Management of congenital tracheal stenosis in infancy.
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Abnormalities, Multiple↗
Biomedical subjects
Siegfried Hagl
Publications and source records attributed to Siegfried Hagl.
Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy.
PURPOSE: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. METHODS AND MATERIALS: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. RESULTS: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. CONCLUSIONS: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.
Animals↗
Opposite effects of vascular irradiation on inflammatory response and apoptosis induction in the vessel wall layers via the peroxynitrite-poly(ADP-ribose) polymerase pathway.
PURPOSE: We investigated in a surgical rat model of vascular injury the potential role of the peroxynitrite - poly(ADPribose) polymerase (PARP) pathway in inflammatory response and apoptosis induction after vascular gamma irradiation. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n = 10) and were irradiated with 15 Gray (n = 13) or 20 Gray (n = 10) postoperatively and compared with sham-operated rats (n = 10). Additional animals were solely irradiated with 15 Gy (n = 10) and with 20 Gy (n = 10) to distinguish between primary effects of vascular injury and secondary effects due to irradiation. RESULTS: After 21 days, neointima formation was significantly suppressed after irradiation (control: 0.07 mm(2) +/- 0.04 mm(2), 15 Gy: 0.003 mm(2) +/- 0.004 mm(2), 20 Gy: 0.001 mm(2) +/- 0.0006 mm(2), P< 0.0001). However, a significant inflammation of the vessel wall with focal wall necrosis was detected (control: 0.2 +/- 0.15, 15 Gy: 0.82 +/- 1.2, 20 Gy: 1.25 +/- 0.86, P= 0.003). Immunohistochemistry showed significant staining for nitrotyrosine, poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor in the neointima of the control group. In the irradiated groups these stainings were significantly higher in the media and adventitia compared to the non-irradiated groups. CONCLUSION: Activation of the peroxynitrite-PARP pathway was demonstrated during neointima proliferation in a rat model of surgical vascular injury. Vascular irradiation suppressed neointima formation, but induced significant activation of the peroxynitrite - PARP pathway in the outer vessel wall layers concomitant to inflammation and focal wall necrosis. This may contribute to adverse effects of vascular irradiation such as fibrosis and constrictive remodeling.
Animals↗
Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation.
PURPOSE: The generation of reactive oxygen species during gamma-irradiation may induce DNA damage, leading to activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) culminating in endothelial dysfunction. In the present study, we assessed the effect of PARP inhibition on changes in vascular function after acute and short-term irradiation. METHODS AND MATERIALS: In the acute experiments, aortic rings were exposed to 20 Gy of gamma-irradiation. The aortae were harvested after 1 or 7 days. Two additional groups received the ultrapotent PARP inhibitor, INO-1001, for 1 or 7 days after irradiation. The aortic rings were precontracted by phenylephrine and relaxation to acetylcholine and sodium nitroprusside were studied. RESULTS: The vasoconstrictor response to phenylephrine was significantly lower both acutely and 1 and 7 days after irradiation. Vasorelaxation to acetylcholine and sodium nitroprusside was not impaired acutely after irradiation. One and seven days after irradiation, vasorelaxation to acetylcholine and sodium nitroprusside was significantly enhanced. Treatment with INO-1001 reversed vascular dysfunction after irradiation. CONCLUSION: Vascular dysfunction was observed 1 and 7 days after irradiation, as evidenced by reduced vasoconstriction, coupled with endothelium-dependent and -independent hyperrelaxation. PARP inhibition restored vascular function and may, therefore, be suitable to reverse vascular dysfunction after irradiation.
Acetylcholine↗
L-arginine improves endothelial and myocardial function after brain death.
BACKGROUND: Recently, we showed that brain death (BD) leads to a severe impairment of endothelial function. METHODS: To test the hypothesis, that nitric oxide supply improves endothelial function, we infused L-arginine (40 mg/kg) in 6 dogs after BD induction (subdural balloon). Six vehicle-treated BD animals served as controls. Coronary blood flow (CBF), preload recruitable stroke work (PRSW), and plasma L-arginine and nitrite/nitrate levels were measured before and 6 hr after BD induction. In addition, endothelium-dependent vasodilatation after intracoronary application of acetylcholine (ACH) and endothelium-independent vasodilation after sodium nitroprusside (SNP) were assessed. RESULTS: Six hours after BD, CBF decreased significantly in the control group (38.2+/-3.5 vs. 26.8+/-3.1 ml/min, P<0.05), whereas the decrease was less pronounced in the L-arginine group (41.8+/-6.9 vs. 36.0+/-1.2 ml/min, P<0.05 vs. control). Before BD, ACH led to a similar vasodilative response in both groups (81+/-6 vs. 75+/-7%). After BD, a paradox vasoconstriction occurred after ACH in the control group, while the vasodilative response did not change in the L-Arginine group (36+/-6 vs. 69+/-7%, P<0.05). The response to SNP did not differ between the groups and over the time. After BD PRSW decreased in both groups, however, it was still significantly higher in the L-arginine group (56+/-7 vs. 71+/-7 kerg, P<0.05). L-arginine (711+/-144 vs. 234+/-54 microM P<0.05) and nitrite/nitrate (39+/-3 vs. 27+/-3 microM P<0.05) levels were significantly higher in the L-arginine group. CONCLUSION: L-arginine treatment prevents endothelial dysfunction and improves myocardial performance after BD via enhancement of endogenous nitric oxide synthesis.
Animals↗
Morphometric changes of the right ventricle in the first two weeks after clinical heart transplantation: analysis of myocardial biopsies from patients with complicated versus uncomplicated course.
OBJECTIVE: The early phase following heart transplantation (HTx) is characterized by the development of right ventricular myocardial fibrosis (MF) and cardiomyocyte hypertrophy (CH). The question is if there are differences in development of MF and CH between patients with complicated versus patients with uncomplicated postoperative course. METHODS: Endomyocardial biopsies were taken from 58 donor hearts before implantation and one and two weeks after HTx. According to the clinical course in the first year after HTx and the rejection grading (ISHLT), four groups were classified: (a) uneventful course, (b) transplant failure, (c) infections, and (d) rejection episodes > or = 1R. The volume densities of various tissue components and cardiomyocyte diameters were measured by stereological and morphometrical methods. RESULTS: From implantation to the first two weeks, most groups showed a significant increase of endomysial and perimysial connective tissues. There was a significant CH recognizable, especially in the rejection group. However, nucleus surface, a hypertrophy parameter, showed no significant change during follow-up. There were no statistically significant differences in volume densities of interstitial space, capillaries, nuclei and cardiomyocytes between the collectives and points in time. Sarcomere length as marker of contraction status of cardiomyocytes remained at the same level and showed no significant differences. Demographic data showed no significant differences and will be presented. CONCLUSIONS: Patients with complicated and uncomplicated courses show different degrees of histopathological changes after HTx. The extent of hypertrophy differs especially between the collectives. Measurement of endomysial connective tissue points to later postoperative course in the recipient. These findings may reflect a pattern of remodeling specific to the transplanted heart.
Adult↗
Effects of inosine on reperfusion injury after heart transplantation.
OBJECTIVE: 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. METHODS: 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. RESULTS: After 1h, coronary blood flow (4.1+/-0.3 ml/(ming) vs 2.9+/-0.3 ml/(ming), p<0.05), left ventricular systolic pressure (102+/-9 mmHg vs 83+/-4 mmHg, p<0.05) and dP/dt (2765+/-609 mmHg/s vs 1740+/-116 mmHg/s, p<0.05) 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%, p<0.05). Energy charge potential was significantly higher in the inosine group (1.69+/-0.10 micromol/g vs 0.74+/-0.27 micromol/g, p<0.05). 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%, p<0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine. CONCLUSIONS: 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.
Animals↗
A clinical study of annular geometry and dynamics in patients with ischemic mitral regurgitation: new insights into asymmetrical ring annuloplasty.
OBJECTIVE: Recent studies in animals showed that regional annulus distortion is a major determinant of ischemic mitral regurgitation (IMR) and accordingly suggested new surgical approaches with asymmetrical annuloplasty rings. As accurate measurement of annulus in patients is still a challenge, we performed this study to analyze the changes in three-dimensional annular geometry in patients with IMR compared to primary valvular lesions. METHODS: We studied 110 patients divided into three groups: (1) 30 with coronary artery disease without IMR, (2) 38 with chronic IMR, and (3) 42 with MR due to primary valvular lesions. Longitudinal and septal-lateral annulus diameters; global diastolic and systolic annular area and its percentual shortening, diastolic and systolic areas of six regions corresponding to the segmental Carpentier classification were measured by 3D-echocardiography. The degree of MR was assessed by three-dimensional color Doppler. Global and regional left ventricular geometry were assessed by sphericity index and by measuring anterior and posterior tethering of papillary muscles. RESULTS: Patients with significant IMR (group 2) showed larger longitudinal (52.7+/-3.9 mm vs 41.8+/-2.9 mm; p<0.01) and antero-lateral (31.8+/-3.5mm vs 26.7+/-2.8mm; p<0.01) annular diameters than the patients with MR due to primary valvular lesions (group 3). Diastolic (997.8+/-64.9 mm(2) vs 700.7+/-46.8mm(2); p<0.01) and systolic (894.9+/-57.3mm(2) vs 547.3+/-35.0mm(2); p<0.01) annular areas were larger in group 2 than in group 3. Annular area change was significantly lower in the group with ischemic mitral regurgitation than in the group with primary valvular lesions (10.3+/-1.1% vs 21.9+/-1.6%; p<0.01). Regional annular areas of the six sectors were homogeneously larger in group 2 than in group 3. The sector P3 did not show larger area than the other ones. The degree of MR, as assessed by the volumes of regurgitant jets, was higher in the group with primary valvular lesions than in the patients with IMR (32.6+/-13.4 cm(3) vs 23.1+/-11.1cm(3); p<0.01). CONCLUSIONS: This study showed that annular enlargement in patients with IMR affects the different annular regions to the same extent. An ideal surgical repair of IMR should be individually tailored after quantitative assessment measurement of geometry and function of each single component of the mitral valve complex.
Aged↗
Adjunct brachytherapy: a new concept to prevent intimal hyperplasia after surgical endarterectomy?
OBJECTIVE: Endarterectomy represents a therapeutical option for patients with advanced coronary artery disease. The mid-term results are compromised by restenosis due to neointima formation. The aim of this study was to evaluate a new treatment concept - endarterectomy with consecutive gamma-irradiation - in a rat model. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n=10) or were irradiated with 15 Gray (Gy) (n=13) or 20 Gy (n=10) postoperatively and compared with sham-operated rats (n=10). After 3 weeks, carotid arteries were perfusion-fixed and vessel compartment areas were measured. Transmission electron microscopy and immunohistochemical staining were used to confirm neointima formation. RESULTS: Three weeks after endarterectomy, neointimal hyperplasia was found in the control group (0.07+/-0.04 mm(2)). After irradiation, a dose-dependent reduction of neointima was observed (0.003 mm(2) at 15 Gy and 0.0007 mm(2) at 20 Gy, P<0.0001). However, immunohistochemical staining revealed that thin re-endothelialization after irradiation was not inhibited. CONCLUSIONS: Gamma-irradiation significantly suppressed neointimal hyperplasia in a rat model of surgical endarterectomy. Despite inhibition of intimal hyperplasia, re-endothelialization after adjuvant brachytherapy was present. Adjuvant brachytherapy may be therefore a new concept to prevent restenosis after endarterectomy in patients.
Animals↗
Expression of platelet-derived growth factor and fibroblast growth factor in cryopreserved endomyocardial biopsies early and late after heart transplant.
BACKGROUND: Growth factors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) appear to play a key role in immunologic reactions in the long-term course after heart transplant. Their expression in the early phase after transplant has been recently described. The aim of the present study was, therefore, to examine the growth factor expression in the early and later periods, up to three years after transplant in the same patient cohort. METHODS: Right ventricular endomyocardial biopsies were obtained from 29 heart transplant recipients before implantation, after one and two weeks, and after one, two, and three years after heart transplant, and immediately frozen in liquid nitrogen. The growth factor expression was examined immunohistochemically. RESULTS: The PDGFs were mainly expressed in vascular structures and they were less pronounced in cardiomyocytes. Especially after the first week, a significant increase was found in the expression of PDGF A and B as well as PDGF-receptors alpha and beta. In the yearly biopsies, PDGF expression was rarely found. The bFGF expression was merely weak in the later period three years after transplant and the aFGF was only expressed in the early phase. A comparison of recipients with short and long ischemic time did not reveal any significant differences in the intensity of expression. CONCLUSIONS: The increased expression of PDGF and FGF in the first postoperative week can be interpreted as an unspecific reaction to peritransplant injury. This might be related to important reparative, angioprotective, and wound-healing processes shortly after the heart transplant had taken place. The weak expression in the later period appears to be linked to a stable transplant function and a direct influence by the immunosuppressive therapy.
Adolescent↗
Late results after extended pulmonary artery reconstruction in the arterial switch operation.
BACKGROUND: Pulmonary artery stenosis remains the most frequent late complication and cause of reintervention after the arterial switch operation for transposition of the great arteries. We investigated the influence of an extended pericardial patch augmentation of the neopulmonary root and pulmonary artery on late pulmonary artery stenosis development. METHODS: Augmentation of the neopulmonary root and pulmonary artery was achieved by reconstructing the posterior wall using a large glutaraldehyde-treated autologous pericardial patch. Reviewed were regular follow-up echocardiograms from 58 out of 87 patients undergoing the arterial switch operation who presented a follow-up period of at least 5 years. An actual follow-up echocardiographic evaluation focusing on the maximal instantaneous transpulmonary continuous-wave (cw)-Doppler gradient was performed, followed by cardiac catheterization when indicated (peak cw-Doppler gradient > 40 mm Hg). RESULTS: Follow-up was 8.9 [5 to 15] years. There was no reintervention due to residual pulmonary artery stenosis. Actual Doppler examination revealed a transpulmonary peak gradient of 19.5 [0 to 56] mm Hg, compared with 20 [0 to 60] mm Hg at discharge. Forty-three patients (74.1%) had no or only trivial pulmonary artery stenosis (pressure gradient < 25 mm Hg), 14 patients (24.2%) had mild stenosis (25 to 49 mm Hg), and 1 patient (1.7%) had moderate stenosis (50 to 79 mm Hg). CONCLUSIONS: Compared with the majority of literature data, we could demonstrate a low incidence of late pulmonary artery stenosis after the arterial switch operation by employing an extended pericardial patch reconstruction technique with augmentation of the neopulmonary root and pulmonary artery.
Bioprosthesis↗
Adaptation of the right ventricle to an increased afterload in the chronically volume overloaded heart.
BACKGROUND: Increased right ventricular afterload is a common problem after correction of various heart diseases with chronic volume overload. We determined the effects of an acute increase of right ventricular afterload in normal and chronically volume overloaded hearts. METHODS: In 6 dogs, volume overload was induced by chronic arteriovenous shunts for 3 months. Six sham-operated animals served as controls. After closing the shunts, right ventricular systolic and end-diastolic pressure as well as end-diastolic volume were measured by conductance catheter. In addition, pressure-volume loops were recorded. Myocardial contractility was described by the slope of the end-systolic pressure-volume relationship. Afterload was increased to right ventricular systolic pressure to 35 mm Hg and to 50 mm Hg by pulmonary banding. RESULTS: Chronic volume overload resulted in a significant increase of right ventricular systolic pressure (34 +/- 2 versus 25 +/- 2 mm Hg, p < 0.05), end-diastolic pressure (10.4 +/- 1.7 versus 6.8 +/- 0.4 mm Hg, p < 0.05), and end-diastolic volume (39 +/- 2 versus 33 +/- 3 mL, p < 0.05). Baseline contractility (1.47 +/- 0.24 versus 1.53 +/- 0.32 mm Hg/mL) did not differ. While afterload increase to 35 and 50 mm Hg led to stepwise increase in contractility (2.73 +/- 0.30 mm Hg/mL and 4.15 +/- 0.30 mm Hg/mL, p < 0.05 versus baseline, respectively) at unchanged end-diastolic pressure and volume in controls, it showed only a slight increase (2.11 +/- 0.38 mm Hg/mL and 2.99 +/- 0.29 mm Hg/mL, p < 0.05 versus sham) with concomitant increase in end-diastolic pressure (12.4 +/- 2.2 mm Hg/mL and 16.3 +/- 1.9 mm Hg, p < 0.05) and volume (42 +/- 4 mL and 48 +/- 8 mL, p < 0.05) in the chronically volume overloaded group. CONCLUSIONS: Chronic volume overload per se does not impair right ventricular contractility. However, the inotropic adaptation (homeometric autoregulation) to an increased afterload is limited, which is partly compensated by the Frank-Starling mechanism (heterometric autoregulation).
Adaptation, Physiological↗
Immunomodulatory effects of poly(ADP-ribose) polymerase inhibition contribute to improved cardiac function and survival during acute cardiac rejection.
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.
Animals↗
Contractile dysfunction in experimental cardiac allograft rejection: role of the poly (ADP-ribose) polymerase pathway.
Recent studies suggested that the peroxynitrite-poly (ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. We investigated whether PARP inhibition improves transplant function during cardiac rejection. Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti-to-Lewis rat cardiac transplants were studied under treatment with placebo or with the PARP-inhibitor INO-1001 (1 mk/kg/day), Functional, biochemical and histological analysis were performed 3 and 5 days after transplantation. After 3 days, baseline left ventricular pressure-volume relationships did not differ between the groups. However, coronary blood flow (4.3 +/- 0.5 vs. 2.2 +/- 0.2 vs. 4.1 +/- 0.3 ml/min/g, P < 0.05) and contractile response to dobutamine (Delta+dP/dt: 98 +/- 11 vs. 57 +/- 7 vs. 88 +/- 8%, P < 0.05) decreased significantly in the placebo group, which was abolished by INO-1001. Vasodilatory response to acethylcholine was reduced in the placebo group (78 +/- 6 vs. 36 +/- 9 vs. 72 +/- 7%, P < 0.05). After 5 days, baseline systolic and diastolic pressure-volume relationships were impaired (P < 0.05) in the placebo group and the response to dobutamine and to acethylcholine deteriorated further which was abolished by INO-1001. Histology confirmed mild to moderate rejection after 3 days and severe acute rejection after 5 days in the allogeneic groups. Thus, contractile and vasomotor dysfunction occur in a typical time dependent manner during cardiac rejection, which can be reduced by PARP-inhibition.
Animals↗
Magnetic resonance blood flow measurements in the follow-up of pediatric patients with aortic coarctation - a re-evaluation.
BACKGROUND: Previous studies have suggested the feasibility of a non-invasive quantification of vascular trans-stenotic pressure gradients (DeltaP) by phase-contrast MR imaging (PC-MRI). Our purpose was to assess the value of MRI estimated pressure gradients as a screening tool for assessing hemodynamically significant (re-)coarctation of the aorta (CoA) in pediatric patients. METHODS: Forty-three patients (median age (range), 16 (5-25) years) with CoA (38 postoperative and 5 native) and clinically suspected hemodynamically significant stenosis underwent quantitative and semi-quantitative PC-MRI blood flow measurements and 3D MR-angiography, Doppler ultrasound (US) and conventional catheter angiography (CCA, n=20). Estimated DeltaP for each modality was correlated with percent stenosis. RESULTS: The percent stenosis correlated only moderately with DeltaP(MRI) (r=0.55, p<0.001) and DeltaP(CCA) (r=0.48, p<0.001). Only moderate correlations were observed between DeltaP(MRI) vs. DeltaP(CCA) (r=0.54, p=0.02) and vs. DeltaP(US) (r=0.40, p=0.01). In contrast, semi-quantitative analysis of PC-MRI flow profiles predicted with good sensitivity (88%) and specificity (88%) who would be operated on. Thirteen patients met hemodynamic and percent stenosis criteria by CCA for surgical intervention. CONCLUSION: Measured pressure gradients using PC-MRI should be used cautiously when assessing patients for recoarctation of the aorta. The analysis of blood flow profiles by PC-MRI might be a promising alternative in assessing the hemodynamic significance of CoA.
Adolescent↗
Influence of different implantation techniques on AV valve competence after orthotopic heart transplantation.
OBJECTIVE: About a decade after the introduction of the bicaval and pulmaonary venous heart transplantation technique a reduction of tricuspid and mitral valve incompetence compared to the standard technique by Lower and Shumway is still discussed controversially. We used this technique regularly since the year 1993 and report about our 10 years experience. METHODS: A total of 297 patients were transplanted at our institution between 1989 and 2003, 158 with the standard and 139 in the total orthotopic technique (TOHT). Ninety-four of the standard and 72 of the TOHT group were followed up as outpatients and were examined with right-heart catheterisation and trans-thoracic echocardiography. RESULTS: Patients in both groups were similar in demographic data. Right heart catheterisation showed no statistical significant differences between the two groups. The left atrium was significantly enlarged in the standard group. The TOHT group showed a significant reduction of tricuspid regurgitation in 5-year follow up echocardiography. CONCLUSION: This study showed excellent long-term survival rates for both groups. The significant reduction of left atrial size and atrio-ventricular valve regurgitation in the TOHT group might have important impact on the long-term preservation of cardiac function. Total orthotopic heart transplantation with bicaval and pulmonary venous anastomosis should be preferred for heart transplantation.
Adult↗
Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest.
The aim of this study was to investigate effects of poly(ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass (CPB) with cardiac arrest. Twelve anesthetized dogs underwent 90-min hypothermic CPB. After 60 min of cardiac arrest, reperfusion was started for 40 min following application of either saline vehicle (control, n = 6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv bolus and 0.5 mg.kg(-1).min(-1) infusion for 20 min, n = 6). PJ-34 led to better recovery of cardiac output (2.2 +/- 0.1 vs. 1.8 +/- 0.2 l/min in control) and mesenteric blood flow (175 +/- 38 vs. 83 +/- 4 ml/min, P < 0.05 vs. control) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine, assessed in the control group after CPB (-32.8 +/- 3.3 vs. -57.6 +/- 6.6% at baseline, P < 0.05), was improved by PJ-34 (-50.3 +/- 3.6 vs. -54.3 +/- 4.1% at baseline, P < 0.05 vs. control). Although plasma nitrate/nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 group (P < 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 +/- 1 vs. 135 +/- 9 ng/ml, P < 0.05). Pharmacological PARP inhibition protects against development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production, and reducing neutrophil adhesion.
Animals↗
Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation.
OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. METHODS: In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. RESULTS: INO-1001 led to significantly better recovery of contractility (91+/-3 vs. 44+/-7%, P<0.05) and CBF (44+/-4 vs. 29+/-3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61+/-10 vs. 27+/-8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0+/-2.1 vs. 4.5+/-1.1 micromol/g drw). Immunohistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. CONCLUSIONS: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.
Animals↗