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Siegfried Hagl

Publications and source records attributed to Siegfried Hagl.

54 records · Page 3Linked to original sources
PubMed2004

Myocardial protection after systemic application of L-arginine during reperfusion.

The L-arginine-nitric oxide (NO) pathway plays an important role in ischemia-reperfusion injury. In the present study we investigated the role of NO-precursor L-arginine on cardiac and pulmonary function after reversible hypothermic ischemia. Twelve anesthetized dogs underwent cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started with application of either saline vehicle (control, n = 6) or L-arginine (40 mg/kg i.v. bolus then 3 mg/kg i.v. infusion during the first 20 minutes of reperfusion, n = 6). The vasodilative response to acetylcholine was significantly higher in the L-arginine group (P < 0.05). The preload recruitable stroke work of the left ventricle decreased significantly after reperfusion, however remained unchanged in the L-arginine group. Arterial blood gas analysis did not show any difference between the two groups. Plasma L-arginine concentration reached peak level at 20 minutes of administration (675.0 +/- 66.6 versus 207.7 +/- 14.5 in the L-arginine group, P < 0.05) and returned to baseline at 40 minutes, while in the control group remained unchanged during ischemia and reperfusion (276.2 +/- 71.6 versus 283.8 +/- 38.5, P < 0.05). Plasma nitrite concentration followed L-arginine changes parallel, however nitrate levels increased slower. Supplementation with L-arginine during reperfusion prevents myocardial and endothelial dysfunction, however does not have any overriding effect on pulmonary function. Considerably rapid elimination of plasma L-arginine was demonstrated during early reperfusion.

Animals↗
PubMed2004

INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation.

Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.

Acetylcholine↗
PubMed2004

Mesenteric injury after cardiopulmonary bypass: role of poly(adenosine 5'-diphosphate-ribose) polymerase.

OBJECTIVES: To investigate the effects of the ultrapotent poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitor INO-1001 on cardiac and mesenteric function during reperfusion in an experimental model of cardiopulmonary bypass with cardioplegic arrest. DESIGN: Prospective, randomized, and blinded experimental study. SETTING: Research laboratory. SUBJECTS: : Twelve anesthetized dogs underwent cardiopulmonary bypass with hypothermic cardioplegic cardiac arrest. INTERVENTIONS: After 60 mins of hypothermic cardiac arrest, either PARP inhibitor INO-1001 (1 mg/kg, n = 6) or vehicle (control, n = 6) was administered during reperfusion. MEASUREMENTS AND MAIN RESULTS: Left ventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and mesenteric blood flow and vasodilatory responses to acetylcholine and sodium nitroprusside as well as mesenteric lactate and creatinine phosphokinase release were also determined. The administration of INO-1001 led to a significantly improved recovery of left ventricular systolic function (p < .05) after 60 mins of reperfusion. Coronary and mesenteric blood flow were also significantly higher in the INO-1001 group (p < .05). Although the vasodilatory response to sodium nitroprusside was similar in both groups before and after cardiopulmonary bypass and similar in response to acetylcholine before cardiopulmonary bypass, PARP-inhibited dogs had lower mesenteric vascular resistance after cardiopulmonary bypass (p < .05). Mesenteric lactate and creatinine phosphokinase release was significantly lower in the PARP inhibitor treated group (p < .05). CONCLUSION: PARP inhibition with INO-1001 improves the recovery of myocardial function and prevents mesenteric vascular dysfunction and tissue injury after cardiopulmonary bypass with hypothermic cardiac arrest.

Animals↗
PubMed2004

Extracorporal-circulation-induced leukocyte/endothelial cell interaction is inhibited by dextran.

Clinical complications of Extracorporeal Circulation (ECC) are the consequence of a systemic activation of cellular and humoral factors resulting in a dysregulation of the microcirculation. Previously we developed an animal model to study effects of ECC on the microcirculation in vivo. To prevent the systemic inflammatory reaction (SIRS) seen after ECC, colloids were used as priming solution. Intravital fluorescence microscopy was used on the hamster skinfold chamber model. ECC was introduced and the ECC-tube system was flushed with Ringer solution (control), with Dextran 60 (group I) or HES 10% (group II). ECC for 30 minutes resulted in an increase in rolling and adherent leukocytes in postcapillary venules (Roller: 11 +/- 3% to 38% +/- 20% 4 h after ECC, p < 0.05, Sticker: 19 +/- 16 cells/mm2 to 215 +/- 145 cells/mm2 4 h after ECC, p < 0.05; n = 7). Use of Dextran prevented L/E cell interaction (10 +/- 5%; 63 +/- 40 cells/mm2 at 4 h), whereas HES affected only adherent white cells. L/E cell interaction in the microcirculation is an indicator of the systemic activation induced by ECC. Dextran 60 prevented L/E cell interaction without side effects and may be preferable for ECC in regard to inhibition of SIRS.

Animals↗
PubMed2004

Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Calcific aortic stenosis, the major heart valve disease encountered in the elderly, leads to massive calcium deposition in the valve leaflets that morphologically resembles bone formation. Recent studies have demonstrated the expression of various bone-associated proteins in stenotic valves, suggesting that valvular calcification may be an actively regulated process. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, and bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor cytokine superfamily, are known to participate in the regulation of bone development and maturation. Their pathogenetic role in calcific aortic stenosis is unknown. METHODS: Using an immunoperoxidase technique and antibodies against BSP and BMP-2, the expression of BSP and BMP-2 was examined in 16 human aortic valves with calcific aortic stenosis obtained at valve replacement, and in seven normal autopsy controls without signs of aortic stenosis. RESULTS: By semiquantitative scoring, stenotic valves showed a significantly increased staining of BSP in cells and extracellular matrix as compared to control valves (2.7 +/- 0.1 versus 0.6 +/- 0.2 score units, p <0.001). Marked BMP-2 expression was detected in stenotic valves, mostly in cell-rich areas associated with focal calcium deposits, but no specific staining for BMP-2 was detected in control valves (1.5 +/- 0.2 versus 0.0 +/- 0.0 score units, p <0.001). CONCLUSION: These results demonstrate for the first time that BSP and BMP-2 are differentially expressed in normal aortic valves and in aortic stenosis, thereby supporting the concept that valvular calcification might be based on an actively regulated process involving BSP and BMP-2.

Aged↗
PubMed2003

Long-term results after reconstruction of the left ventricular outflow tract by aortoventriculoplasty.

BACKGROUND: Aortoventriculoplasty is an established method of reconstruction of complex left ventricular outflow tract (LVOT) obstruction by insertion of a mechanical valve prosthesis after patch enlargement of the LVOT. Little data exist with respect to long-term outcome. METHODS: Between March 1991 and June 2001, 24 patients with a median age of 10.7 (range, 2.1 to 66) years underwent aortoventriculoplasty, which was performed as a primary procedure in 4 and as a secondary intervention in 20 patients. On follow-up, all patients were restudied with an actual prospective evaluation. Data were statistically analyzed using a paired t test. RESULTS: There was one early death from low cardiac output. Four patients had to be reoperated on for bleeding. All 23 postoperative survivors were followed up for 63 (range, 12 to 123) months. Aortic anulus size of 14 (7 to 19) mm could be significantly enlarged to a size of 24 (19 to 27) mm for insertion of a mechanical valve prosthesis (p < 0.001). Blood flow velocity across the LVOT significantly decreased to 1.8 (1.3 to 2.9) m/s (preoperative, 4.1 [2.7 to 5.8] m/s) (p < 0.001). There were no late deaths. One patient underwent late repair of a paraprosthetic leak. On follow-up, there was no hemorrhage related to anticoagulation observed, but there was one minor thromboembolic complication. Relief of LVOT obstruction and good function of the valve prostheses could be demonstrated in all patients. CONCLUSIONS: Aortoventriculoplasty is an easily applicable, low-risk procedure for the effective relief of complex LVOT obstruction, and provides excellent long-term results.

Adolescent↗
PubMed2003

In vivo validation of cardiac spiral computed tomography using retrospective gating.

BACKGROUND: Cardiac functional assessment represents the basis for diagnostics and cardiac operation planning. Spiral computed tomography (CT) combines the advantages of three-dimensional imaging and high temporal resolution when using gating techniques. However, in vivo validation data of this novel imaging technology are lacking. The purpose of this study was to validate in vivo the new imaging method using retrospective gating and to evaluate the clinical usefulness of the achieved temporal resolution. METHODS: In domestic pigs (n = 10, weight 35 to 40 kg) a flowmeter was placed surgically on the ascending aorta. Flow velocity integrated over systole served as the gold standard for left ventricular (LV) stroke volume (LVSV-FM). CT signal, projection data, pacemaker signal, and flow velocity were recorded simultaneously at constant heart rate (pacemaker, 90 beats per minute). End-systolic and end-diastolic frames were calculated by retrospective gating. LV volumes were traced, the difference representing CT stroke volume (LVSV-CT). Image data were three-dimensionally reconstructed using ray-tracing. RESULTS: Temporal resolution was 170 ms. Correlation of stroke volumes was high (r = 0.94, mean difference 1.75 mL). Intraobserver (0.49 mL for LVEDV, 0.31 for LVESV) and interobserver variability (p = 0.21 and p = 0.06, respectively) were low. Postprocessing resulted in four-dimensional beating-heart models useful for operation planning. CONCLUSIONS: Spiral CT using retrospective gating was validated in vivo. Clinically acceptable temporal resolution and accuracy in determining cardiac stroke volumes were found. As a true volumetric imaging modality the method may now play an important role in computer-assisted diagnostics and surgery.

Animals↗
PubMed2003

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis.

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.

Aortic Valve Stenosis↗
PubMed2003

Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest.

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 <.05). CONCLUSIONS: Poly-ADP-ribose synthetase inhibition improves the recovery of myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

Animals↗
PubMed2003

L-arginine protects the mesenteric vascular circulation against cardiopulmonary bypass-induced vascular dysfunction.

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 <.05 vs control group) and RH partially recovered (-34 +/- 4%, P <.05). Administration of l-arginine resulted in a higher mesenteric oxygen delivery, increased nitrite/nitrate production, and lower lactate release from the mesenteric vascular circulation after reperfusion. CONCLUSIONS: CPB disrupts some of the regulatory functions of the endothelial cell in the mesenterium and these are mostly related to nitric oxide unavailability. Systemic supplementation of l-arginine at reperfusion prevents the CPB-induced mesenteric endothelial dysfunction in association with an increased blood distribution and a reduced metabolic impairment.

Acetylcholine↗
PubMed2003

Ventricular energetics after the Fontan operation: contractility-afterload mismatch.

OBJECTIVE: Fontan-type operations offer the opportunity to create pulmonary and systemic circulation in series with a single pumping chamber. The effectiveness of such a circulatory pattern determines resting and exercise hemodynamics in these patients. The present study investigated cardiac performance after the Fontan operation by using ventricular-vascular coupling framework analysis. METHODS: In 12 anesthetized open-chest dogs, Fontan circulation was established by using a cavopulmonary anastomosis. Left ventricular hemodynamic variables were measured by using a combined pressure-volume-conductance catheter. Additionally, aortic flow and pressure were recorded continuously. Ventricular contractility was quantified by using the load-independent slope of the end-systolic pressure-volume relationship. Arterial system properties were quantified by using the end-systolic pressure/stroke volume ratio. The coupling between the left ventricle and arterial system was expressed by using the ratio of end-systolic pressure/stroke volume to slope of the end-systolic pressure-volume relationship. Additionally, external stroke work, total mechanical energy and mechanical efficiency (Mechanical efficiency = Stroke work/Total mechanical energy) were calculated. Impedance spectra were determined by means of Fourier analysis. RESULTS: During Fontan circulation, the slope of the end-systolic pressure-volume relationship (5.3 +/- 0.6 vs 7.5 +/- 0.6 mm Hg/mL, P <.05) decreased, and the end-systolic pressure-stroke volume relationship (4.2 +/- 0.7 vs 3.3 +/- 0.5 mm Hg/mL, P =.23) increased with parallel increased characteristic impedance. Furthermore, the end-systolic pressure-stroke volume/slope of the end-systolic pressure-volume relationship ratio increased significantly (0.76 +/- 0.04 vs 0.42 +/- 0.03, P <.005). Simultaneously, stroke work (1846 +/- 146 vs 1389 +/- 60 mm Hg/mL, P <.05) and mechanical efficiency (0.82 +/- 0.09 vs 0.56 +/- 0.05, P <.05) were significantly reduced. CONCLUSIONS: Fontan circulation leads to contractility-afterload mismatch by means of increased impedance caused by additional connection of the pulmonary vascular bed to the systemic vasculature and by means of deterioration of myocardial contractility. The increased ventriculoarterial coupling ratio and reduced mechanical efficiency predict limited cardiac functional reserve after the Fontan operation.

Animals↗
PubMed2002

Brain death impairs coronary endothelial function.

BACKGROUND: To characterize the impact of brain death (BD) on endothelial dysfunction after cardiac transplantation we investigated coronary circulation and vasomotor function in a canine model. METHODS: Left ventricular pressure-volume data (conductance catheter) and coronary blood flow (CBF) were monitored continuously. Endothelium-dependent vasodilatation after acetylcholine and endothelium-independent vasodilation after sodium nitroprusside were assessed before and 3 hr after BD induction (inflation of a subdural balloon). RESULTS: BD led to an initial hyperdynamic reaction with significant (P<0.05) increase of CBF. After 3 hr, CBF decreased significantly (P<0.05). Although before BD, application of acetylcholine led to a monophasic vasodilatative response, after BD a short mild vasodilatation was followed by a longer vasoconstriction. Endothelium-independent vasodilatation remained unchanged. CONCLUSIONS: BD affects coronary circulation by two means: (1) impairment of CBF to decrease in parallel in afterload with consecutive hemodynamic deterioration and (2) severe endothelial dysfunction that may be a contributing factor to posttransplant outcome.

Acetylcholine↗
PubMed2002

Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2.

BACKGROUND: This study investigated the changes of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during acute cardiac transplant rejection. METHODS: Isogeneic Lewis to Lewis and allogeneic Dark Agouti (DA) to Lewis rat cardiac transplants were studied 3 and 5 days after heterotopic intraabdominal transplantation (n=6/group). Myocardial blood flow (MBF), left ventricular systolic pressure (LVSP), maximum pressure development (+dP/dt), and end-diastolic pressure (LVEDP) were measured using an intraventricular balloon. Contractile response to dobutamine (5 microg/kg/min) was also assessed. In separate groups beta-adrenergic receptor density and adenylyl cyclase activity were measured in the grafts, in the recipients' native hearts and in native hearts of sham-operated controls. RESULTS: During mild to moderate rejection cardiac function indices remained unchanged, although MBF and contractile response to dobutamine decreased significantly (P<0.05) in the allogeneic group. The beta-adrenergic receptor density was significantly (P<0.05) increased in both isografts and allografts and in the native hearts of allografted recipients in comparison to native hearts of controls. Adenylyl cyclase activity showed a significant decrease (P<0.05) only in allografts. During severe rejection, LVSP and +dP/dt decreased and LVEDP increased in allografts in comparison to isografts (P<0.05). This was accompanied by a significant decrease in MBF, contractile response to dobutamine, beta-adrenergic receptor density, and adenylyl cyclase activity (P<0.05). CONCLUSIONS: Both microcirculatory disturbances and primary alteration in adenylyl cyclase activity may contribute to decreased contractile reserve in mild to moderate cardiac allograft rejection, whereas beta-adrenergic receptor density seems to be also influenced by cardiac denervation. Severe rejection leads to systolic and diastolic heart failure with complex dysregulation of the beta-adrenergic receptor/adenylyl cyclase pathway and impaired microcirculation.

Adenylyl Cyclases↗
PubMed2002

Bronchial artery revascularization affects graft recovery after lung transplantation.

Restitution of bronchial artery circulation might alter ischemia- reperfusion injury and improve organ function after lung transplantation. Weight-matched dogs underwent a left lung allotransplantation either with bronchial artery revascularization (BAR; n = 6) or as conventional lung transplantation (LTX; n = 6), to evaluate effects of BAR on lung cell function over a period of 5 h postischemically. Lactate dehydrogenase (LDH) and marker enzymes for pneumocytes type I (carboxypeptidase M [CPM], pneumocytes type II (alkaline phosphatase [AP]), and pulmonary endothelium (angiotensin-converting-enzyme [ACE]) were determined from bronchoalveolar lavage fluid. Donor lungs were preserved with Euro-Collins solution. Total ischemic time was kept at 6 h. CPM and LDH activities were significantly higher in both groups at 2 h and 4 h of reperfusion compared with control dogs (p < 0.01). AP and ACE activities in lavage after 2 h of reperfusion were significantly elevated in animals that underwent LTX (AP: 60 +/- 28 IU/L; ACE: 1.39 +/- 1.13 IU/L) compared with animals with BAR (AP: 33 +/- 29 IU/L; ACE: 0.35 +/- 0.6 IU/L; p < 0.05) and with control animals (AP: 13.58 +/- 11.0 IU/L; ACE: 0.06 +/- 0.14 IU/L; p < 0.01). According to these results, BAR protects pulmonary endothelium and type II pneumocytes in the early phase after lung transplantation and might have consequences for lung tissue in the long term.

Alkaline Phosphatase↗
PubMed2002

Poly(ADP-Ribose) polymerase inhibition reduces reperfusion injury after heart transplantation.

The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure-volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.

Adenosine Diphosphate↗
PubMed2002

Atrial cardiomyoplasty in a Fontan circulation.

INTRODUCTION: The Fontan circulation is a direct connection between the systemic veins and the pulmonary artery (PA). Consequently, the pulmonary flow is passive due to the gradient between the right and left atrial pressure. In patients with increased pulmonary vascular resistance, the surgical procedure of atrio-pulmonary connection is therefore prone to failure. The goal of this experiment was to increase the pulmonary flow in an experimental model of a Fontan circulation by performing a right atrial cardiomyoplasty (ACMP). METHODS: In 19 Foxhounds the left m. latissimus dorsi (LD) was mobilised and transferred as a pedicle into the chest. After sternotomy a 'Fontan circulation' was created under cardiopulmonary bypass (CPB) by connecting the right atrium (RA) with the PA by a valveless conduit. The tricuspid valve was closed with a patch. In 11 dogs (group 1) a valve was implanted in the inferior vena cava (IVC) and pulmonary inflow impedance was increased by partial occlusion of the conduit to a gradient of 10 mmHg between RA and PA. In the other eight dogs (group 2) no valve was implanted, but flowmeters were placed in the IVC and the superior vena cava (SVC). In all dogs the RA was enlarged by a fascia lata patch before the LD was wrapped over the RA and stimulated synchronously to the R-wave with burst impulses. RESULTS: After coming off CPB, relatively high central venous pressures (22.5+/-5.8 mmHg) were necessary to maintain haemodynamic stability. With LD-stimulation in a 1:3 mode in group 1, RA pressure (P) increased from 23.1+/-7.7 to 45+/-10.5 mmHg (P<0.001), pulmonary atrial pressure (PAP) from 15.5+/-4.3 to 25.5+/-7.6 mmHg (P<0.001) and central venous pressure increased to 33.1+/-11.3 mmHg (P<0.05). Stroke volume increase from 11.4+/-4.7 to 17.2+/-4.3 ml and peak conduit-flow from 1286.3+/-880.3 to 2329+/-1173 ml/min (all P<0.001). In a 1:1 stimulation mode a pulsatile pressure/flow profile was obtained in the PA-conduit. Furthermore, at higher frequencies of about 120 beats/min muscle relaxation was still fast enough as not to interfere with the RA filling. In group 2 caval flow without stimulation occurred mainly during diastole. However, with LD-stimulation, a strong backflow into IVC and SVC was observed resulting in a less pronounced pressure/flow increase in the PA. CONCLUSIONS: Our experimental model demonstrates the possibility of a 'ventricularisation' of the RA by using the force of the LD. However, the haemodynamic benefit of ACMP was achieved only, when a valve was implanted in the ICV.

Animals↗
PubMedDate not supplied

Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis.

BACKGROUND: Calcific aortic stenosis (AS), the most frequent heart valve disorder in developed countries, leads to the calcification and fibrous thickening of the valve. While several studies have addressed the process of valvular calcification, the molecular pathomechanisms of the extensive matrix remodeling remain unclear. Because inflammation is present in stenotic valves, we hypothesized that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) might influence cell proliferation and regulate the expression and activation of matrix metalloproteinases (MMPs)--enzymes that are thought to be involved in calcific AS. METHODS: Immunohistochemistry for leukocytes, TNFalpha, MMP-1, and the endogenous MMP inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 was performed on human stenotic (n = 19) and control (n = 8) valves. Primary cultures of human aortic valve myofibroblasts were incubated with and without TNFalpha, and cell proliferation was assessed. The expression and activation of MMP-1 were detected by Western blotting and a specific MMP-1 activity assay. RESULTS: Control valves showed scattered macrophages and low expression of TNFalpha, MMP-1, and TIMP-1. In stenotic valves, leukocyte infiltration and a strong, colocalized expression of TNFalpha and MMP-1 were present, while TIMP-1 remained unchanged. Double-label immunofluorescence localized TNFalpha mainly to macrophages. In cultured human aortic valve myofibroblasts, TNFalpha stimulated proliferation and induced a time-dependent increase in MMP-1 expression and activation, while TIMP-1 remained unchanged. CONCLUSION: The results indicate that matrix remodeling in calcific AS involves the expression and activation of MMPs. Activated leukocytes, by the secretion of TNFalpha, may stimulate valvular myofibroblasts to proliferate and express MMPs, thus regulating actively the matrix remodeling in calcific AS.

Aortic Valve Stenosis↗