itself modulate the inflammatory responses of PMNs. METHODS AND RESULTS: In patients with acute myocardial infarction (AMI; n = 20) neutrophil beta-2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L) were determined at different time points before and after PTCA or PTCA plus stenting. After PTCA alone but not after PTCA plus stenting a significant rise in Mac-1 (136 +/- 43%) was demonstrated. This elevation decreased after 60 minutes if the duration of the recanalization procedure was shorter than 30 minutes but remained elevated after longer interventions. After delayed intervention a significant and more pronounced increase of Mac-1 (142 +/- 37%) was observed, while early intervention prevented this increase. After PTCA alone or delayed intervention a significant shedding of L-selectin (77 +/- 20%; 77 +/- 23%) was demonstrated. Early intervention or PTCA plus stenting caused no significant changes in L-selectin. CONCLUSIONS: It is concluded that PMN activation is attenuated by early and short intervention as well as by stenting. Induction of PMN activation might contribute to the superior outcome following stenting and early intervention compared to conventional PTCA in particular when performed delayed.

Age Factors↗
PubMed2004

Changes of blood pressure and left ventricular mass in pediatric renal transplantation.

Cardiovascular events are among the most frequent causes for long-term morbidity and mortality in children after renal transplantation. The aim of this study was to analyze the effects of post-transplant changes in arterial hypertension, as assessed by 24-h ambulatory blood pressure measurement (ABPM), on myocardial architecture, as assessed by echocardiography. In a retrospective chart review analysis, 39 children were identified in whom 24-h ABPM and echocardiography had been assessed within a 3-month interval after a mean of 4 years post transplantation; 20 repeated pairs of measurements after a mean of 2 years of follow-up were available to analyze the longitudinal effects of post-transplant changes of blood pressure control on left ventricular mass index (LVMI). Arterial hypertension (59%) and left ventricular hypertrophy (50%) were highly prevalent in children after renal transplantation. Renal allograft function and number of antihypertensive medications, but not ABPM variables, were correlated with LVMI at the initial observation. However, at repeat assessment, a significant correlation between ABPM and LVMI was found. In the longitudinal assessment, left ventricular remodeling was dependent on change of dosage of cyclosporine and interval changes of blood pressure levels. Hence, control of blood pressure correlates with changes of LVMI in children with renal allografts. These results clearly underline the importance of blood pressure control for the maintenance of the myocardial architecture.

Adolescent↗
PubMed2004

Clinical value of routine predischarge testing after ICD-implantation.

AIMS: After implantation of a cardioverter/defibrillator (ICD) predischarge testing is often performed to ensure appropriate therapy function. Nevertheless there is no proven evidence for the necessity of this examination. In this retrospective single-centre analysis we investigated the clinical value of routine predischarge testing. METHODS AND RESULTS: Predischarge testing was performed in 161 patients 6+/-2 days after primary implantation of an ICD. There were no complications related to ICD-testing. In 17 of 161 patients (11%) there was at least one pathological finding. In 4 of 17 patients we observed a defibrillation energy requirement (DER) with a safety margin of less than 10J. In two of these patients an early lead repositioning was undertaken and in two patients reversal of the shock polarity was used to achieve an adequate DER. In 13 of 17 patients we detected a distinct deviation of pacing thresholds or R-wave sensing amplitudes. In two of these patients an early electrode repositioning was performed because of lead displacement. In the remaining 11 patients we found an adequate DER at first, whereas in two patients a further lead repositioning was still necessary during follow-up. In 144 of 161 patients (89%) predischarge testing was without pathological findings. None of these patients needed revision of the ICD-lead during a mean follow-up of 24+/-13 months. CONCLUSIONS: Abnormal measurements during predischarge testing are not rare findings in ICD-recipients. Noninvasive methods cannot rule out inadequate defibrillation function. A normal predischarge test seems to be a reliable predictor for a stable electrode function during the first years of follow-up.

Defibrillators, Implantable↗
PubMed2004

Impact of biphasic electrical cardioversion of atrial fibrillation on early recurrent atrial fibrillation and shock efficacy.

INTRODUCTION: Early recurrent atrial fibrillation (ERAF) after external cardioversion of atrial fibrillation (AF) occurs in 12% to 26% of patients. Whether biphasic cardioversion has an impact on the incidence of ERAF after cardioversion of AF is unclear. METHODS AND RESULTS: Consecutive patients (n = 216, mean age 66 years, 71% male, 88% with structural cardiovascular disease or hypertension) underwent cardioversion with a biphasic (Bi) or monophasic (Mo) shock waveform in randomized fashion. Energies used were 120-150-200-200 Ws (Bi) or 200-300-360-360 Ws (Mo). The two study groups (Bi vs Mo) did not differ with regard to age, sex, body mass index, underlying cardiovascular disease, left atrial diameter, left ventricular ejection fraction, duration of AF fibrillation, and antiarrhythmic drug therapy. Mean delivered energy was significantly lower in the Bi group (Bi: 186 +/- 143 Ws vs Mo: 324 +/- 227 Ws; P < 0.001). Overall incidence of ERAF (AF relapse within 1 minute after successful cardioversion) was 8.9% and showed no difference between the two groups (Bi: 8.1% vs Mo: 9.7%, P = NS). Cardioversion was successful in 95.4% of patients. The success rate was comparable in both groups (Bi: 94.3% vs Mo 96.8%; P = NS). First shock efficacy did not differ between Bi and Mo (76.4% vs 67.7%; P = NS). Mean number of shocks were 1.4 shocks per patient in both groups. CONCLUSION: Biphasic cardioversion allows comparable success rates with significantly lower energies. However, the incidence of ERAF is not influenced by biphasic cardioversion. With the energies used, biphasic and monophasic shock waveforms are comparable with regard to first shock and cumulative shock efficacy.

Aged↗
PubMed2004

Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms.

OBJECTIVES: Variable expression of the ABC-type multidrug resistance membrane protein P-glycoprotein (P-gp, MDR1, ABCB1) in human heart is a potential modulator of drug effects or drug-induced cardiotoxicity. Expression of P-gp is known to be affected by single nucleotide polymorphisms in the MDR1 gene. Therefore, genotype-dependent expression of P-gp could be an important modulator of action of cardiac drugs. METHODS: Heart tissue (auriculum) from 51 patients undergoing coronary artery bypass graft surgery was screened for genotype-dependent P-gp expression. P-gp was identified by immunoblotting and localized using immunohistochemistry. MDR1 mRNA was quantified by real-time PCR and immunohistochemistry and related to the MDR1 genotypes G2677T/A (Ala893Ser/Thr) and C3435T. RESULTS: MDR1/18S rRNA mRNA copy numbers in heart auriculum were 3.48 +/- 2.25 x 10(-6) compared to 4.56 +/- 0.58 x 10(-6) in non-failing ventricular samples studied before. While the exon 26 C3435T genotype did not influence MDR1 mRNA expression, we found significantly elevated MDR1 mRNA expression in 10 patients carrying the exon 21 2677 AT or TT genotype as compared to 12 patients carrying the GG-variant with intermediate MDR1 mRNA expression in 29 heterozygous samples. P-gp was detected in the endothelial wall. Quantitative immunohistochemistry of protein expression, however, did not reveal significant influence of the studied SNPs. CONCLUSION: The present study based on auricular samples suggests that genetic factors play a rather limited role in modulating P-gp expression in human heart. Therefore, the substantial interindividual variability in cardiac P-gp expression is likely related to environmental or disease related factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

The Arg389Gly beta1-adrenoceptor gene polymorphism determines contractile response to catecholamines.

OBJECTIVES: Recently, the Arg389Gly beta1-adrenoceptor (beta1AR) gene polymorphism has been detected. The Arg variant exhibited increased responsiveness to agonist-induced stimulation in vitro. Functional studies in isolated human atrial muscle strips and in-vivo studies revealed contradictory results regarding the functional relevance of this polymorphism. We sought to characterize the functional consequences of the Arg389Gly beta1-AR polymorphism in 30 consecutive healthy male volunteers in vivo. METHODS: beta1-AR genotype was determined by PCR and restriction analysis, which was confirmed by DNA sequencing. We compared heart rate, blood pressure, and contractile response of the various genotype carriers with a modified dobutamine stress echocardiography protocol. RESULTS: Subjects homozygous for the Arg389 beta1AR showed a significantly higher increase in fractional shortening upon cumulative doses of dobutamine as compared to subjects carrying one or two copies of the Gly389 allele. A statistically significant difference was observed at a dobutamine dose of 10 microg/kg/min (46.5 +/- 1.3 vs. 41.8 +/- 1.0 %; P = 0.023) and was maximal at 40 microg/kg/min (61.9 +/- 1.4 vs. 52.8 +/- 1.6; P = 0.001). As a result, the systolic blood pressure response to dobutamine was significantly enhanced in individuals homozygous for the Arg389 allele, whereas the effect on heart rate did not differ between the two groups. Normalization for changing afterload conditions by calculating the pressure-dimension ratio revealed similar effects, indicating that the beta1AR-mediated effects are mainly a result of increased myocardial inotropy. CONCLUSION: These data indicate that the Arg389Gly beta1AR polymorphism is functionally relevant in vivo and determines contractile responsiveness to catecholamines in humans.

Arginine↗
PubMed2004

The role of olmesartan medoxomil in the management of hypertension.

Intensive blood pressure control is a desirable and obtainable goal in patients with hypertension, according to the most recent treatment guidelines from Europe and the US. Achieving target blood pressure depends on the efficacy of antihypertensive treatment and patient compliance. Olmesartan medoxomil, a non-peptidergic angiotensin AT1 receptor antagonist, has been shown to be effective and well tolerated. Continuation of initial treatment is higher with AT1 receptor antagonists than for any other class of antihypertensive drugs. Olmesartan medoxomil may also have end-organ protective effects that provide additional clinical benefit. Optimal blood pressure control may be achieved faster if initial treatment contains the most efficacious and well tolerated antihypertensive drug or drugs. The ongoing European study, known as OLMEBEST (Efficacy and safety of OLMEsartan: reduction of Blood pressure in the treatment of patients suffering from mild to moderate ESsenTial hypertension), will provide important information on the use of olmesartan medoxomil as an initial treatment for hypertension.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.

Angiotensin II type 1 (AT1) receptor activation as well as proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the development and progression of atherosclerosis. The detailed underlying mechanisms including interactions between inflammatory agonists and the renin-angiotensin system are poorly understood. Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments. Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT1 receptor mRNA de novo synthesis but not mRNA stability. Preincubation of VSMCs with IL-6 resulted in an enhanced angiotensin II-induced production of reactive oxygen species, as assessed by DCF fluorescence laser microscopy. Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation. These effects were completely omitted in AT1 receptor knockout mice (AT1A-/- mice). Upregulation of vascular AT1 receptor expression in vitro and in vivo is decisively involved in IL-6-induced propagation of oxidative stress and endothelial dysfunction. This interaction of the proinflammatory cytokine IL-6 with the renin-angiotensin system may represent an important pathogenetic mechanism in the atherosclerotic process.

Animals↗
PubMed2003

Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis.

BACKGROUND: The molecular mechanisms by which physical training improves peripheral and coronary artery disease are poorly understood. Bone marrow-derived endothelial progenitor cells (EPCs) are thought to exert beneficial effects on atherosclerosis, angiogenesis, and vascular repair. METHODS AND RESULTS: To study the effect of physical activity on the bone marrow, EPCs were quantified by fluorescence-activated cell sorter analysis in mice randomized to running wheels (5.1+/-0.8 km/d, n=12 to 16 per group) or no running wheel. Numbers of EPCs circulating in the peripheral blood of trained mice were enhanced to 267+/-19%, 289+/-22%, and 280+/-25% of control levels after 7, 14, and 28 days, respectively, accompanied by a similar increase of EPCs in the bone marrow and EPCs expanded from spleen-derived mononuclear cells. eNOS-/- mice and wild-type mice treated with N(G)-nitro-l-arginine methyl ester showed lower EPC numbers at baseline and a significantly attenuated increase of EPC in response to physical activity. Exercise NO dependently increased serum levels of vascular endothelial growth factor and reduced the rate of apoptosis in spleen-derived EPCs. Running inhibited neointima formation after carotid artery injury by 22+/-2%. Neoangiogenesis, as assessed in a subcutaneous disc model, was increased by 41+/-16% compared with controls. In patients with stable coronary artery disease (n=19), moderate exercise training for 28 days led to a significant increase in circulating EPCs and reduced EPC apoptosis. CONCLUSIONS: Physical activity increases the production and circulating numbers of EPCs via a partially NO-dependent, antiapoptotic effect that could potentially underlie exercise-related beneficial effects on cardiovascular diseases.

Aged↗
PubMed2003

Urotensin II causes fatal circulatory collapse in anesthesized monkeys in vivo: a "vasoconstrictor" with a unique hemodynamic profile.

Urotensin II (UII) is a vasoactive peptide that has recently emerged as a likely contributor to cardiovascular physiology and pathology. Acute infusion of UII into nonhuman primates results in circulatory collapse and death; however, the exact cause of death is not well understood. This study was undertaken to elucidate the mechanism underlying the fatal cardiovascular event on UII application in vivo in nonhuman primates. To this end, cynomolgus monkeys (n = 4) were anesthetized and tracheal intubation was performed. One internal jugular vein was cannulated for administration of drugs, and one femoral artery for recording of blood pressure and heart rate using a transonic pressure transducer. Cardiac parameters were not significantly changed after administration of 0.003 nmol/kg human UII. A bolus of human UII (0.03 nmol/kg) caused a decrease of heart rate (HR) (13%), mean blood pressure (MBP) (18%), and first-order derivative of left ventricular pressure (dP/dt) (11%). Carotid and coronary blood flow were reduced by 9% and 7%, respectively; 0.3 nmol/kg of human UII resulted in a further reduction of HR (50.3%), MBP (65%), dP/dt (45%), carotid (38%), and coronary blood flow (30%), ultimately leading to cardiovascular breakdown and death. Pulmonary pressure, however, was increased by 30%. Plasma histamine levels were found to be unaffected by administration of UII. Our results indicate that systemic administration of human UII has negative inotropic and chronotropic effects and reduces total peripheral resistance ultimately leading to severe myocardial depression, pulmonary hypertension, and fatal circulation collapse in nonhuman primates. We suggest that successful design of UII antagonists might offer a new therapeutic principle in treating cardiovascular diseases.

Anaphylaxis↗
PubMed2003

Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation.

OBJECTIVES: The present study was designed to test the efficacy of paclitaxel added to the contrast agent iopromide in the prevention of restenosis. BACKGROUND: Contrast media adhere to the coronary vessel wall for some seconds after injection. Such a layer of contrast agent could serve as a matrix for antiproliferative drugs. METHODS: Thirty-four stents were implanted into the left anterior descending and circumflex coronary arteries of 17 pigs, using a 1.2:1.0 overstretch ratio. The unsupplemented contrast agent iopromide-370 was used as a control; the treatment groups were treated with 80 ml intracoronary iopromide plus either 100 or 200 mumol/l paclitaxel, or 80 ml intravenous iopromide plus 200 mumol/l paclitaxel. Quantitative angiography and histomorphometry were used to assess comparable baseline parameters between the treatment groups. RESULTS: A short time incubation (3 min) almost completely inhibited vascular smooth muscle cell proliferation, sustained for up to 12 days. Whereas intravenous paclitaxel had no effect, intracoronary application of paclitaxel reduced the diameter stenosis from 55 +/- 13% to 29 +/- 18% and 13 +/- 12%. Late lumen loss dropped from 1.94 +/- 0.35 mm under the control condition to 1.19 +/- 0.55 mm with 100 mumol/l paclitaxel and to 0.82 +/- 0.54 mm with 200 mumol/l paclitaxel. Histomorphometry revealed a corresponding dose-dependent reduction of the neointimal area and restenosis by intracoronary iopromide paclitaxel. Assessment of left ventricular function and myocardial histology revealed no adverse effects of intracoronary paclitaxel application. CONCLUSIONS: This study provides evidence that intracoronary application of a taxane dissolved in a contrast medium profoundly inhibits in-stent restenosis. This novel, widely feasible approach may be suited for the prevention of restenosis in a broad spectrum of interventional treatment regimens.

Animals↗