Biomedical subjects

Carsten J Beller

Publications and source records attributed to Carsten J Beller.

12 recordsLinked to original sources

PubMed2006

The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction.

Overproduction of oxidants and free radicals in ageing tissues induces nitro-oxidative stress, which has recently been implicated in the pathogenesis of cardiovascular dysfunction associated with ageing. Peroxynitrite, a strong cytotoxic oxidant damages proteins and DNA and activates several pathways causing tissue injury, including the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway. In this study, we investigated the effectiveness of the peroxynitrite decomposition catalyst FP15 on ageing-associated cardiac and vascular dysfunction. Young and ageing rats were treated with vehicle or FP15 intraperitoneally. Using a microtip Millar pressure catheter we performed left ventricular blood pressure analysis to assess systolic and diastolic function. Endothelium-dependent and -independent vasorelaxation of isolated aortic rings were investigated by using acetylcholine and sodium nitroprusside. Ageing animals showed a marked reduction of systolic and diastolic cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. FP15-treatment significantly improved cardiac performance and endothelial function. Immunohistochemical staining confirmed that FP15 effectively reduced nitrosative stress and prevented the activation of PARP in the aortic wall of ageing rats. Our results demonstrate the importance of endogenous peroxynitrite-overproduction in the pathogenesis of ageing-associated cardiovascular dysfunction. Pharmacological decomposition of peroxynitrite by FP15 may represent a novel therapeutic utility to improve cardiac and vascular dysfunction associated with ageing.

Acetylcholine↗

PubMed2006

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↗

PubMed2006

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↗

PubMed2006

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↗

PubMed2006

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↗

PubMed2006

Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation: a new target to prevent restenosis after endarterectomy.

OBJECTIVE: In a rat model of endarterectomy, we investigated the potential role of the peroxynitrite-poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) pathway in neointima formation and the effect of pharmacologic inhibition of PARP on vascular remodeling. METHODS: Carotid endarterectomy was performed in male Sprague-Dawley rats by incision of the left carotid artery with removal of intima. Three groups were studied: sham-operated rats (n = 10), control rats with endarterectomy (n = 10) or rats with endarterectomy treated with the PARP inhibitor, INO-1001 (5 mg/kg daily) postoperatively (n =10). After 21 days, neointima formation and vascular remodeling were assessed. RESULTS: Immunohistochemistry analysis demonstrated activation of the peroxynitrite-PARP pathway with significant staining for nitrotyrosine, poly(ADP-ribose), and nuclear translocation of apoptosis-inducing factor (AIF) in the neointima of the control group. Treatment with INO-1001 significantly reduced the neointima area (0.024 mm2 +/- 0.019 mm2 vs 0.089 mm2 +/- 0.033 mm2 in the control group), the neointima/media thickness ratio (0.81 +/- 0.05 vs 2.76 +/- 1.57 in the control group), and the inflammation score (0.1 +/- 0.07 vs 0.3 +/- 0.12 in the control group) after endarterectomy. CONCLUSIONS: Pharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.

Adenosine Diphosphate Ribose↗

PubMed2005

Geometric modeling of functional trileaflet aortic valves: development and clinical applications.

The dimensions of the aortic valve components condition its ability to prevent blood from flowing back into the heart. While the theoretical parameters for best trileaflet valve performance have already been established, an effective approach to describe other less optimal, but functional models has been lacking. Our goal was to establish a method to determine by how much the dimensions of the aortic valve components can vary while still maintaining proper function. Measurements were made on silicone rubber casts of human aortic valves to document the range of dimensional variability encountered in normal adult valves. Analytical equations were written to describe a fully three-dimensional geometric model of a trileaflet valve in both the open and closed positions. A complete set of analytical, numerical and graphical tools was developed to explore a range of component dimensions within functional aortic valves. A list of geometric guidelines was established to ensure safe operation of the valve during the cardiac cycle, with practical safety margins. The geometry-based model presented here allows determining quickly if a certain set of valve component dimensions results in a functional valve. This is of great interest to designers of new prosthetic heart valve models, as well as to surgeons involved in valve-sparing surgery.

Algorithms↗

PubMed2005

Increased aortic wall stress in aortic insufficiency: clinical data and computer model.

OBJECTIVE: The study was aimed at determining which cardiac pathologies are associated with increased longitudinal stress in the aorta and therefore may be responsible for the intimal transverse tears seen in aortic dissections. METHODS: Aortic root contrast injections were analyzed in 90 cardiac patients to measure the downward motion of the annulus during a cardiac cycle. A finite element model of the pressurized aortic root, arch and supra-aortic vessels was created to assess the influence of the aortic root motion on the aortic wall stress. RESULTS: The axial displacement of the aortic root ranged from 0 to 14 mm. A multivariate analysis showed that aortic insufficiency (AI) grade, hypokinesis of the left ventricle (HKI), and myocardial hypertrophy (HTR) were 3 independent variables which correlated with the axial displacement of the aortic root (DISP), such that ARM (mm)=5.379 (P<0.0001) +1.186 x AI grade (P=0.0016) - 1.611 x HKI (P=0.0078) - 1.399 x HTR (P=0.0355) with R2=0.23. The major finding of the stress analysis was that in the ascending aorta, at approximately 2 cm above the sino-tubular junction, the longitudinal stress due to aortic root motion was 32% higher in patients with AI than in patients without AI, thereby increasing the risk of transverse intimal rupture. CONCLUSIONS: Cardiac patients with AI are likely to experience enhanced longitudinal stress in the ascending aorta due to increased aortic root motion. Thus, these patients should be targeted and their aortic root movement monitored because it may be an important risk factor for aortic dissection.

Adult↗

PubMed2005

Are there surgical implications to aortic root motion?

BACKGROUND AND AIM OF THE STUDY: By increasing the longitudinal stress in the ascending aorta, downward movement of the aortic root might promote the proximal transverse tears seen in aortic dissections. The study aim was to evaluate the influence of five common cardiac conditions on the magnitude of aortic root displacement in cardiac patients. METHODS: Aortic root contrast injections were analyzed in 90 patients (mean age 68 years) to measure downward motion of the root perpendicular to the plane of the sinotubular junction (STJ). RESULTS: Displacement of the aortic root ranged from 0 to 14 mm (mean 4.8 mm). Patients with aortic insufficiency (AI) showed increased aortic root movement (7.3 versus 4.3 mm, p = 0.003), whereas those with left ventricular hypokinesis (3.7 versus 5.5 mm, p = 0.014) or with myocardial hypertrophy (3.8 versus 5.1 mm, p = 0.073) exhibited reduced downward movement. These variables were independent, and correlated with the magnitude of aortic root motion. A stress analysis of the aortic root, arch and branches of the arch determined that the longitudinal stress approximately 2 cm above the STJ, in the outer curve of the aorta, was increased by 32% in patients with AI compared to patients without AI. CONCLUSION: Patients with cardiac conditions associated with increased aortic root motion such as AI may be at greater risk of aortic dissection because of increased longitudinal stress in the ascending aorta. Therefore, AI should be used as an indicator and aortic root displacement monitored to prevent the risk of aortic dissection.

Adult↗

PubMed2004

Role of aortic root motion in the pathogenesis of aortic dissection.

BACKGROUND: The downward movement of the aortic root during the cardiac cycle may be responsible for producing the circumferential tear observed in aortic dissections. METHODS AND RESULTS: Contrast injections were investigated in 40 cardiac patients, and a finite element model of the aortic root, arch, and branches of the arch was built to assess the influence of aortic root displacement and pressure on the aortic wall stress. The axial displacement of the aortic root ranged from 0 to 14 mm. It was increased in patients with aortic insufficiency (22+/-13% of the sino-tubular junction diameter versus 12+/-9%) and reduced in patients with hypokinesis of the left ventricle (10+/-9% of sino-tubular junction versus 17+/-12%). The largest stress increase due to aortic root displacement was found approximately 2 cm above the sino-tubular junction, where the longitudinal stress increased by 50% to 0.32 Nmm(-2) when 8.9-mm axial displacement was applied in addition to 120-mm Hg luminal pressure. A similar result was observed when the pressure load was increased to 180 mm Hg without axial displacement. CONCLUSIONS: Both aortic root displacement and hypertension significantly increase the longitudinal stress in the ascending aorta. For patients with hypertension who are at risk of dissection, aortic root movement may be monitored as an important risk factor.

Aged↗

PubMed2004

A new computer model of mitral valve hemodynamics during ventricular filling.

OBJECTIVE: Quantitative description of left ventricular diastolic filling and mitral valve function remains difficult despite advances in echocardiography. The purpose of the present study was to develop a lumped parameter model of left ventricular filling and validate it in porcine trials under physiological conditions and after valve replacement. METHODS: Six animals were instrumented with aortic flow meter, left atrial pressure catheter and combined left ventricular pressure-conductance catheter. The model simulates ventricular and arterial pressures and flows during diastolic filling. Input parameters include maximum mitral valve area, blood viscosity and density, atrial compliance, left ventricular active relaxation characteristics and initial pressure and flow values. The outputs of the model are atrial and ventricular pressure as well as transmitral flow as a function of time. The model primarily consists of a system of four first-order, non-linear ordinary differential equations which were solved with MATLAB software. RESULTS: Left atrial and ventricular pressure data and model flow curves were nearly identical under baseline conditions, during rapid preload reduction by vena caval occlusion and after prosthetic valve replacement. Measured and model based calculation of early diastolic filling volume (E-wave), showed an excellent correlation under all three conditions (r = 0.998, P < 0.0001; r = 0.997, P < 0.0001; r = 0.974, P < 0.0001, respectively) with a mean difference less then two percent. CONCLUSION: The new lumped parameter model of left ventricular filling allows for the first time a detailed simulation of pressure and flow curves in the left heart including transmitral hemodynamics.

Animals↗

PubMed2003

Preoperative high leukocyte count: a novel risk factor for stroke after cardiac surgery.

BACKGROUND: Stroke after cardiac surgery is a devastating complication. The relationship between white blood cell count (WBC) and perioperative cerebrovascular accident (CVA) has not been investigated. An effort was made to identify how preoperative WBC may relate to CVA development during or after cardiac surgery. METHODS: Prospective data were collected from 7,483 patients who underwent coronary artery bypass grafting or valvular surgery or both. WBC was determined preoperatively and postoperatively. Differentiation of WBC was examined only preoperatively. RESULTS: There were a total of 125 CVAs (10 transient ischemic attacks [TIAs], 115 strokes). WBC was significantly higher preoperatively and directly postoperatively in patients with stroke. Qualitative changes in preoperative WBC were also found in these patients (chi2; p < 0.001). The predictive power of the stepwise logistic regression model for CVA was greater when preoperative WBC was included. The risk for perioperative CVA increased starting at preoperative WBC of 9 x 10(9)/L (p = 0.044) and progressed in higher WBC ranges. WBC had a significant impact on CVA outcome (analysis of variance, p = 0.001). CONCLUSIONS: Our studies have established the correlation between high preoperative WBC and stroke during or after cardiac surgery. Furthermore, elevated preoperative WBC was related to the clinical outcome of CVA. Preoperative measures aimed at preventing or treating conditions such as infections that may cause elevated WBC may be beneficial in the prevention of stroke during or after cardiac surgery.

Aged↗