Autoren H. A. Adams, G. Baumann, I. Cascorbi, M. Emmel, D. Fischer, D. Fries, A. Gansslen, A. R. Heller, F. Hildebrand, E. Klar,H. J. Klippe, W. T. Knoefel, C. Krettek, L. Lampl, H. Maul, H. Prange, U. Rolle, A. Sarrafzadeh, M. Sasse, T. Standl,W. Teske, H. R. ZerkowskiBibliografieDOI http://dx.doi.org/10.1055/s-0031-1292880Notarzt 2012; 28: 12–16© Georg Thieme Verlag KGStuttgart · New YorkISSN 0177-2309KorrespondenzadresseProf. Dr. med. Hans AntonAdamsSprecher der Sektion Schockder DIVI, Stabsstelle furInterdisziplinare Notfall- undKatastrophenmedizin,Medizinische HochschuleHannoverCarl-Neuberg-Strase 130625 HannoverTel.: +49 (0)511 532-3495/-3496Fax: +49 (0)511 532-8033adams.ha@mh-hannover.de

Background  The efficacy of angiotensin‐converting enzyme (ACE) inhibitors has been demonstrated in large clinical trials, but knowledge of the underlying mechanisms remains incomplete. Therefore, this study investigated the impact of ACE inhibitor therapy on cardiac nitric oxide (NO) synthases in patients with coronary artery disease (CAD) or heart failure.

We undertook this study to evaluate the dependence of Doppler microembolic signal (MES) counts, detected during cardiopulmonary bypass, on the type of oxygenator used. A total of 90 patients, 71 men and 19 women, aged 60 +/- 10 years (mean +/- SD), undergoing elective cardiac surgery for coronary artery bypass grafting (one vessel, n = 6; two vessels, n = 24; three vessels, n = 33; four vessels, n = 9) or valve replacement (mitral valve, n = 2, aortic valve, n = 15, both valves, n = 1) were monitored with transcranial Doppler sonography during the complete surgical procedure. The surgical and anesthetic techniques were standardized in all patients, except for the type of membrane oxygenator used (COBE CML Duo, n = 55 or DIDECO D 703, n = 35). MES count was expressed as total number of MES detected in both middle cerebral arteries during cardiopulmonary bypass (CPB) and also as total MES number divided by the CPB duration in minutes (MES min(-1)). No significant differences in patients' age or sex and type and duration of operation were noted between the two groups. MES incidence while the patients were on cardiopulmonary bypass was 100%. MES counts during CPB were 309 (236-502) and 143 (86-233) for DIDECO and COBE oxygenators, respectively (p < 0.00001). MES min(-1) were also significantly higher in patients operated with DIDECO, as compared to COBE oxygenators (3.7 (2.4-5.6) versus 1.5 (1-2.4), respectively, p < 0.0001). Inter-observer variability was satisfactory (k = 0.72). Use of a DIDECO D 703 oxygenator resulted in significantly higher MES counts as compared to the COBE CML Duo oxygenator. The clinical relevance of this finding remains to be determined.

Endothelin-1 (ET-1) is considered to be involved in the development and progression of heart failure. Therefore, we analysed the expression of endothelin-converting enzyme-1 (ECE-1), endothelin receptors A (ET(A)) and B (ET(B)) mRNAs by standard-calibrated, competitive reverse transcriptase-PCR using an internal-deleted in vitro-transcribed cRNA standard. ET-1 peptide levels were measured using isoform-specific rabbit antibodies against synthetic ET-1. mRNA and protein expression was determined in the right atrial myocardium of New York Heart Association class I patients and class IV patients undergoing aorto-coronary bypass surgery. ECE-1 mRNA was upregulated in failing atrial myocardium. Furthermore, ET-1 peptide levels were increased in failing atrial myocardium. Atrial ET(A) mRNA expression was not changed, while ET(B) mRNA was downregulated in the failing atrial myocardium. Our results support an upregulation of ET-1 synthesis by induction of ECE-1 in failing atrial myocardium. Pharmacological inhibition of augmented ECE-1 expression might provide a new therapeutic perspective in the treatment of heart failure.

In this study, we investigated the role of the renin–angiotensin system in expression of the endothelin system in atrial myocardium of patients with congestive heart failure. Atrial myocardium of control patients without angiotensin-converting enzyme (ACE) inhibitor therapy and heart failure patients without or with ACE inhibitor therapy undergoing aorto-coronary bypass surgery was studied. Endothelin-converting enzyme-1 (ECE-1) expression and endothelin-1 peptide level was upregulated in myocardium of heart failure patients without ACE inhibition. ACE inhibitor therapy prevented upregulation of ECE-1 and endothelin-1 in failing myocardium. Prepro-endothelin-1 and endothelin receptor A expression were not affected by heart failure. Endothelin receptor B was downregulated in heart failure patients. Our data demonstrate an upregulation of ECE-1 mRNA expression in failing human myocardium. Inhibition of the renin–angiotensin system by ACE inhibitor treatment prevents upregulation of ECE-1, suggesting that angiotensin II regulates ECE-1 expression in vivo.

Hemodynamic unloading using the ventricular assist device [VAD] results in partial functional recovery of failing hearts that show increased susceptibility to cardiomyocyte apoptosis. The caspase cascade is the central element of the apoptotic process in cells. We therefore tested expression shifts of left ventricular mRNA of caspases and their endogenous inhibitors from 15 patients with VAD support and successful bridging to transplantation using semiquantitative RT-PCR. Cardiac unloading was shown by the reduction in ventricular Pro-ANP mRNA under VAD. No alteration of mRNA expression under VAD could be observed for initiator caspases, for their selective inhibitors or for apoptotic signal molecules from the mitochondrial intermembrane space. Only two unselective cardiac IAPs (inhibitor of apoptosis protein) were increased under VAD with better recovery in younger patients. In conclusion, our findings indicate that successful hemodynamic unloading by VAD support causes only minor, age-dependent recovery in the expression of IAPs, while presumed alterations in antiapoptotic modulator systems upstream of the caspase cascade still remain to be identified.

FK506 (tacrolimus) is a new immunosuppressant being used in cardiac allograft transplantation. While cyclosporine A has been shown to exert an acute negative inotropic effect on isolated heart muscle preparations, little is known of the inotropic influence of FK506. The Ca(2+) release channel of human skeletal muscle and cardiac muscle is associated with FK506 binding proteins (FKBP), FKBP12 and FKBP12.6, respectively. FKBPs can be dissociated by treatment with FK506. As a consequence of FK506 exposure, isolated skeletal muscle and cardiac muscle ryanodine receptors show altered gating characteristics. Therefore, we analyzed the direct inotropic effect of FK506 exposure to isolated, intact heart muscle preparations from the human and rabbits. Experiments were performed on isolated, electrically stimulated right atrial auricular muscle strips obtained from human myocardium during elective open heart surgery and on intact right ventricular trabeculae from rabbit hearts. The human preparations were exposed to concentrations of 8 x 10(-9), 8 x 10(-8) and 8 x 10(-6) M FK506 followed by a cumulative dose-response curve with isoprenaline as a non-selective beta-adrenoceptor agonist. Our data suggest that FK506 does not exert any positive or negative inotropic effect in either human or rabbit myocardium.

Myocardial ischemia during cardiopulmonary bypass terminated by reperfusion generally leads to different degrees of damage of the cardiomyocytes induced by transient cytosolic Ca2+ overload. Recently, much attention has been paid to the role of heart-specific Ca2+-binding proteins in the pathogenesis of myocardial ischemia-reperfusion injury. S100A1 is a heart-specific EF-hand Ca2+-binding protein that is directly involved in a variety of Ca2+-mediated functions in myocytes. The aim of our study was to investigate the localization and translocation of S100A1 in the human heart under normal (baseline) conditions and after prolonged ischemia and reperfusion of the myocardium. Our data suggest that S100A1 is directly involved in the transient perioperative myocardial damage caused by ischemia during open heart surgery in humans. Given its role in the contractile function of muscle cells, this S100 protein could be an important “intracellular link” in ischemia-reperfusion injury of the heart.

OBJECTIVESThis study was performed to evaluate the prevalence and counts of Doppler microembolic signals in patients with St Jude Medical valves (St Jude Medical, Inc, St Paul, Minn) and patients with ATS valves (ATS Medical, Inc, Minneapolis, Minn) and their relation to clinical parameters.METHODSA total of 179 outpatients of the department of cardiothoracic surgery were examined. They included 98 men and 81 women, aged 61 +/- 11 years, with ATS (n = 91) or St Jude Medical (n = 88) valves in the aortic (n = 110), mitral (n = 39), or both positions (n = 30). Neurologic examination was followed by transcranial Doppler monitoring for microembolic signals. Monitoring was performed bilaterally over the middle cerebral arteries for 1 hour per session.RESULTSMicroembolic signal counts and prevalence were significantly higher in patients with St Jude Medical as compared with ATS valves. Valve type and presence of diabetes mellitus were the only predictors of microembolic signal prevalence on multivariate analysis. No influence of microembolic signals on cerebral embolic complications was established. Additionally, patients with a postoperative history of cerebral embolic complications did not have a higher number of microembolic signals than remaining patients. Interobserver variability was satisfactory.CONCLUSIONSPatients with St Jude Medical valves were shown to have significantly higher microembolic signal counts than patients with ATS valves. However, our results suggest that microembolic signal counts cannot be used to predict cerebral embolic complications. Their relation to neuropsychologic deficits remains to be evaluated.

Background-Elevated oxidative stress and superoxide anion formation in vascular cells could promote conversion of LDL to atherogenic oxidized LDL (oxLDL), contributing to endothelial dysfunction and atherosclerosis. As a major source of vascular superoxide anion formation, an endothelial NAD(P)H oxidase, similar to the leukocyte enzyme, has been identified.Methods and Results-To elucidate functional differences between NAD(P)H oxidases of endothelial cells and leukocytes, DNA sequences of endothelial NAD(P)H oxidase subunits were determined. Gp91phox cDNA sequence showed no difference between the 2 cell types. Endothelial p67phox cDNA sequence revealed 2 known polymorphisms, which do not affect NAD(P)H oxidase function. Next, we analyzed relative mRNA expression of NAD(P)H subunits in human umbilical vein endothelial cells (HUVECs) and leukocytes using a common cRNA standard in competitive reverse transcription-poly me rase chain reaction. NAD(P)H oxidase subunits p22phox and p47phox are expressed at a similar level in both cell types, whereas p67phox (2.5%) and gp91phox (1.1%) are expressed at a much lower level in endothelial cells than in leukocytes. Differences of gp91phox expression in leukocytes and HUVECs correlate with differences in superoxide release. Gp91phox mRNA and endothelial superoxide anion formation are induced in response to oxLDL in HUVECs. Furthermore, a lower gp91phox mRNA expression was found in internal mammary artery biopsy samples of patients with coronary artery disease treated with HMG-CoA reductase inhibitors before coronary bypass surgery.Conclusions-We conclude that oxLDL induces proatherosclerotic NAD(P)H oxidase expression and superoxide anion formation in human endothelial cells and an antioxidative potential of HMG-CoA reductase inhibition via reduction of vascular NAD(P)H oxidase expression.