Ralf Koester

Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species.

A dysregulated metabolism of oxygen-derived free radicals, nitric oxide and endothelin-1(ET-1) in conditions such as hypercholesterolaemia or hypertension may promote the development of atherosclerosis. We therefore subjected cultured human umbilical vein endothelial cells and coronary artery smooth muscle cells to oxidative stress induced by xanthine oxidase or hydrogen peroxide and observed alterations in ET-1 metabolism. Incubation with oxygen-derived free radicals increased preproET-1 promoter activity, ET-1 mRNA synthesis and big ET-1 concentrations in both cell types. This interaction of oxidative stress and ET-1 expression may be relevant in atherogenic conditions such as hypercholesterolaemia and hypertension since our data indicate that oxidative stress further aggravates the injurious effects attributed to ET-1.

Endothelin-1 in Humans Is Increased by Oxygen-Derived Radicals Ex Vivo and In Vivo

Endothelin-1, angiotensin II, and oxygen-derived radicals are pivotal factors in the development and progression of atherosclerosis. In vitro studies suggest that generation of oxygen-derived radicals by angiotensin II is an important mechanism increasing endothelin-1 synthesis, which consecutively may trigger effects such as cell proliferation and hypertrophy. The aim of this study was to confirm our previous data in an ex vivo and an in vivo setting. Explanted segments of internal mammary arteries were analyzed for big endothelin-1 expression following incubation with xanthine oxidase, angiotensin II, superoxide dismutase, and catalase to stimulate or to specifically inactivate oxygen-derived radicals. Endothelin-1 concentrations were determined by immunostaining and enzyme-linked immunosorbent assay. Further, oxypurinol was given to patients undergoing coronary angioplasty, a procedure known to increase plasma endothelin-1 concentrations. Angiotensin II and xanthine oxidase dose-dependently increased big endothelin-1 concentrations (p < .01 and p < .0001); the effects could be inhibited by coincubation with superoxide dismutase and catalase as determined by both semiquantitative immunofluorescence and enzyme-linked immunosorbent assay (p < .01). Patients undergoing coronary angioplasty exhibited significantly elevated big endothelin-1 concentrations 60 minutes after angioplasty (p = .03); in patients also receiving oxypurinol immediately after angioplasty, big endothelin-1 concentrations decreased (p = .001). Our results may explain the association between elevated angiotensin II levels, increased oxidative stress, and increased endothelin-1 concentrations in atherosclerosis. The data therefore support the concept that oxygen-derived free radicals stimulate the release of endothelin-1, which subsequently induces effects such as proliferation and enhanced agonist-induced vasoconstriction, previously attributed directly to angiotensin II.

Interleukin-3 is elevated in patients with coronary artery disease and predicts restenosis after percutaneous coronary intervention.

BACKGROUND Interleukin-3 (IL-3) synthesized by activated T-lymphocytes is a mediator in chronic inflammation and is suspected to promote atherosclerosis. Since there is no data on IL-3 in patients with coronary artery disease (CAD) available, we compared IL-3 concentrations in different subsets of patients with CAD to healthy control patients. METHODS 205 consecutive patients with CAD, 136 with stable angina and 69 with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention, 61 patients with asymptomatic CAD and 41 patients with normal coronary arteries were investigated. Serum concentrations of IL-3 and hs-CRP were assessed at baseline and after 6 weeks, 6, and 12 months. RESULTS In patients undergoing coronary angioplasty, IL-3 was detectable more frequently than in those with asymptomatic CAD or without CAD, 21 vs. 8%, p=0.02, and 21 vs. 1%, p<0.001, respectively. Patients undergoing coronary angioplasty who developed symptomatic restenosis more frequently had detectable IL-3 levels than patients without restenosis, 45 vs. 17%, p=0.02. IL-3 was the only independent predictor for restenosis in a multivariate analysis. Hs-CRP was significantly elevated in patients with ACS, 230+/-170 mg/l vs. 100+/-140 mg/l, p=0.02, but did not correlate with IL-3 concentrations at any time. CONCLUSION IL-3, an important regulator of chronic inflammation, is elevated in patients with CAD, particularly in symptomatic patients undergoing percutaneous coronary intervention. Furthermore, high IL-3 concentrations were found to be predictive of symptomatic restenosis.

Comparison of quantitative coronary angiography and first-pass perfusion magnetic resonance imaging for the detection of an impaired coronary perfusion in nonsevere coronary stenosis.

To compare quantitative coronary angiography (QCA) and first‐pass perfusion magnetic resonance imaging (FPP‐MRI) in symptomatic patients with nonsevere coronary stenosis to detect a reduced coronary flow velocity reserve (CFVR).

Association between eotaxin (CCL11), C-reactive protein, and antimicrobial antibodies in patients undergoing coronary angioplasty.

Eotaxin (CCL11) is a potent chemoattractant for eosinophils and lymphocytes. Apart from its functions in the eosinophilic system, eotaxin has been shown to be overexpressed in atherosclerosis. We therefore sought to determine whether chronic infection with Chlamydia pneumoniae or other infectious agents is correlated with concentrations of eotaxin or C-reactive protein since this mechanism could explain the finding that chronic infection stimulates smooth muscle cell migration and plaque development. Patients undergoing percutaneous coronary angioplasty (PCI) for acute coronary syndrome or stable angina were included in the study. Blood was drawn before PCI, at 6 weeks, and 6 and 12 months after coronary intervention. Eotaxin and C-reactive protein were determined by enzyme-linked immunosorbent assay (ELISA). Antibodies against Candida, C. pneumoniae, cytomegalovirus, Helicobacter pylori, and herpes simplex virus were measured by ELISA or immunofluorescence. Two hundred five consecutive patients undergoing PCI (stable angina, n = 136; acute coronary syndrome, n = 69) and 83 patients with normal coronary arteries were enrolled in the study. Eotaxin concentrations at inclusion were higher in patients with coronary artery disease than in control patients, p = .01, and comparable in patients with stable angina and those with acute coronary syndrome but did not correlate with C-reactive protein. Eotaxin concentrations at inclusion and during follow-up weakly correlated with concentrations of antibodies against C. pneumoniae, H. pylori, and herpes simplex virus but not with concentrations of antibodies against Candida or cytomegalovirus. Eotaxin concentrations and antibody titers against C. pneumoniae significantly increased following angioplasty and remained elevated thereafter. In conclusion, our data demonstrate that eotaxin concentrations are elevated independently from C-reactive protein in patients with coronary artery disease and correlate with antibodies against infectious agents known for chronic infection in humans.

Interventricular Mechanical Dyssynchrony: Quantification with Velocity-encoded MR Imaging

PURPOSE To evaluate the performance of velocity-encoded (VENC) magnetic resonance (MR) imaging, as compared with pulsed-wave echocardiography (PW-ECHO), in the quantification of interventricular mechanical dyssynchrony (IVMD) as a predictor of response to cardiac resynchronization therapy (CRT). MATERIALS AND METHODS The study was approved by the local ethics committee, and all patients provided written informed consent. The study involved the examination of 45 patients (nine women, 36 men; median age, 60 years; interquartile age range, 47-69 years) with New York Heart Association class 2.0-3.0 heart failure and a reduced left ventricular ejection fraction (median, 25%; interquartile range, 21%-32%), with (n = 25) or without (n = 20) left bundle branch block. Aortic and pulmonary flow curves were constructed by using VENC MR imaging and PW-ECHO. IVMD was defined as the difference between the onset of aortic flow and the onset of pulmonary flow. Intraclass correlation coefficient, Spearman correlation coefficient, Bland-Altman, and Cohen kappa analyses were used to assess agreement between observers and methods. RESULTS Inter- and intraobserver agreement regarding VENC MR imaging IVMD measurements was very good (intraclass r = 0.96, P < .001; mean bias, -3 msec +/- 11 [standard deviation] and 0 msec +/- 10, respectively). A strong correlation (Spearman r = 0.92, P < .001) and strong agreement (mean difference, -6 msec +/- 16) were found between VENC MR imaging and PW-ECHO in the quantification of IVMD. Agreement between VENC MR imaging and PW-ECHO in the identification of potential responders to CRT was excellent (Cohen kappa = 0.94). CONCLUSION VENC MR measurements of IVMD are equivalent to PW-ECHO measurements and can be used to identify potential responders to CRT.

Diastolic dysfunction in patients with preserved ejection fraction: identification by velocity encoded magnetic resonance imaging

Diastolic dysfunction was recently recognized as an important cause for heart failure in patients with preserved ejection fraction. Diastolic dysfunction is typically assessed in clinical routine using transmitral and pulmonary-venous flow characteristics by Doppler-echocardiography. We hypothesized that VENC-MRI has a similar ability to identify patients with diastolic dysfunction compared to Doppler-echocardiography.

Restrictive filling patterns in patients with reduced systolic left ventricular function: identification by velocity encoded magnetic resonance imaging

A restrictive filling pattern is an independent prognostic marker for an increased mortality in patients with reduced systolic LV function. The diagnosis is currently established by characterization of transmitral and pulmonary-venous flow using Doppler-echocardiography. VENC-MRI enables robust quantification of transmitral as well as pulmonary-venous flow.

Prediction of response to cardiac resynchronization therapy by cine- and velocity encoded cardiac magnetic resonance imaging

Methods The study included twenty patients with heart failure NYHA class III and reduced ejection fraction (24 (18-28) %), scheduled for CRT device implantation. All patients underwent cineand VENC-MRI before device implantation. Intra-ventricular dyssynchrony was measured by cine-MRI as the septal-to-lateral mechanical delay (SLMD). The inter-ventricular mechanical delay (IVMD) was assessed by VENC-MRI as the difference between onset of aortic and pulmonary flow. Clinical response to CRT was assessed at 6-month follow-up after device implantation.

1120 Detection of mechanical ventricular asynchrony by cine-MRI

Methods 32 patients with (n = 17) and without (n = 15) LBBB in surface ECG underwent HTRC-MRI at 1.5 Tesla. For a temporal resolution of 6.3 ms, a shared-phases trueFISP sequence and parallel imaging was used. Time to peak contraction (TPC) was defined as the interval between Rwave and the peak of systolic contraction. Interand intraventricular delays in HTRC-MRI were calculated as the difference of TPC of lateral LVto lateral RV-wall and lateral to septal LV-wall, respectively. 1) Analysis of interand intraobserver agreement for the assessment of HTRC-MRI delays was performed. 2) HTRC-MRI delays were compared between patients with and without LBBB. 3) HTRCMRI delays were correlated with standard echocardiographic parameters in patients with LBBB.