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Methylene blue (MB) is a frequently used in patients with systemic inflammatory response syndrome with the effect of an increase in systemic vascular resistance. Recent studies assume that MB improves contractility and sensitizes myocardium to catecholamines.

Background Myxomatous degeneration of the mitral valve is a common pathological finding in mitral valve surgery and the most common reason for severe mitral valve regurgitation. Considering the importance of right ventricular remodeling and global function after mitral valve surgery we tried to elucidate a possible association of myxomatous mitral valve and impairment of right atrial and ventricular function, which might have an impact on global ventricular performance after mitral valve surgery. Methods Right atrial tissue was harvested from 47 patients undergoing mitral valve surgery. We took the trabeculae from the right auricle, which was resected at the right auricle for implementation of extracorporal circulation. The tissue was skinned and prepared in a 24 h-lasting procedure to create small fibers for hinging them in the "muscle machine", an experimental set-up, created for pCa-force measurements. Results Patients without myxomatous mitral valve developed significantly more force (4.0 mN ± 0.8 mN) at the highest step of calcium concentration compared to 2.7 mN ± 0.4 mN in group of patients with myxomatous valve degeneration (p 0.03). Calcium sensitivity in the myxomatous valve group was at pCa 6.0 and in the non-myxomatous group at pCa 5. Furthermore we observed a significant difference in ejection fraction (EF) among the groups: 49% in the non-myxomatous group versus 57% in the myxomatous group (p 0.03). In the non-myxomatous group 5 patients had diastolic dysfunction grade I-II (22,7%), in group I 10 patients (40%). This was also significant (p 0.04). Conclusions Patients with myxomatous mitral valve degeneration seem to have reduced force capacities. Calcium sensitivity is higher compared to the non-myxomatous group, which might be a compensatory mechanism to cover the physiological demand. Furthermore we suggest a higher incidence of diastolic dysfunction in patients with myxomatous mitral valve degeneration, which might have an impact on ventricular remodeling after mitral valve surgery.

Inosine, a break-down product of adenosine, has been recently shown to exert inodilatory and anti-inflammatory properties. We investigated the effects of inosine on ischemia/reperfusion injury in a rat heart transplantation model.Intraabdominal heterotopic transplantation was performed in Lewis rats. After 1h of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n=12) or inosine (100 mg/kg, n=12). Coronary blood flow, left ventricular function, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside, and high energy phosphate content were measured after 1 and 24h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology.After 1h, coronary blood flow (4.1+/-0.3 ml/(ming) vs 2.9+/-0.3 ml/(ming), p0.05), left ventricular systolic pressure (102+/-9 mmHg vs 83+/-4 mmHg, p0.05) and dP/dt (2765+/-609 mmHg/s vs 1740+/-116 mmHg/s, p0.05) were significantly higher in the inosine group in comparison to control. Vasodilatatory response to sodium nitroprusside was similar in both groups. Acetylcholine resulted in a significantly higher increase in coronary blood flow in the inosine group (76+/-5% vs 48+/-9%, p0.05). Energy charge potential was significantly higher in the inosine group (1.69+/-0.10 micromol/g vs 0.74+/-0.27 micromol/g, p0.05). After 24h, there was no difference between the groups in basal coronary blood flow, left ventricular systolic pressure, dP/dt, and the response to sodium nitroprusside. However, acetylcholine led to a still significantly higher response in the inosine group (112+/-13% vs 88+/-7%, p0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine.Thus, inosine improves myocardial and endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.

In der Literatur finden sich zunehmend Hinweise darauf, dass intaktes Endokard mit dem arbeitenden Myokard interagiert. Die vorliegende Studie untersuchte den Einfluss des Endokards auf den Kontraktionsverlauf, die Kraftentwicklung und den intrazellularen Kalziumtransienten am intakten, menschlichen Herzmuskelpraparat. Eine Gruppe der verwendeten Trabekel (n=9) aus dem rechten Vorhof wurde mit einer 0,1%igen Saponinlosung behandelt, um das Endokard zu zerstoren. Der Erfolg dieser Behandlung wurde exemplarisch durch eine Farbung mit Evan’s blue und mittels Lichtmikroskopie uberpruft. Ein direkter Einfluss der Saponinbehandlung auf die Kontraktilitat wurde ausgeschlossen, indem in Vorversuchen die untersuchten Parameter vor und nach der Applikation von Saponin verglichen wurden. Herzmuskelfasern, die nicht mit Saponin behandelt wurden (n=9), dienten als Kontrolle. Die Zeit bis zum Erreichen der maximalen Kraft war in der de-endothelialisierten Gruppe (DG) signifikant verkurzt, 265,4±14,40 ms vs. 283±14,4 ms in der Kontrollgruppe (CG), p=0,034. Die benotigte Zeit der diastolischen Relaxation auf 75% und 50% der jeweils erreichten Maximalkraft wurde ebenfalls gemessen. Die DG erreichte 75% der Maximalkraft nach 340±18,1 ms vs. 366,6±22,5 ms in der CG, p=0,020. Die Relaxation auf 50% der maximalen Kraft erfolgte nach 389,9±29,2 ms in der DG vs. 423,1±34,3 ms in der CG, p=0,036. Die Verkurzungsfahigkeit gegen eine vorgegebene Nachlast (75%, 50%, 25% und 0% der jeweiligen Maximalkraft) der DG war im Vergleich zur Kontrollgruppe signifikant verringert, die Einschrankung betrug im Mittel 52,5%. Im Vergleich der intrazellularen Kalziumtransienten war der Abfall auf 75%, 50% und 25% in der DG statistisch signifikant beschleunigt: 75%: DG %: 237,5±46,3 ms vs. CG 287,2±25,9 ms (p=0,022); 50%: DG 352,6±59,5 ms vs. CG 401,4±46,5 ms (p=0,009); 25%: DG 490±72,2 ms vs. CG 556±68,8 ms (p=0,012). Diese Ergebnisse zeigen, dass das Endokard einen erheblichen Einfluss auf die Kenngrosen der elektromechanischen Kopplung des atrialen Myokards besitzt.

Objective: Free radical production and related cytotoxicity during ischemia and reperfusion might lead to DNA strand breakage, which activates the nuclear enzyme poly-ADP-ribose synthetase and initiates an energy-consuming and inefficient cellular metabolic cycle with transfer of the adenosine diphosphate-ribosyl moiety of nicotinamide adenine dinucleotide (NAD+) to protein acceptors. We investigated the effects of poly-ADP-ribose synthetase inhibition on myocardial and endothelial function during reperfusion in an experimental model of cardiopulmonary bypass. Methods: Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6) or PJ34 (10 mg/kg), a potent poly-ADP-ribose synthetase inhibitor (n = 6). Biventricular hemodynamic variables were measured by means of a combined pressure-volume conductance catheter, and the slope of the end-systolic pressure-volume relationships was calculated at baseline and after 60 minutes of reperfusion. Left anterior descending coronary blood flow, endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to sodium nitroprusside were also determined. Results: The administration of PJ34 led to a significantly better recovery of left and right ventricular systolic function (P < .05) after 60 minutes of reperfusion. In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved in the PJ34 group. Coronary blood flow was also significantly higher in the PJ34 group (P < .05). Although the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the PJ34 group (P Conclusions: Poly-ADP-ribose synthetase inhibition improves the recovery of myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

Background. The aim of our study was to determine whether addition of the nitric oxide donor l-arginine at reperfusion may prevent the cardiopulmonary bypass (CPB)-induced vascular alterations in the intestine. Methods. Twelve dogs underwent 90-minute hypothermic CPB. After 60 minutes, the cardiac arrest-treated group (n = 6) received 40 mg/kg intravenous bolus l-arginine, followed by 3 mg/kg/min infusion for 20 minutes. Hemodynamic parameters, blood gases, lactate, and glucose were monitored. Reactive hyperemia (RH) in response to superior mesenteric artery ischemia and vasorelaxation to systemically administered vasoactive drugs (acetylcholine [ACH] and sodium nitroprusside) were assessed before and after CPB and defined as percent change of vascular resistance. Results. In the control group, CPB reduced reactive hyperemia (RH) (−26 ± 15% vs −53 ± 5%), and the response to ACH (−30 ± 3% vs −42 ± 7%). In the treated group, the post-CPB endothelial dysfunction was reversed (−37 ± 1%, P

BACKGROUND This study was designed to investigate the effects of the selective endothelin-A receptor antagonist BQ123 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion. METHODS Isogenic intra-abdominal heterotopic heart transplantation was performed in Lewis rats. After one hour of cold ischemic preservation reperfusion was started after application of either saline vehicle or BQ123 (1 micromol/L). Left-ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Responses to endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator sodium nitroprusside were also determined. RESULTS BQ123 significantly improved myocardial contractility, as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during early reperfusion (p < 0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly higher in the BQ123 group (p < 0.05). CONCLUSIONS These results suggest that endothelin-A receptor antagonists may be useful in reducing ischemia/reperfusion injury after heart transplantation by preservation of myocardial and endothelial function.

Gender-based differences in the cardiac morphology and function in patients with volume-overload cardiac pathologies has been widely examined. However the relationship between gender and contractility is not well defined.

Body mass is reported to influence myocardial performance. Latest studies have emphasized the importance of negative inotropic Adipocyte-derived factors and assume an impact on cardiac contractile function. However the underlying mechanism remains unclear.

Background Recent studies have suggested that the peroxynitrite–poly(ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. Therefore, we investigated whether PARP inhibition improves transplant outcome and the extent to which immunologic factors contribute to the effects of PARP inhibition. Methods Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti (DA)-to-Lewis rat cardiac transplants were studied under treatment with placebo, the PARP inhibitor INO-1001 (1 mg/kg/day), cyclosporine (2.5 or 5 mg/kg/day) or the combination of INO-1001 and low-dose cyclosporine. Functional, biochemical and histologic analyses were performed 3 and 5 days after transplantation in control and INO-1001–treated animals. In addition, stimulated T cells and endothelial cells were treated with INO-1001 to evaluate the potential immunosuppressive effects of PARP inhibition. Results PARP inhibition alone and in combination with cyclosporine significantly prolonged graft survival. Acute rejection led to a typical sequence of initial endothelial dysfunction and reduced contractile reserve followed by progressive systolic and diastolic dysfunction, which were reduced by PARP inhibition. PARP inhibition led to reduced antigen-specific and non-specific proliferation in stimulated T cells and dose-dependently inhibited intracellular adhesion molecule-1 (ICAM-1) up-regulation in stimulated endothelial cells. Conclusions PARP inhibition was found to prolong graft survival and improve cardiac function during acute cardiac rejection. Direct immunosuppressive properties contribute at least partially to the beneficial effects of PARP inhibitors in graft rejection.

The aim of the study was to characterize the course of systolic and diastolic function, myocardial blood flow, and histologic changes during acute rejection in a model of heterotopic transplantation in rats. For this purpose isogenic Lewis-to-Lewis and allogenic DA (Dark Agouti)-to-Lewis rat cardiac transplants were studied 1 hour and 1, 3, and 5 days, respectively, after heterotopic intraabdominal transplantation. Myocardial tissue blood flow (MBF) was assessed by the hydrogen-clearance method. An implanted balloon was used to measure pressure–volume relations in the transplanted heart. Myocardial water content was determined at the end of the experiments, and histologic examinations were performed. The MBF recovered during the first day postoperatively in both groups and decreased again in the allogenic group after 3 and 5 days (p < 0.05); it remained stable in the isogenic group. Myocardial relaxation was already prolonged in the allogenic group after 3 days and deteriorated further. Left ventricular end-diastolic pressure progressively increased in the allogenic group, whereas it remained unchanged in the isogenic group up to 5 days. After recovery from ischemia, the left ventricular peak systolic pressure was stable in the isogenic group for the entire further observation period, but it significantly decreased in the allogenic group after 5 days (p < 0.05). Myocardial water content showed a significant increase in the allogenic group compared to that in the isogenic group after 5 days. In the allogenic group histologic examination confirmed mild to moderate rejection after 3 days and severe acute rejection after 5 days. Thus, after recovery from ischemia, mild to moderate cardiac rejection was associated with reduced MBF and impaired relaxation. In a typical sequence, generation of edema and impaired diastolic compliance were terminally followed by systolic dysfunction during severe rejection.

Global myocardial ischemia and reperfusion injury play a major role in early postoperative myocardial graft dysfunction. The aim of the present study was to investigate the effects of the nitric oxide (NO) precursor L-arginine on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After 1 hour ischemic preservation, reperfusion was started after application of placebo (control, n = 12) or L-arginine (L-Arg 40 mg/kg, n = 12), a substrate of NO synthesis. Myocardial blood flow (MBF) was assessed by the hydrogen clearance method. An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Left ventricular developed pressure (LVDP), rate of pressure development (dP/dt), end-diastolic pressure (LVEDP), isovolumic relaxation constant (TE), and MBF were measured after 60 minutes and 24 hours of reperfusion. endothelium-dependent vasodilatation in response to acetylcholine (ACh) and endothelium-independent vasodilatation in response to sodium nitroprusside (SNP) were also determined. After 1 hour the MBF was significantly higher in the L-Arg group (3.6 +/- 0.6 vs. 1.9 +/- 0.2 ml/min/g, p < 0.05). The L-Arg group showed better recovery of systolic function and myocardial relaxation (LVDP 106 +/- 6 VS. 70 +/- 7 mmHg, p < 0.05; maximal dP/dt 5145 +/- 498 vs. 3410 +/- 257 mmHg/s, P < 0.05; TE 12.1 +/- 0.9 vs. 16.1 +/- 1.5 ms, p < 0.05, at an intraventricular volume of 80 microliters). LVEDP was similar in the two groups. After 24 hours no difference was found between the groups for basal MBF, LVP dP/dt, TE, LVEDP, or the response of MBF to SNP. However, ACh led to a significantly higher increase in MBF in the L-Arg group (52 +/- 8% vs. 29 +/- 7%, p < 0.05). These results indicate that (1) NO donation improves myocardial and endothelial functional recovery during early reperfusion after heart transplantation; and (2) initial treatment with L-Arg has a persisting beneficial effect against reperfusion-induced graft coronary endothelial dysfunction during late reperfusion.

Purpose: Over the past two decades, the demand for donor organs continues to outpace the number of organs available for transplantation. Donors are also becoming older and more marginal. A comprehensive donor management regimen was developed in our institution 15 years ago (1). The aim of this study is to assess our recent experience with resuscitation of initially unacceptable donors compared with that of 15 years ago. Methods and Materials: Full haemodynamic data were collected prospectively from 146 multiorgan donors between September 2004 and September 2007. The data were collected at the time of donor team arrival, after insertion of a pulmonary artery floatation catheter and immediately before cardiac explant. Donors were given hormone replacement therapy (HRT) including bolus of methylprednisolone 15mg/kg, insulin at 1 unit/hr, arginine vasopressin 1 unit bolus and 1-3 units/hr, Tri-iodothyronine 4 g bolus followed by 3 g/hr. Invasive haemodynamic monitoring was used to guide fluid and inotropic management. Results

INO-1001, A NOVEL POLY(ADP-RIBOSE) POLYMERASE INHIBITOR REDUCES MYOCARDIAL AND ENDOTHELIAL REPERFUSION INJURY AFTER ORTHOTOPIC HEART TRANSPLANTATION G. Szabo, N. Stumpf, C. Flechtenmacher, Z. Zsengeller, S. Mandera, U. Heger, C.F. Vahl, C. Szabo, S. Hagl, Department of Cardiac Surgery, University of Heidelberg, Heidelberg, BW, Germany; Institue of Pathology, University of Heidelberg, Heidelberg, BW, Germany; Inotek Pharmaceuticals, Beverly, MA, Germany

Free radical production and related cytotoxicity during ischemia/reperfusion may lead to DNA strand-breakage which activates the nuclear enzyme poly-ADP-ribose polymerase (PARP) and initiates an energy consuming, inefficient repair cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. We investigated the effects of PARP inhibition on ischemia/reperfusion injury in a rat heart transplantation model. Intraabdominal heterotopic transplantation was performed in Lewis rats. After one hour of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n=12), or AIQ5 (2 mg/kg) a selective PARP-inhibitor (n=12). Coronary blood flow (CBF), left ventricular pressure (LVP), dP/dt, end-diastolic pressure (LVEDP), endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were measured after one and 24 hours of reperfusion. Myocardial ATP content, the expression of the adhesion molecules P-Selectine and ICAM-1 were determined. After one hour, CBF (4.01±0.55 vs. 2.86±0.35, ml/min/g, p