Medical graphics to improve patient understanding and anxiety in elderly and cognitively impaired patients scheduled for transcatheter aortic valve implantation (TAVI).

BACKGROUND: Anxiety and limited patient comprehension may pose significant barriers when informing elderly patients about complex procedures such as transcatheter aortic valve implantation (TAVI). OBJECTIVES: We aimed to evaluate the utility of medical graphics to improve the patient informed consent (IC) before TAVI. METHODS: In this prospective, randomized dual center study, 301 patients were assigned to a patient brochure containing medical graphics (Comic group, n = 153) or sham information (Control group, n = 148) on top of usual IC. Primary outcomes were patient understanding of central IC-related aspects and periprocedural anxiety assessed by the validated Spielberger State Trait Anxiety Inventory (STAI), both analyzed by cognitive status according to the Montreal Cognitive Assessment (MoCA). RESULTS: Patient understanding was significantly higher in the Comic group [mean number of correct answers 12.8 (SD 1.2) vs. 11.3 (1.8); mean difference 1.5 (95% CI 1.2-1.8); p < 0.001]. This effect was more pronounced in the presence of cognitive dysfunction (MoCA < 26) [12.6 (1.2) in the Comic vs. 10.9 (1.6) in the Control group; mean difference 1.8 (1.4-2.2), p < 0.001]. Mean STAI score declined by 5.7 (95% CI 5.1-6.3; p < 0.001) in the Comic and 0.8 points (0.2-1.4; p = 0.015) in the Control group. Finally, mean STAI score decreased in the Comic group by 4.7 (3.8-5.6) in cognitively impaired patients and by 6.6 (95% CI 5.8 to 7.5) in patients with normal cognitive function (p < 0.001 each). CONCLUSIONS: Our results prove beneficial effects for using medical graphics to inform elderly patients about TAVI by improving patient understanding and reducing periprocedural anxiety (DRKS00021661; 23/Oct/2020). Medical graphics entailed significant beneficial effects on the primary endpoints, patient understanding and periprocedural anxiety, compared to the usual patient informed consent (IC) procedure. Patient understanding of IC-related aspects was significantly higher in the Comic group, with a more pronounced benefit in patients with cognitive impairment (p for IC method and cognitive status < 0.001, respectively; p for IC method x MoCA category interaction = 0.017). There further was a significant decline of periprocedural anxiety in patients with and without cognitive impairment (p for IC method x measuring time point < 0.001; p for IC method x MoCA category x measuring time point interaction = 0.018).

Informed Consent before coronary angiography and percutaneous coronary intervention from the patient's perspective: A picture is worth a thousand words.

Background: Patients scheduled for coronary angiography may feel insufficiently informed about the planned procedure. We aimed to evaluate the patient-rated quality of the Informed Consent (IC) process and to investigate the efficacy of medical graphics to assist and improve the IC procedure. Methods: A graphic-based information broschure illustrating central steps of the procedure was created in collaboration with scientific illustrators. In a randomized, controlled, prospective trial, 121 patients undergoing coronary angiography/PCI were randomized to a group obtaining the usual IC (Control group) or to a group that additionally obtained a graphic-based IC (Comic group). The perceived quality of the IC was compared between groups using single items of the Client Satisfaction Questionnaire-8 and self-designed single items. Results: Only 67.8% of patients stated to have completely read the standard written IC sheet. The quality of the IC was perceived to be very good in 45.0% of patients in the Comic group compared to 24.6% in the Control group (p =.023). 57.4% of the Control group compared to 76.7% of the Comic group stated that all of their questions were satisfactorily adressed (p =.015). 43.3% of the Comic group, in contrast to only 18.0% of the Control group, declared to feel "very satisfied" with the obtained IC procedure (p =.002). The acceptance of this new IC approach was very high: no patient expressed feelings of not being taken seriously when reading medical graphics. Conclusions: Our data confirm pronounced limitations of the usual IC practice. The use of medical graphics positively impacts on patient-evaluated endpoints and may significantly improve the IC procedure.

RAGE-dependent regulation of calcium-binding proteins S100A8 and S100A9 in human THP-1.

Proinflammatory cell activation via the receptor for advanced glycation end products (RAGE) pathway may play a central pathogenetic role in atherosclerosis. Since S100A8/A9 was recently identified as ligand of RAGE, we determined the effects of proinflammatory cytokines on RAGE-mediated induction of gene expression of S100A8 and S100A9. mRNA levels of S100A8 and S100A9 were upregulated following cytokine stimulation with IL-6 (1, 10, 100 ng/ml) or TNFα (10 ng/ml) in human THP-1 cells. Preincubation of cells with 2000 ng/ml AGE (advanced glycation end products) before cytokine stimulation resulted in upregulation of RAGE. Pretreatment of THP-1 with AGE followed by stimulation with IL-6 (10 ng/ml) or TNFα (10 ng/ml) further increased S100A8 and S100A9 mRNA expression and S100A8/A9 release into cell culture supernatant, as compared to pretreatment with non-glycated albumin as control. Binding of AGE to RAGE was blocked with a neutralizing anti-RAGE antibody. Normal mouse IgG served as control. Cytokine-stimulated induction of S100A8 and S100A9 mRNA levels as well as of S100A8/A9 release after preincubation of cells with AGE were significantly suppressed by RAGE blockade, indicating a RAGE-dependent pathway of AGE-mediated S100A8/A9 expression.The cytokine-induced potentiated S100A8 and S100A9 expression under conditions with a high AGE burden is able to aggravate proinflammatory conditions via activation of the RAGE pathway.

[Management of cardiac high risk pregnancy. Caesarean section in a primagravida with cyanotic cardiac defect]. / Management bei kardialer Hochrisikoschwangerschaft. Sectio bei einer I. Gravida mit zyanotischem Vitium.

A 37-year-old gravida I with cyanotic heart disease presented for caesarean section in the 31st week of gestation. Caesarean section was performed uneventfully with the patient under epidural anaesthesia accompanied by invasive monitoring. Postoperative echocardiography showed no change in the shunt fraction, volumes or the ventricular function. Every patient with complex comorbidities has to be managed according to individual prerequisites and the experiences and preferences of the team. For such high risk pregnancies regional anaesthesia seems to be a possible option although no clear evidence can be found in the literature.

Cessation of pulmonary and coronary secretion of adrenomedullin peptides in the progression of human heart failure.

In human heart failure (CHF), adrenomedullin (AM) counteracts vasoconstriction and sodium retention. We investigated circulating levels of proadrenomedullin N-20 peptide (PAMP) and AM, and left ventricular expression of preproAM and calcitonin receptor-like receptor (CRLR) mRNA. Peptide levels were determined from the left ventricle, pulmonary artery, coronary sinus, and antecubital vein in patients demonstrating severe CHF (n = 12; mean +/- SEM cardiac index, 1.9 +/- 0.2 l/min/m(2); pulmonary wedge pressure, 32 +/- 1 mmHg), moderate CHF (n = 11; cardiac index, 2.9 +/- 0.2; pulmonary wedge pressure, 14 +/- 2), and in controls (n = 11). Left ventricular mRNA was quantified using RT-PCR and Southern blot hybridization. Depending on sites of measurement, PAMP and AM in severe CHF were 1.3 - 2.0 and 1.2 - 1.9 times as high as in moderate CHF, and 3.8 - 4.6 and 2.3 - 2.8 times as high as in controls. Only patients with moderate CHF demonstrated pulmonary and coronary net release of both peptides, that is, significant step-ups in concentrations between the pulmonary artery, left ventricle, and coronary sinus. In failing ventricles, preproAM mRNA increased 2.9 times above control, but CRLR mRNA was unchanged. Altogether, the heart and the lungs release AM peptides in moderate CHF. This secretion breaks down in severe CHF: a process that may contribute to and indicate decompensation. Unlike AM, the CRLR is not transcriptionally upregulated in severe CHF.

Computer-aided measurement of cell shortening and calcium transients in adult cardiac myocytes.

The contractile cycle of the cardiac myocyte is essentially controlled by the concentration of intracellular calcium ([Ca2+]i). Measurement of [Ca2+]i using Ca2+-dependent fluorescence and simultaneous monitoring of cell dynamics enable characterization of a variety of substances interacting with ion channels and contractile proteins. In this report we describe a novel method featuring up to 480 frames/s for monitoring rapid changes in cellular calcium and cell length, in which every individual cycle allows effective evaluation of major cell parameters. Computers aid in determination of time to peak (in ms), time to 50% decrease (ms), diastolic Ca2+ (relative fluorescence units, rfu), systolic Ca2+ (rfu), Ca2+ transients (rfu), DeltaCa2+/Delta(t) rise (rfu/s), and DeltaCa2+/Delta(t) fall (rfu/s). Contractile parameters are as follows: maximum cell length (microm), minimum cell length (microm), absolute cell shortening (microm), peak DeltaL/Delta(t) shortening (microm/s), and peak DeltaL/Delta(t) relaxation (microm/s). In summary, we succeeded in demonstrating that this system is a unique and valuable tool that allows simultaneous and accurate assessment of contractile parameters and of calcium movements of isolated adult cardiac myocytes.

Acute hemodynamic effects of beta-blockers in patients with severe congestive heart failure: comparison of celiprolol and esmolol.

The present study was designed to investigate, in patients with severe heart failure, the dose-dependent acute hemodynamic effects of celiprolol versus those of esmolol. Celiprolol is a beta 1 -receptor blocker with vasodilating properties, whereas esmolol is an ultra-short-acting beta 1 -blocker. Included were 14 patients with decompensated chronic heart failure (NYHA class IV) due to coronary heart disease (n = 8) or to dilated cardiomyopathy (n = 6). Each patient received both celiprolol and esmolol in random fashion. The beta-blockers were administered in four dose tiers, with an increase in dosage every 15 min. Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. Administration of celiprolol (5, 10, 20, and 50 microg/kg) took place intravenously. After intravenous administration of a loading dose of 500 microg/kg, we continuously infused esmolol at increasing doses, which were individually titrated for each patient. Mean infusion rates of esmolol were as follows: 40, 75, 140, and 230 micromol/kg per minute. Celiprolol and esmolol induced a comparable dose-dependent decrease in heart rate to a minimum of -10% below baseline. Esmolol caused a significant dose-dependent decrease (-25% below baseline at the highest dose level) in cardiac index (CI). After administration of celiprolol, CI decreased only transiently (-10% below baseline at the second and third dose level) and did not differ from the baseline at the highest dose level. For treatment of severe heart failure, initiation of intravenous beta-blocker therapy with low doses of a beta 1 -blocker with vasodilating effects may have hemodynamic advantages over conventional beta-blockade.

Role of Kozak sequence polymorphism of platelet glycoprotein Ibalpha as a risk factor for coronary artery disease and catheter interventions.

OBJECTIVES: We sought to determine the role of the -5T/C polymorphism of the platelet glycoprotein (GP) Ibalpha as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention. BACKGROUND: The platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The -5T/C polymorphism of GP Ibalpha is associated with increased receptor density. METHODS: We genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death. RESULTS: Carriers of the -5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The -5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029). CONCLUSIONS: The -5C allele of the GP Ibalpha Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA.

beta(1)-Adrenoceptor antibodies induce positive inotropic response in isolated cardiomyocytes.

beta(1)-Adrenoceptor autoantibodies are present in approximately 30% of patients suffering from dilated cardiomyopathy. The inotropic effects mediated by these antibodies remain to be studied. Monoclonal antibodies were raised against a peptide corresponding to the second extracellular loop of the human beta(1)-adrenoceptor in balb/C mouse (n=6), and were characterized by enzyme immunoassay after purification by protein A. Purified immunoglobulin G from non-immunized animals (controls) did not influence Ca(2+) transient and cell shortening of rat cardiomyocytes measured by confocal-laser-scanning-microscopy. beta(1)-adrenoceptor antibodies caused a dose-related increase in Ca(2+) transient (dilution 1:2: +35.3+/-5.1%), and in cell shortening (dilution 1:2: +40.5+/-6.3%) (P<0.01 vs. controls). The effect of the beta(1)-adrenoceptor antibodies was blocked by the antigenic peptide and by the antagonist metoprolol. In addition, beta(1)-adrenoceptor antibodies induced a dose-dependent increase of the cyclic adenosine monophosphate. The inotropic response induced by isoproterenol was attenuated by the beta(1)-adrenoceptor antibody. beta(1)-adrenoceptor antibodies as partial agonists induce a specific positive inotropic effect via the protein-kinase-A-cascade.

Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution.

BACKGROUND: Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction. METHODS AND RESULTS: From 25 DCM patients (EF <30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (<7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3+/-1.7% (+/-SEM) to 27.0+/-1.3% (P<0.01 versus baseline/controls) and reduction of the beta-receptor autoantibody serum levels (P<0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7+/-0.8 to 2.9+/-0.5 cells/mm(2) (P<0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 (P<0.01 versus baseline/controls) and CD8 (P<0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen-positive cells (leukocytes) was reduced from 20.0+/-3.2 to 9.9+/-2.8 cells/mm(2) (P<0.01 versus baseline/P<0.05 versus controls). HLA class II expression decreased from 2.1+/-0.7% to 1.1+/-0.4% (P<0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged. CONCLUSIONS: IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.

Pulmonary adrenomedullin counteracts deterioration of coronary flow and myocardial performance evoked by pulmonary endothelins in experimental acute respiratory distress syndrome.

OBJECTIVES: We recently showed that pulmonary endothelins may affect coronary circulation under various experimental and clinical conditions. Here, we investigated the effect of pulmonary mediators on coronary tone in experimental acute respiratory distress syndrome. We focused particularly on pulmonary endothelin-1, a major vasoconstrictor in acute respiratory distress syndrome, and on adrenomedullin, a potent vasodilator that is up-regulated by inflammatory stimuli. DESIGN: Controlled experiment that used isolated organs. SETTING: Experimental laboratory. SUBJECTS: Wistar rats. INTERVENTIONS: The saline effluent from an isolated lung was used to serially perfuse the coronary vessels of an isolated heart. We compared serial perfusion after 2-hr pretreatment of lungs with vehicle or endotoxin (50 microg/mL), and we used the following drugs to elucidate the coronary response observed: the endothelin type A receptor antagonist BQ-123 (2 microM), the endothelin type B antagonist A-192621 (500 nM), the endothelin-converting enzyme inhibitor phosphoramidon (50 microM), the calcitonin gene-related peptide type-1 receptor antagonist hCGRP(8-37) (2 microM), and the adrenomedullin receptor antagonist hAM(22-52) (200 nM) (n = 6 each). MEASUREMENTS AND MAIN RESULTS: In controls, serial perfusion decreased coronary flow to 87 +/- 3% of baseline (p < .05). BQ-123 and phosphoramidon prevented this effect, whereas blockade of endothelin type B and adrenomedullin-binding receptors had no effect. After endotoxin challenge, coronary flow significantly increased to 110 +/- 2%. This response was augmented by BQ-123 (124 +/- 2%) and phosphoramidon (123 +/- 3%); A-192621 had no effect. Application of hCGRP(8-37) and hAM(22-52) significantly decreased coronary flow to 81 +/- 3% and 88 +/- 2%, respectively. Flow decrease after blockade of both adrenomedullin-binding receptors (73 +/- 2%) significantly deteriorated peak left ventricular pressure, to 82 +/- 6% of baseline; rate of pressure increase, to 81 +/- 5%; and rate of pressure decline, to 77 +/- 6%. Endotoxin pretreatment elevated pulmonary venous big endothelin-1 (three-fold), endothelin-1 (two-fold), and adrenomedullin (five-fold). CONCLUSION: In experimental acute respiratory distress syndrome, pulmonary adrenomedullin--via calcitonin gene-related peptide type-1 receptor and adrenomedullin receptor--outweighs the coronary vasoconstrictor impact of pulmonary big endothelin-1 exerted via endothelin type A receptors after conversion to mature endothelin-1. The consequence is prevention of flow-related deterioration of myocardial performance.

[Pregnancy risks in acquired heart diseases]. / Schwangerschaftsrisiken bei erworbenen Herzerkrankungen.

Optimal management of pregnancies for patients with acquired heart disease requires exact knowledge of the hemodynamic influence of pregnancy-related cardiovascular adaptation processes on the heart disease. Maternal and fetal risks must be carefully considered and mutually weighed. Critical time periods, during which closely networked, interdisciplinary support for the patient is essential, are primarily during the 30th to 32nd week of pregnancy. This is the period in which maximum increases in heart rate, cardiac output, and plasma volume are observed. The peripartal phase represents another critical period. Owing to the mechanically related fixation of cardiac output, stenotic valvular diseases are generally tolerated much poorer than are valvular insufficiency defects. Therapeutic objectives are reduction in heart rate and--in cases of pulmonary-venous congestion--decrease in preload. Vaginal deliveries are possible with slight to moderate valvular stenosis; cesarean section is to be preferred in more severe cases. In patients with valvular insufficiency and normal left ventricular function pregnancy is usually well tolerated. Reduction in regurgitation is even often observed owing to pregnancy-induced decrease in peripheral vascular resistance. Since ACE inhibitors and AT1 antagonists are contraindicated during pregnancy, afterload reduction can be achieved by a combination of hydralazin and nitrates, or calcium antagonists. Peripartal cardiomyopathy is rare and is associated with a high degree of maternal mortality (25-50%). Apart from the necessary consideration of pregnancy-related contraindications, therapeutic principles do not differ from those for other forms of heart failure. Most patients exhibiting hypertrophic obstructive cardiomyopathy satisfactorily pass through their pregnancies. Individual cases have been described, however, of both pregnancy-related cardiac decompensation as well as sudden death. Aortal and coronary-arterial dissections represent rare, life-endangering complications for mother and fetus: these developments can occur among predisposed patients as a result of the hormonal and hemodynamic adaptation processes during pregnancy. Close interdisciplinary collaboration and tightly networked support for patients are the prerequisite for successful management of high-risk pregnancies involving maternal heart disease.

The beta3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease.

There is some evidence that the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) is associated with atherogenic risk factors that include weight gain, insulin resistance, and diabetes. The objective of this cross-sectional study was to investigate the relationship between the Trp64Arg polymorphism and coronary artery disease (CAD). A total of 1,000 consecutive patients with angiographically confirmed CAD and 1,000 controls, carefully matched for age and sex, were genotyped for the Trp64Arg polymorphism by polymerase chain restriction and subsequent restriction fragment length polymorphism analysis. Among cases with CAD, 83.3% were wild-type Trp/Trp, 15.8% were heterozygotes, and 0.9% were homozygous Arg/Arg compared with 82.3%, 17.3%, and 0.4%, respectively, among controls (P = .27). The odds ratios for the presence of Trp/Arg and Arg/Arg in cases and controls were 0.90 (95% confidence interval [CI] 0.7 to 1.2; P = .40) and 2.2 (95% CI 0.7 to 7.2; P = .17), respectively. There was no effect modification by gender and atherogenic risk factors, including diabetes, hypercholesterolemia, hypertension, and smoking. Furthermore, there was no evidence of an association with premature disease onset (< 40 years) or extent of disease. In conclusion, the results of this study in a large sample of clinically well-characterized patients indicate that neither the Trp/Arg nor the Arg/Arg genotype represents a major risk factor for angiographically confirmed coronary artery disease.

Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C). The frequencies were *1: 36.4 and 34.4%; *2: 30.8 and 32.3%; and *3: 32.8 and 33.3%, in cases and controls, respectively. Only one patient was heterozygous for 1317C. None of the six resulting genotypes showed significant influence on tHcy levels. Moreover, there was no significant association with CAD risk or with disease severity or early disease manifestation. In the subgroup presenting with acute coronary syndromes, MTHFR genotypes *2/*3 and *3/*3 were surprisingly underrepresented (relative risk of *3/*3, 0.40; 95% confidence interval 0.20-0.79, P=0.009). We conclude from our genotype-based analysis that, in this well-fed Middle-European population, the observed common allelic variants of the MTHFR gene have no significant influence on tHcy levels or on the chronic process of CAD development.

Soluble substances released from postischemic reperfused rat hearts reduce calcium transient and contractility by blocking the L-type calcium channel.

OBJECTIVES: This study was designed to investigate the effects of cardiodepressant substances released from postischemic myocardial tissue on myocardial calcium-regulating pathways. BACKGROUND: We have recently reported that new cardiodepressant substances are released from isolated hearts during reperfusion after myocardial ischemia. METHODS: After 10 min of global ischemia, isolated rat hearts were reperfused, and the coronary effluent was collected for 30 s. We tested the effects of the postischemic coronary effluent on cell contraction, Ca2+ transients and Ca2+ currents of isolated rat cardiomyocytes by applying fluorescence microscopy and the whole-cell, voltage-clamp technique. Changes in intracellular phosphorylation mechanisms were studied by measuring tissue concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), as well as activities of cAMP-dependent protein kinase (cAMP-dPK) and protein kinase C (PKC). RESULTS: The postischemic coronary effluent, diluted with experimental buffer, caused a concentration-dependent reduction of cell shortening and Ca2+ transient in the field-stimulated isolated cardiomyocytes of rats, as well as a reduction in peak L-type Ca2+ current in voltage-clamped cardiomyocytes. The current reduction resulted from reduced maximal conductance--not from changes in voltage- and time-dependent gating of the L-type Ca2+ channel. The postischemic coronary effluent modified neither the tissue concentrations of cAMP or cGMP nor the activities of cAMP-dPK and PKC. However, the effluent completely eliminated the activation of glycogen phosphorylase after beta-adrenergic stimulation. CONCLUSIONS: Negative inotropic substances released from isolated postischemic hearts reduce Ca2+ transient and cell contraction through cAMP-independent and cGMP-independent blockage of L-type Ca2+ channels.

Homocysteine inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway.

Cellular adhesion molecules play a pivotal role in the pathogenesis of atherosclerosis by mediating the adherence of blood leukocytes. Since hyperhomocysteinemia appears to be an independent risk factor for the development of atherosclerosis, in this study we investigated the effect of homocysteine on basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) on human umbilical-vein endothelial cells. Incubation of endothelial cells with homocysteine resulted in dose-dependent reduction in TNF-alpha-induced (5 ng/ml) expression of VCAM-1, E-selectin, and ICAM-1 (the latter less pronounced). This effect was found to be specific since other thiol compounds-cysteine and glutathione-did not mimic homocysteine activity. Homocysteine attenuated TNF-alpha-stimulated U-937 adhesion to the endothelial monolayer and reduced TNF-alpha-induced activation of the transcription factor NF-kappaB, indicating that NF-kappaB inhibition may play a role in inhibiting expression of adhesion molecules in endothelial cells.

Hyperhomocysteinaemia and adverse events complicating coronary catheter interventions.

BACKGROUND: Since hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA). DESIGN: Consecutive cases receiving coronary catheter interventions. SETTING: Tertiary referral centre in Germany. METHODS: Fasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death. RESULTS: Among the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups. CONCLUSION: The results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.

Adrenomedullin and myocardial contractility in the rat.

The effects of adrenomedullin in the regulation of myocardial contractility were investigated in the rat. In papillary muscles (n=6), adrenomedullin (0.1 to 10 nM) failed to show contractile effects. NO (nitric oxide) synthase inhibition with N(G)-nitro-L-arginine (L-NOARG) did not unmask any inotropic effect of adrenomedullin. The positive inotropic effect of isoprenaline (0. 01 nM to 10 microM) was identical after adrenomedullin, after L-NOARG, and after L-NOARG plus adrenomedullin (n=6 each). In field-stimulated rat ventricular myocytes, adrenomedullin (1, 10, and 100 nM; n=4 each) had impact neither on cell shortening nor on Ca(2+) transients. In isolated constant-flow perfused hearts (7.3+/-0.3 ml/min), adrenomedullin (1 nM, n=9; 10 nM, n=7) induced significant coronary vasodilation (-28%, -50%). In conclusion, adrenomedullin is a potent coronary vasodilator, but has no significant effects on myocardial contractility in the rat.