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Biomedical subjects

Harald Tillmanns

Publications and source records attributed to Harald Tillmanns.

At least 19 recordsLinked to original sources

The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation.

The G534E polymorphism (Marburg I [MI]) of factor VII-activating protease (FSAP) is associated with carotid stenosis and cardiovascular disease. We have previously demonstrated that FSAP is present in atherosclerotic plaques and it is a potent inhibitor of vascular smooth muscle proliferation and migration in vitro. The effect of wild-type (WT)- and MI-FSAP on neointima formation in the mouse femoral artery after wire-induced injury was investigated. Local application of WT-FSAP led to a 70% reduction in the neointima formation, and this effect was dependent on the protease activity of FSAP. MI-FSAP did not inhibit neointima formation in vivo. This is due to a reduced proteolytic activity of MI-FSAP, compared to WT-FSAP, toward platelet-derived growth factor BB, a key mediator of neointima development. The inability of MI-FSAP to inhibit vascular smooth muscle accumulation explains the observed linkage between the MI-polymorphism and increased cardiovascular risk. Hence, FSAP has a protective function in the vasculature, and analysis of MI polymorphism is likely to be clinically relevant in restenosis.

Actins↗

STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival.

OBJECTIVE: Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model. METHODS: Wistar-Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 micromol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation. RESULTS: As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6+/-0.5 days to 7.8+/-1.3 days and 7.4+/-0.5 days, respectively (mean+/-S.D., p<0.01, n=5 in each group). Immunohistochemical examination on days 1, 3 and 6 revealed a marked reduction of infiltrating leukocytes (AP-1 dODN: 85%, STAT-1 dODN: 50%), namely T-cells, in the dODN-perfused grafts at day 3 post transplantation. In addition, as demonstrated by immunohistochemical analysis, endothelial expression of ICAM-1 and VCAM-1 was found to be markedly reduced in dODN-treated grafts. CONCLUSION: Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.

Acute Disease↗

Isolation and transduction of monocytes: promising vehicles for therapeutic arteriogenesis.

BACKGROUND AND AIMS: Augmentation of collateral vessel growth (arteriogenesis) is of particular clinical interest for the treatment of vascular occlusive disease. Monocytes play a key role for arteriogenesis. They localize to areas of collateral development and create a highly arteriogenic environment. "Homing" of ex vivo genetically engineered monocytes could therapeutically be exploited for augmentation of arteriogenesis. However, isolation and ex vivo transduction of monocytes is problematic. METHODS: In this study, we established a valid method of monocyte isolation from peripheral blood and evaluated different in vitro transduction methods. RESULTS: Our results revealed that liposomes and electroporation were unsuccessful for monocyte transduction. However, high-efficiency gene transfer (almost 95%) was achieved by adenoviral infection. Subsequent homing of virally transduced monocytes to sites of arteriogenesis could be demonstrated. CONCLUSION: Our study may offer a new method for the augmentation of arteriogenesis, all of which makes the ultimate goal of applying this strategy to humans for therapy of vascular disease eminently attractive.

Adenoviridae↗

Antioxidant vitamin C improves endothelial function in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) is associated with oxidative stress, endothelial dysfunction, and increased cardiovascular morbidity and mortality. OBJECTIVE: We tested the hypothesis that endothelial dysfunction in patients with OSA is linked to oxidative stress. METHODS: In the present study, we measured flow-mediated dilation (FMD) of the brachial artery by ultrasound in 10 otherwise healthy, untreated patients with OSA and 10 age-and sex-matched control subjects without sleep-disordered breathing before and after intravenous injection of the antioxidant vitamin C. The investigator performing the FMD measurements was blinded to the status of the patients. RESULTS: When compared with control subjects, baseline FMD was significantly reduced in the patients with OSA. After intravenous injection of 0.5 g vitamin C, vasoreactivity remained unchanged in the control subjects. In the patients with OSA, ascorbate led to an increase in FMD to a level comparable to that observed in the control group. CONCLUSION: The reduced endothelial-dependent vasodilation in untreated patients with OSA acutely improves by the free radical scavenger vitamin C. These results are in favor of oxidative stress being responsible for the endothelial dysfunction in OSA. Antioxidant strategies should be explored for the treatment of OSA-related cardiovascular disease.

Administration, Sublingual↗

Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study.

BACKGROUND: Asymmetric dimethylarginine (ADMA) plasma levels have been shown to be elevated in diseases related to endothelial dysfunction such as hypertension, hyperlipidemia, diabetes mellitus, and others. It has been shown that ADMA predicts cardiovascular mortality in patients who have coronary heart disease (CHD). However, the question whether ADMA is an independent risk factor for CHD still remains unresolved. METHODS: The CARDIAC study is a multicenter case-control study, designed to detect differences in ADMA plasma levels between patients with CHD and controls from the general population. We included in our analysis 131 cases and 131 controls, matched for age, sex, and body mass index. RESULTS: We found that cases had higher ADMA plasma levels than controls (0.70 micromol/L [0.59-0.87 micromol/L] vs 0.60 micromol/L [0.54-0.69 micromol/L], P < .001). To evaluate the predictive power of ADMA regarding CHD, we calculated 2 multivariate logistic regression models including laboratory parameters and traditional risk factors. The odds ratio for ADMA in the multivariate model including the laboratory characteristics was 2.59 (1.61-4.17; P < .001); the odds ratio for the multivariate model including other risk factors was 6.04 (2.56-14.25; P < .001) for the third tertile (>0.72 micromol/L) versus the first (<0.58 micromol/L). CONCLUSIONS: We conclude from the results of our study that ADMA is an independent risk factor for CHD.

Aged↗

Role of cGMP in sildenafil-induced activation of endothelial Ca2+-activated K+ channels.

Intracellular cGMP is an important second messenger in endothelial cells. Because Ca(2+)-activated K(+) channels with large conductance (BK(Ca)) have been shown to regulate endothelial cell functions, the aim of the present study was to examine whether sildenafil modulates BK(Ca) activity in cultured human endothelial cells. Changes of the endothelial cell membrane potential were analyzed using the fluorescence dye DiBAC. The patch-clamp technique was used to study BK(Ca) in human endothelial cells of umbilical cord veins (HUVEC). Intracellular Ca(2+) levels were analyzed using Fura-2 fluorescence imaging. Sildenafil caused a dose-dependent (0.05-5 micromol/l) hyperpolarization of the endothelial cells with a maximum at a concentration of 1 micromol/l. A significant increase of BK(Ca) activity was induced by sildenafil (1 micromol/l) perfusion. BK(Ca) open state-probability (NPo) was also increased by the cGMP-analogue 8-bromo-cGMP (0.5 mmol/l), whereas inhibition of the cGMP-dependent kinase (PKG) had no effect on NPo. PKG-inhibition abolished 8-bromo-cGMP induced BK(Ca) activation, and reduced sildenafil induced NPo. Furthermore, sildenafil caused a significant increase of intracellular calcium that was blocked by the BK(Ca) inhibitor iberiotoxin (100 nmol/l). In conclusion sildenafil activates BK(Ca) by a mechanism, which involves cGMP. The activation of the BK(Ca) is responsible for the sildenafil-induced increase of intracellular Ca(2+).

3',5'-Cyclic-GMP Phosphodiesterases↗

Value of soluble adhesion molecules and plasma coagulation markers in assessing transplant coronary artery disease in pediatric heart transplant recipients.

BACKGROUND: With an increasing number of heart transplantations (HTx) performed in children and an extended long-term survival of these patients, the importance of transplant coronary artery disease (TCAD) rises in this group of transplant recipients. Reliable serum markers for diagnosis or non-invasive monitoring of this disease in pediatric transplant recipients are still missing. We studied the systemic expression of adhesion molecules as well as plasma coagulation markers and the occurrence of TCAD and/or rejection in pediatric heart transplant recipients. METHODS AND RESULTS: The systemic plasma levels of soluble forms of sVCAM-1 and sICAM-1, d-dimer, tissue factor (TF), prothombin fragments F(1+2), and tissue factor pathway inhibitor (TFPI) were assessed in serial venous blood samples (2-4 per patient) in 50 pediatric transplant recipients children and 63 age- and sex-matched non-transplanted controls. TCAD and rejection were diagnosed angiographically or by combined histological, echocardiographic, or clinical signs, respectively. Plasma levels of sICAM-1 and sVCAM-1, d-dimers and prothrombin fragment F(1+2) but not TF and TFPI were significantly increased in children following HTx compared with non-transplanted controls (p<0.001). Among the transplanted patients, sICAM-1 levels were significantly higher in patients with angiographically detectable TCAD than in patients without evidence of TCAD (p<0.005). Plasma sICAM-1 levels above a cutoff value of 1500 ng/mL (95.5 percentile of control values) were indicative of the presence of TCAD (odds ratio 2.7; 95% confidence interval, 1.34-5.56, p = 0.022; Fisher's exact test). Only d-dimers were found to be significantly elevated in children with signs of myocardial rejection compared with those without rejection. CONCLUSIONS: Our results suggest that plasma sICAM-1 and d-dimer levels may be potentially useful to non-invasively assess TCAD and rejection, respectively, in pediatric heart transplant recipients.

Adolescent↗

Lipopolysaccharide-induced proliferation and adhesion of U937 cells to endothelial cells involves barium chloride sensitive hyperpolarization.

The adhesion of monocytes to the endothelium and their proliferation in the subendothelial space play an important role in atherosclerosis. Since the proliferation and migration of cells are influenced by the activity of ion channels, the aim of this study was to examine whether barium chloride (Ba(2+))-sensitive potassium channels (K(iCa)) are involved in lipopolysaccharide (LPS)-induced proliferation of monocytic U937 cells, and in the adhesion of these cells to endothelial cells. The adhesion of LPS-stimulated U937 cells to endothelial cells reached a maximum at a concentration of 5 microg/ml. This effect of LPS was completely abolished in the presence of Ba(2+) (100 micromol/l). In addition, LPS-induced proliferation was significantly reduced by Ba(2+) (control, 100%; LPS 5 microg/ml, 175%; LPS + Ba(2+) 100 micromol/l, 136%; n = 12, P < 0.05). To examine whether K(iCa) are activated by LPS, changes of U937 membrane potential were determined. LPS (5 microg/ml) caused a hyperpolarization of U937 cells indicating a flux of K(+) ions out of the cells. This effect was completely blocked by Ba(2+) (100 micromol/l). In conclusion, we demonstrate that LPS activates K(iCa) in U937 cells, which is responsible for LPS-induced adhesion of these cells to endothelial cells, and to the proliferation of U937 cells.

Barium Compounds↗

Signalling mechanisms of SDF-induced endothelial cell proliferation and migration.

The aim of our study was to investigate the effect of stromal-derived factor-1-alpha (SDF-1-alpha) on endothelial angiogenic effects. SDF-1-alpha (50 ng/ml) increased the number of cultured endothelial cells from 33,653 +/- 1183 to 55,398 +/- 2741, which significantly reduced by adding the BK(Ca)-inhibitor iberiotoxin, or the endothelial nitric oxide synthase-blocker, L-NMMA (n = 24, p < 0.05). Using the "Fences"-assay a significant increase of HUVEC migration induced by SDF-1-alpha was reported, which was blocked by the addition of iberiotoxin or L-NMMA (n = 12, p < 0.05). BK(Ca) open-state probability (NPo) was analysed using the patch-clamp technique and NPo was increased from 0.003 (control) to 0.052 (SDF-1-alpha; n = 10, p < 0.05). NO synthesis was measured using a cGMP-radioimmunoassay. A significant increase of cGMP levels from 0.952 pmol/mg protein to 2.179 pmol/mg protein was observed, that was abolished by L-NMMA and significantly reduced by iberiotoxin (n=15, p<0.05). SDF-1-alpha increases endothelial proliferation and migration involving the activation of BK(Ca) and an increased production of NO.

Cell Movement↗

Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation.

Pathological hypoxia plays an important role in many diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. The aim of the present study was to examine the effects of different statins on hypoxia-induced endothelial cell signalling. Human umbilical cord vein endothelial cells (HUVEC) were treated with NaCN (CN, 2.5 mmol/l) to simulate a transient hypoxia. The CN-induced increase of endothelial cell numbers was significantly (n = 10, p < 0.01) reduced by the Ca(2+) chelator BAPTA (10 micromol/l), or the reactive oxygen species (ROS) scavenger N-acetylcysteine (ACC, 1 mmol/l), or the NAD(P)H-oxidase inhibitor diphenyleneiodonium (DPI, 5 micromol/l). In detail, cell numbers were (in percentage of control): 163.24 (CN), 90.06 (CN+ACC), 92.06 (CN+DPI). Intracellular-Ca(2+) and -ROS, analysed by fluorescence imaging, were significantly increased by CN. Interestingly, the CN-induced increase of ROS was in part Ca(2+)-dependent, whereas the Ca(2+) increase was not ROS-dependent. Simvastatin (5 micromol/l), fluvastatin (2.5 micromol/l), and cerivastatin (0.1 micromol/l) all reduced CN-induced proliferation, ROS generation and Ca(2+) increase. Cell viability was not reduced by the statins and the antiproliferative effect was completely reversed by mevalonate (500 micromol/l). In conclusion our study demonstrates that statins block hypoxia-associated endothelial proliferation by preventing the increase of Ca(2+) and ROS.

Acetylcysteine↗

Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells.

Statins have been linked to a wide range of vascular benefits, many of them are likely to be due to attenuation of chronic vascular inflammation. Nuclear factor kappaB (NF-kappaB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. Therefore, we investigated the effect of statins on TNF-alpha-induced NF-kappaB signaling in human endothelial cells (EC). ECs were pre-incubated for 16 h with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20 ng/ml TNF-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.

Cells, Cultured↗

Margatoxin inhibits VEGF-induced hyperpolarization, proliferation and nitric oxide production of human endothelial cells.

BACKGROUND: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells (EC) in vitro and angiogenesis in vivo. Furthermore, a role of VEGF in K(+) channel, nitric oxide (NO) and Ca(2+) signaling was reported. We examined whether the K(+) channel blocker margatoxin (MTX) influences VEGF-induced signaling in human EC. METHODS: Fluorescence imaging was used to analyze changes in the membrane potential (DiBAC), intracellular Ca(2+) (FURA-2) and NO (DAF) levels in cultured human EC derived from human umbilical vein EC (HUVEC). Proliferation of HUVEC was examined by cell counts (CC) and [(3)H]-thymidine incorporation (TI). RESULTS: VEGF (5--50 ng/ml) caused a dose-dependent hyperpolarization of EC, with a maximum at 30 ng/ml (n=30, p<0.05). This effect was completely blocked by MTX (5 micromol/l). VEGF caused an increase in transmembrane Ca(2+) influx (n=30, p<0.05) that was sensitive to MTX and the blocker of transmembrane Ca(2+) entry 2-aminoethoxydiphenyl borate (APB, 100 micromol/l). VEGF-induced NO production was significantly reduced by MTX, APB and a reduction in extracellular Ca(2+) (n=30, p<0.05). HUVEC proliferation, examined by CC and TI, was significantly increased by VEGF and inhibited by MTX (CC: -58%, TI --121%); APB (CC --99%, TI--187%); N-monomethyl-L-arginine (300 micromol/l: CC: -86%, TI --164%). CONCLUSIONS: VEGF caused an MTX-sensitive hyperpolarization which results in an increased transmembrane Ca(2+) entry that is responsible for the effects on endothelial proliferation and NO production.

Calcium↗

Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo.

Mechanotransduction represents an integral part of vascular homeostasis and contributes to vascular lesion formation. Previously, we demonstrated a mechanosensitive activation of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) resulting in p27Kip1 transcriptional downregulation and cell cycle entry of vascular smooth muscle cells (VSMC). In this study, we further elucidated the signaling from outside-in toward PI3-K/Akt in vitro and in an in vivo model of elevated tensile force. When VSMC were subjected to cyclic stretch (0.5 Hz at 125% resting length), PI3-K, Akt, and Src kinases were found activated. Disrupting caveolar structures with beta-cyclodextrin or transfection of VSMC with caveolin-1 antisense oligonucleotides (ODN) prevented PI3-K and Akt activation and cell cycle entry. Furthermore, PI3-K and Akt were resistant to activation when Src kinases were inhibited pharmacologically or by overexpression of a kinase-dead c-Src mutant. alpha(V)beta3 integrins were identified to colocalize with PI3-K/caveolin-1 complexes, and blockade of alpha(V)beta3 integrins prevented Akt activation. The central role of caveolin-1 in mechanotransduction was further examined in an in vivo model of elevated tensile force. Interposition of wild-type (WT) jugular veins into WT carotid arteries resulted in a rapid Akt activation within the veins that was almost abolished when veins of caveolin-1 knockout (KO) mice were used. Furthermore, late neointima formation within the KO veins was significantly reduced. Our study provides evidence that PI3-K/Akt is critically involved in mechanotransduction of VSMC in vitro and within the vasculature in vivo. Furthermore, caveolin-1 is essential for the integrin-mediated activation of PI3-K/Akt.

Anastomosis, Surgical↗

Discordant effects of nicotine on endothelial cell proliferation, migration, and the inward rectifier potassium current.

The inward rectifier K+ current (K(ir)) determines the resting membrane potential of endothelial cells. Basic fibroblast growth factor (bFGF) has been shown to activate K(ir) and acts as angiogenic factor and vasodilator. In contrast, nicotine has been demonstrated to reduce endothelium-dependent vasorelaxation by increasing radical formation. Aim of the present study was to investigate whether nicotine modulates K(ir) and if this plays a role in bFGF-mediated proliferation, migration and nitric oxide (NO)-formation of endothelial cells. Using the patch-clamp technique in cultured endothelial cells of human umbilical cord veins (HUVEC), we found characteristic K(ir), which were blocked by extracellular barium (100 micromol/l). Perfusion with nicotine (1 nmol/l-10 micromol/l) revealed a dose-dependent reduction of K(ir). The simultaneous perfusion with bFGF (50 ng/ml) and nicotine (10 micromol/l) still significantly reduced K(ir) (n = 8; P < 0.01). Cell counts revealed that bFGF-mediated proliferation of HUVEC was significantly inhibited when using 1-10 micromol/l nicotine (n = 8, P < 0.01). The bFGF-induced endothelial cell migration--examined using the "Fences-Migration-Assay"--was significantly reduced by 10 mumol/l nicotine (n = 12; P < 0.05). NO-production was examined using a cGMP-Radioimmunoassay. The significant bFGF-induced increase of cGMP-levels was reduced by nicotine (n = 10; P < 0.05). Our data indicate that the modulation of K(ir) seems to be an essential pathway in the antagonistic effects of nicotine on bFGF-mediated endothelial cell growth, migration and NO-formation.

Cell Movement↗

Gender differences in the outcome of cardiac interventions.

I. The actual data base on the decision-making process of indication for revascularization reveals that angiographic severity of coronary artery disease (CAD) is the primary determinant of referral to coronary interventional procedures. Several recent studies demonstrated that after an acute myocardial infarction, women undergo cardiac catheterization to a lesser extent than men. Data of the MITI study and of the Cooperative Cardiovascular Project suggested that during acute treatment of myocardial infarction a somewhat less aggressive therapy is performed in women as compared to men. II. With respect to sex-related differences in the early and late outcome after elective PCI, the main problem is the small, limited amount of data due to the lack of randomized clinical studies including a larger number of women. The vast majority of data was obtained in patients with PTCA and stents. All the older studies and registers until 1993 revealed a three times higher periprocedural complication rate and in-hospital mortality in women. In recent studies such as BARI, after successful PCI women have an excellent long-term prognosis comparable or even better than in men. III.1. Several studies on the effect of interventional strategies in patients with unstable angina or non-ST elevation myocardial infarction NSTEMI) revealed superiority of an early invasive versus a more conservative, noninvasive approach. However, the data of the FRISC II and RITA-3 trials indicated that an early intervention strategy resulted in a beneficial effect only in men which was not seen in women. On the other hand, two studies (e.g., the TACTICS-TIMI- 18 study) showed an improved outcome of women with acute coronary syndrome after early invasive therapy. III.2. In numerous investigations, a higher early mortality after acute ST elevation myocardial infarction (STEMI) has been observed in women compared to men. Although placebo-controlled randomized trials of thrombolytic therapy have demonstrated a 25-30% reduction in early mortality, in-hospital survival has remained consistently lower for women than men after thrombolytic reperfusion. -- In our clinic, prospective studies on clinical events during the early phase (30 days) and during long-term follow-up for 4 years after direct (primary) PTCA for acute STEMI were performed in women. Data were obtained in 204 consecutive and unselected women; results in women were compared with those of 577 consecutive and unselected men who had undergone direct angiography/primary PTCA for acute STEMI in the same time span. PTCA of the infarct-related artery was equally successful in both sexes (women 95%, men 94%). In the group of patients with acute STEMI who had been treated with primary infarct PTCA, no difference of early (30 days) mortality was detected in women versus men. Total cumulative mortality during 4 years of follow-up was 12.5%, 14.5%, 18% and 23% in women, respectively, versus 9%, 10.5%, 12% and 15%, respectively, in men. The general trend for a higher postdischarge mortality in women became apparent after 3 years and reached significance after 4 years. After multivariate analysis, female gender was no independent risk factor of increased mortality. Thus, direct (primary) coronary angiography and PCI eliminate significant gender-specific differences in survival early after acute myocardial infarction. Long-term follow-up (4 years) also revealed no sex-related differences in mortality and cardiac morbidity after direct (primary) PCI for acute ST elevation myocardial infarction.

Angioplasty, Balloon, Coronary↗

A 22-year-old woman with lower limb arteriopathy. Buerger's disease, or methamphetamine- or cannabis-induced arteritis?

This case report describes a 22-year-old woman with severe arterial ischemia leading to claudication and ulceration of the feet, presumably due to long-term abuse of amphetamine derivates, such as "speed" or "ecstasy," and cannabis. Known causes for peripheral occlusive disease, such as atherosclerosis, vasculitis, or collagen vascular disease, were excluded. Laboratory test results did not show evidence of risk factors for thromboembolic diseases. Conventional angiography and magnetic resonance-angiography showed occlusions of medium- and small-sized arteries of both calves and feet. In the past, vasculitis-like arteriopathy was attributed to the abuse of amphetamines as well as of cannabis. However, amphetamines have been reported to be associated with necrotizing vasculitis mainly of cerebral arteries. Therefore, the abuse of methamphetamine or "ecstasy" also appears to play a role in the development of peripheral arterial occlusions and seems to have broad similarities with Buerger's disease.

Adult↗

Long-term incidence of malignant ventricular arrhythmia and shock therapy in patients with primary defibrillator implantation does not differ from event rates in patients treated for survived cardiac arrest.

INTRODUCTION: Recent trials have demonstrated benefit of prophylactic defibrillator (ICD) implantation compared to conventional treatment in high-risk patients. However, many patients have rare or no sustained arrhythmias following implantation. Our study addresses the question, whether patients with prophylactic defibrillator implantation have a lower risk for life-threatening ventricular tachycardia (VT) or ventricular fibrillation (VF) compared to sudden cardiac death (SCD) survivors. METHODS AND RESULTS: Over 7 years we enrolled 245 patients. Occurrence of spontaneous sustained VT/VF resulting in adequate ICD treatment was the endpoint. Incidence, type, and treatment of sustained arrhythmia in 43 previously asymptomatic ICD recipients (group B) were compared to data of 202 survivors of imminent SCD (group A). All patients had severely impaired left ventricular ejection fraction (<45%). Group B patients had long runs (>6 cycles, <30 s) of VT during Holter monitoring and inducible sustained arrhythmia. Incidence of rapid VT and VF (cycle length <240 ms/heart rate >250 bpm) after 4 years (35% in both groups, P = ns) and adequate defibrillator therapies (57% vs 55%, P = ns) were similar in both groups after univariate and multivariate analysis. Cumulative mortality tended to be lower in group B compared to group A, but the difference was not statistically significant. CONCLUSION: During long-term follow-up, incidence of sustained rapid ventricular arrhythmia in prophylactically treated patients is as high as that of SCD survivors. Benefit from defibrillator implantation for primary prevention (group B) appears to be comparable to that for survived cardiac arrest (group A).

Adult↗

Quercetin-induced induction of the NO/cGMP pathway depends on Ca2+-activated K+ channel-induced hyperpolarization-mediated Ca2+-entry into cultured human endothelial cells.

Quercetin is one of the dietary-derived flavonoids that are held responsible for the beneficial effects of red wine drinking in coronary artery disease known as the "French paradox". We examined whether quercetin modulates endothelial function by influencing Ca2+-activated K+ channels with large conductance (BK(Ca)) in cultured human endothelial cells. Membrane potential and intracellular Ca2+ concentrations of cultured human endothelial cells derived from umbilical cord veins (HUVEC) were measured using the fluorescence dyes DiBAC, and FURA-2, respectively. NO production was examined using a cGMP radioimmunoassay. HUVEC proliferation was analyzed by cell counts and thymidine incorporation. A dose-dependent hyperpolarization of HUVEC was recorded when quercetin was added (5-100 micromol/L). The maximum effect (50 micromol/L) was significantly reduced by the addition of the highly selective BK(Ca) inhibitor iberiotoxin (100 nmol/L), but not by blockers of other Ca2+-activated K+ channels (n = 30; p < 0.05). This BK(Ca)-induced hyperpolarization caused a transmembrane Ca2+ influx, because the quercetin-induced increase of intracellular Ca2+ was blocked by iberiotoxin, or by applying 2-aminoethoxydiphenylborate (100 micromol/L)--an inhibitor of capacitative Ca2+ entry (n = 30; p < 0.05). Quercetin-induced cGMP levels were significantly reduced by the eNOS-inhibitor l-NMMA (300 micromol/L), and by iberiotoxin (n = 10; p < 0.05). Endothelial proliferation was significantly reduced by 56 % when cells were incubated with quercetin (n = 12; p < 0.05). This effect was due to the increased NO production, because it was reversed when the cells were treated with a combination of quercetin and l-NMMA. In conclusion quercetin improves endothelial dysfunction by increasing NO synthesis involving BK(Ca)-dependent membrane hyperpolarization-induced capacitative Ca 2+ entry. Increased NO production is responsible for the quercetin-dependent inhibition of endothelial proliferation.

Calcium↗