Tobias Hövelborn

Inotropic Effects of Endothelin-1 Interaction With Molsidomine and With BQ 610

-In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 microg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.

ET A receptor blockade improves post-ischaemic functional recovery in 'hibernating' rat myocardium

Endothelin-1 (ET-1) is a potent vasoconstrictor, and ET(A) receptors mainly mediate this effect. Elevated plasma levels of ET-1 are observed in patients with coronary heart disease. The release of this peptide from the damaged endothelium may play a role in the initiation and maintenance of myocardial ischaemia. This study examines the ET(A) receptor-mediated role of endogenous ET-1 in post-ischaemic myocardial function after prolonged hypoperfusion in normal non-failing hearts. In an isolated rat heart model for short-term myocardial hibernation, left ventricular functional recovery after 3 h of hypoperfusion (15% of pre-ischaemic flow) followed by 2 h of reperfusion was determined. Under steady-state conditions, coronary flow, left ventricular pressure (LVP) and dP/dt(max) were measured in the isovolumically beating heart. Additionally, the maximal inotropic response (LVP and dP/dt(max)) to calcium stimulation was determined. To study the role of ET(A) receptors under these pathophysiological conditions, one group was treated with the ET(A) antagonist BQ 610 (0.8 micromol/l) during hypoperfusion, and compared with a control group which received a saline infusion during hypoperfusion. Reperfusion for 2 h after 3 h of hypoperfusion resulted in partial functional recovery in both groups. Post-ischaemic recovery was significantly better in the hearts that were treated with the ET(A) antagonist BQ 610 during hypoperfusion (LVP, +19.5% compared with control; dP/dt(max), +13.7% compared with control). The inotropic response to calcium was nearly normalized after ET(A) blockade. Thus the normal non-failing myocardium profits from ET(A) receptor blockade during a prolonged period of hypoperfusion, resulting in significantly better post-ischaemic recovery of myocardial function.

Management of perioperative stent thrombosis in patients undergoing surgery

Surgery often requires the interruption of standard dual antiplatelet therapy using aspirin and clopidogrel. Here, we present three patients who underwent surgery and suffered from a perioperative stent thrombosis associated with premature discontinuation of dual antiplatelet therapy. Although there are missing evidence-based data and key guidelines, we suggest that patients who undergo surgery after coronary stenting may benefit from an individualized perioperative antiplatelet management strategy. After premature dual antiplatelet therapy discontinuation, when the bridging of the preoperative time interval with the use of a short acting intravenous glycoprotein (GP) IIb-IIIa inhibitor including a platelet function testing has been missed and a coronary stent thrombosis has occurred, the patients should be administered a GPIIb-IIIa inhibitor for 12–24 hours, followed by aspirin for one day and a dual antiplatelet treatment after 24–48 hours. Our patients benefited from this individualized practical approach.

Antithrombotic triple therapy in a patient with multiple thrombi, subacute myocardial infarction and coronary stent implantation

acute chest pain (beginning 6–12 h before) and dyspnea. History-taking was incomplete since the patient does not speak German or English. His daughter negated any cardiac or thrombembolic events in the past. Diabetes and excessive smoking (more than 60 pack years) were identified as cardiovascular risk factors. The ECG showed a Q in the inferior leads (II, III, aVF) as well as a poor R wave progression in V2–V4 plus STelevations in V4–V6 indicating a (sub)acute anterior wall infarction. On admission troponin I (26.04 lg/l; reference value <0.1 lg/l), BNP (1,189 ng/l, reference value <100 ng/l) and D-Dimers were found increased (3.6 lg/ml; reference value <0.5 lg/ml), whereas creatinekinase was within the normal range. Echocardiography showed a reduced left ventricular function with anteroseptal, apical and posterobasal hypokinesia and multiple thrombi in the left atrium and both ventricles (Fig. 1d). Coronary angiography revealed a 3-vessel disease with a chronically occluded RCA and a subtotal occlusion of the medial LAD. Bare metal stenting of the LAD was successfully performed (Fig. 1a or b). A multi-detector CT excluded a relevant pulmonary embolism, did not show any signs of a paraneoplastic process, but confirmed the presence of the cardiac thrombi and additionally revealed a large, almost occluding thrombus reaching from the left internal jugular vein up to the sigmoid and transverse sinus (Fig. 1c). Neurological examination revealed a normal status. These findings prompted us to screen for thrombophilia with the following results: