Evaluation of inflow cannulation site for implantation of right-sided rotary ventricular assist device

Right heart dysfunction is one of the most serious complications following implantation of a left ventricular assist device (LVAD), often leading to the requirement for short or long term right ventricular support (RVAD). The inflow cannulation site induces major haemodynamic changes and so there is a need to optimize the site used depending on the patient's condition. Therefore, this study evaluated and compared the haemodynamic influence of right atrial (RAC) and right ventricular (RVC) inflow cannulation sites. An in-vitro, variable heart failure, mock circulation loop was used to compare RAC and RVC in mild and severe biventricular heart failure (BHF) conditions. In the severe BHF condition, higher ventricular ejection fraction (RAC: 13.6%, RVC: 32.7%) and thus improved heart chamber and RVAD washout was observed with RVC, which suggested this strategy might be preferable for long term support (ie. bridge to transplant or destination therapy) to reduce the risk of thrombus formation. In the mild BHF condition, higher pulmonary valve flow (RAC: 3.33 L/min, RVC: 1.97 L/min) and lower right ventricular stroke work (RAC: 0.10 W, RVC: 0.13 W) and volumes were recorded with RAC. These results indicate an improved potential for myocardial recovery, thus RAC should be chosen in this condition. This in-vitro study suggests that RVAD inflow cannulation site should be chosen on a patient-specific basis with a view to the support strategy to promote myocardial recovery or reduce the risk of long-term complications.

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.

Platelet-derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is an enzyme with angiogenic and cell motility properties. Moreover, it is involved in the transformation of fluoropyrimidines into active cytotoxic metabolites, In the present study, the expression of PD-ECGF in normal lung and lung cancer was immunohistochemically evaluated using the P-GF.44C monoclonal antibody. Alveolar and tumoural macrophages mere invariably stained and mere used as an internal control for assessment of the staining. Alveolar epithelium was always negative, whilst bronchiolar epithelium showed occasional positive reactivity. Normal lung and tumour endothelium was occasionally positive, Positive staining in more than 50 per cent of cells was observed in 23/71 squamous carcinomas (32 per cent), 16/38 (42 per cent) adenocarcinomas, and 2/6 (33 per cent) adenosquamous carcinomas. Differentiated areas and areas of squamous metaplasia mere more strongly positive than other tumour areas. All 22 small cell carcinomas and one carcinoid tumour were negative. The present study provides a baseline for future studies in non-small cell lung cancer to correlate PD-ECGF expression with tumour vascularization, prognosis, and response to chemotherapy.

bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer

Tumour angiogenesis has been recently recognised as one of the most important prognostic factors in lung cancer. Although a variety of angiogenic factors have been identified, the angiogenesis process remains poorly understood. Bcl-2, c-erbB-2 and p53 are well-known oncogenes involved in non- small-cell lung cancer pathogenesis. A direct correlation of thymidine phosphorylase (TP) and of vascular endothelial growth factor (VEGF) with intratumoural angiogenesis has been reported. In the present study we investigated the possible regulatory role if bcl-2, c-erB-2 proteins in angiogenesis and in VEGF and TP expression in non-small-cell lung cancer. Two hundred sixteen specimens from T1,2-NO, 1 staged patients treated with surgery alone were immunohistochemically examined. Bcl-2 and c-erbB-2 were significantly inversely related to each other (P = 0.04) and both were inversely associated with microvessel density (P < 0.02). High TP and VEGF reactivity was statistically related to loss of bcl-2 expression (P < 0.01). A significant co-expression of c-erbB-2 with TP was noted (P = 0.01). However, TP expression was related to high angiogenesis only in cases with absence of c-erB-2 expression (P < 0.0001). c-erbB-2 expression in poorly vascularised tumours was linked with poor outcome (P = 0.03). The present study provides strong evidence that the bcl-2 gene has a suppressive function over genes involved in both angiogenesis (VEGF and TP) and cell migration (c- erbB-2) in NSCLC. TP and c-erbB-2 proteins are significantly, and often simultaneously, expressed in bcl-2 negative cases. However, expression of the c-erbB-2 abolishes the TP-related angiogenic activity. Whether this is a result of a direct activity of the c-erbB-2 protein or a consequence of a c- erbB-2-related immune response remains to be further investigated.

Potential role of bcl-2 as a suppressor of tumour angiogenesis in non- small-cell lung cancer

It has been reported that genes regulating apoptosis may play a role in tumoral angiogenesis. This study examined the relationship between tumour vascularization, a measure of tumour angiogenesis, and bcl-2 and p53 expression in operable non-small-cell lung cancer (NSCLC). The relationship between bcl-2, p53 and tumour vascularization and epidermal-growth-factor- receptor(EGFR) and c-erbB-2 expression was also studied. Tissue sections from resected tumour specimens of 107 NSCLC patients were evaluated immunohistochemically for vascular grade and bcl-2, p53, EGFR and c-erbB-2 expression. bcl-2 expression was found in 20/107 (19%) cases and was associated with squamous-cell histology (p = 0.03). A strong inverse relationship was found between bcl-2 expression and vascular grade (p = 0.005). All c-erbB-2-positive cases were negative for bcl-2 expression (p = 0.01). Overall no association was found between c-erbB-2 expression and vascular grade. However, in bcl-2-negative cases positive c-erbB-2 expression correlated with low angiogenesis (p = 0.05). No relationship was found between p53 and EGFR expression and bcl-2, c-erbB-2 or vascular grade. The improved prognosis reported in bcl-2-positive NSCLC may be related to low tumour vascularization. The results suggest that the anti-apoptotic gene bcl- 2 plays a role in regulating tumour angiogenesis. Since normal lung epithelium expresses bcl-2, a sequence of tumour progression involving loss of bcl-2, then activation of c-erbB-2 or increase in tumour vascularization is proposed.

Angiogenesis as a biomarker and target in cancer chemoprevention

Angiogenesis, the formation of new blood vessels from existing vasculature, is essential to the late stages of carcinogenesis, allowing tumours to grow beyond 1-2 mm in diameter, invade surrounding tissue, and metastasise. However, more than two decades ago, angiogenesis that preceded neoplastic transformation was seen. Indeed, it can be detected in inflammatory and infectious diseases that increase the risk of developing cancer. Recent advances in fluorescence endoscopy and histological assessment suggest that, for certain cancers, the degree of new blood-vessel formation may differ between the early and late stages of carcinogenic progression. The association between angiogenesis and cancer occurrence, and ease of detection of this process in accessible tissues early in carcinogenesis, mean that angiogenesis fulfils the criteria for a biomarker of the effectiveness of chemopreventive intervention. There is also some evidence that biochemical assays of angiogenic growth factors may after similar potential as surrogate biomarkers. Many natural and synthetic chemopreventive agents in development or in clinical use inhibit new vessel formation in vivo. Validation of angiogenesis as a biomarker for the effectiveness of chemoprevention should further the advancement of some chemopreventive agents.

Interactions between hypoxia and epidermal growth factor receptor in non-small-cell-lung cancer

Tumor hypoxia has been recognized to confer resistance to anticancer therapy since the early 20th century. More recently, its fundamental role in tumorigenesis has been established. Hypoxia-inducible factor (HIF)-1 has been identified as an important transcription factor that mediates the cellular response to hypoxia, promoting both cellular survival and apoptosis under different conditions. Increased tumor cell expression of this transcription factor promotes tumor growth In vivo and is associated with a worse prognosis in patients with non-small-cell lung cancer (NSCLC) undergoing tumor resection. The epidermal growth factor receptor (EGFR) promotes tumor cell proliferation and anglogenesis and inhibits apoptosis. Epidermal growth factor receptor expression increases in a stepwise manner during tumorigenesis and is overexpressed in > 50% of NSCLC tumors. This review discusses the reciprocal relationship between tumor cell hypoxia and EGFR. Recent studies suggest that hypoxia induces expression of EGFR and its ligands. In return, EGFR might enhance the cellular response to hypoxia by increasing expression of HIF-1α, and so act as a survival factor for hypoxic cancer cells. Immunohistochemical studies on a series of resected NSCLC tumors add weight to this contention by demonstrating a close association between expression of EGFR, HIF-1α, and:1 of HIF-1's target proteins, carbonic anhydrase IX. In this article we discuss emerging treatment strategies for NSCLC that target HIF-1, HIF-1 transcriptional targets, and EGFR.

A comparative analysis of risk stratification tools for emergency department patients with chest pain

Background: Appropriate disposition of emergency department (ED) patients with chest pain is dependent on clinical evaluation of risk. A number of chest pain risk stratification tools have been proposed. The aim of this study was to compare the predictive performance for major adverse cardiac events (MACE) using risk assessment tools from the National Heart Foundation of Australia (HFA), the Goldman risk score and the Thrombolysis in Myocardial Infarction risk score (TIMI RS). Methods: This prospective observational study evaluated ED patients aged ≥30 years with non-traumatic chest pain for which no definitive non-ischemic cause was found. Data collected included demographic and clinical information, investigation findings and occurrence of MACE by 30 days. The outcome of interest was the comparative predictive performance of the risk tools for MACE at 30 days, as analyzed by receiver operator curves (ROC). Results: Two hundred eighty-one patients were studied; the rate of MACE was 14.1%. Area under the curve (AUC) of the HFA, TIMI RS and Goldman tools for the endpoint of MACE was 0.54, 0.71 and 0.67, respectively, with the difference between the tools in predictive ability for MACE being highly significant [chi2 (3) = 67.21, N = 276, p < 0.0001]. Conclusion: The TIMI RS and Goldman tools performed better than the HFA in this undifferentiated ED chest pain population, but selection of cutoffs balancing sensitivity and specificity was problematic. There is an urgent need for validated risk stratification tools specific for the ED chest pain population.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.

An arteriovenous loop in a protected space generates a permanent, highly vascular, tissue-engineered construct

A major obstacle to 3-dimensional tissue engineering is incorporation of a functional vascular supply to support the expanding new tissue. This is overcome in an in vivo intrinsic vascularization model where an arteriovenous loop (AVL) is placed in a noncollapsible space protected by a polycarbonate chamber. Vascular development and hypoxia were examined from 3 days to 112 days by vascular casting, morphometric, and morphological techniques to understand the model's vascular growth and remodeling parameters for tissue engineering purposes. At 3 days a fibrin exudate surrounded the AVL, providing a scaffold to migrating inflammatory, endothelial, and mesenchymal cells. Capillaries formed between 3 and 7 days. Hypoxia and cell proliferation were maximal at 7 days, followed by a peak in percent vascular volume at 10 days (23.20±3.14% compared with 3.59±2.68% at 3 days, P<0.001). Maximal apoptosis was observed at 112 days. The protected space and spontaneous microcirculatory development in this model suggest it would be applicable for in vivo tissue engineering. A temporal window in a period of intense angiogenesis at 7 to 10 days is optimal for exogenous cell seeding and survival in the chamber, potentially enabling specific tissue outcomes to be achieved.

An endogenously deposited fibrin scaffold determines construct size in the surgically created arteriovenous loop chamber model of tissue engineering

Background: An arteriovenous loop (AVL) enclosed in a polycarbonate chamber in vivo, produces a fibrin exudate which acts as a provisional matrix for the development of a tissue engineered microcirculatory network. Objectives: By administering enoxaparin sodium - an inhibitor of fibrin polymerization, the significance of fibrin scaffold formation on AVL construct size (including the AVL, fibrin scaffold, and new tissue growth into the fibrin), growth, and vascularization were assessed and compared to controls. Methods: In Sprague Dawley rats, an AVL was created on femoral vessels and inserted into a polycarbonate chamber in the groin in 3 control groups (Series I) and 3 experimental groups (Series II). Two hours before surgery and 6 hours post-surgery, saline (Series I) or enoxaparin sodium (0.6 mg/kg, Series II) was administered intra-peritoneally. Thereafter, the rats were injected daily with saline (Series I) or enoxaparin sodium (1.5 mg/kg, Series II) until construct retrieval at 3, 10, or 21 days. The retrieved constructs underwent weight and volume measurements, and morphologic/morphometric analysis of new tissue components. Results: Enoxaparin sodium treatment resulted in the development of smaller AVL constructs at 3, 10, and 21 days. Construct weight and volume were significantly reduced at 10 days (control weight 0.337 ± 0.016 g [Mean ± SEM] vs treated 0.228 ± 0.048, [P < .001]: control volume 0.317 ± 0.015 mL vs treated 0.184 ± 0.039 mL [P < .01]) and 21 days (control weight 0.306 ± 0.053 g vs treated 0.198 ± 0.043 g [P < .01]: control volume 0.285 ± 0.047 mL vs treated 0.148 ± 0.041 mL, [P < .01]). Angiogenesis was delayed in the enoxaparin sodium-treated constructs with the absolute vascular volume significantly decreased at 10 days (control vascular volume 0.029 ± 0.03 mL vs treated 0.012 ± 0.002 mL [P < .05]). Conclusion: In this in vivo tissue engineering model, endogenous, extra-vascularly deposited fibrin volume determines construct size and vascular growth in the first 3 weeks and is, therefore, critical to full construct development.

The influence of extracellular matrix on the generation of vascularized, engineered, transplantable tissue

In a recently described model for tissue engineering, an arteriovenous loop comprising the femoral artery and vein with interposed vein graft is fabricated in the groin of an adult male rat, placed inside a polycarbonate chamber, and incubated subcutaneously. New vascularized granulation tissue will generate on this loop for up to 12 weeks. In the study described in this paper three different extracellular matrices were investigated for their ability to accelerate the amount of tissue generated compared with a no-matrix control. Poly-D,L-lactic-co-glycolic acid (PLGA) produced the maximal weight of new tissue and vascularization and this peaked at two weeks, but regressed by four weeks. Matrigel was next best. It peaked at four weeks but by eight weeks it also had regressed. Fibrin (20 and 80 mg/ml), by contrast, did not integrate with the generating vascularized tissue and produced less weight and volume of tissue than controls without matrix. The limiting factors to growth appear to be the chamber size and the capacity of the neotissue to integrate with the matrix. Once the sides of the chamber are reached or tissue fails to integrate, encapsulation and regression follow. The intrinsic position of the blood supply within the neotissue has many advantages for tissue and organ engineering, such as ability to seed the construct with stem cells and microsurgically transfer new tissue to another site within the individual. In conclusion, this study has found that PLGA and Matrigel are the best matrices for the rapid growth of new vascularized tissue suitable for replantation or transplantation.

Expression profile of endothelin 1 and its receptor endothelin receptor A in papillary thyroid carcinoma and their correlations with clinicopathologic characteristics

The endothelin axis is a group of signaling molecules and their receptors that have been implicated in vascularization of cancers, with their expression being observed to change in different cancer types. In this research, we examined the expression of endothelin 1 and endothelin receptor A at the protein and messenger RNA (mRNA) levels in 123 papillary thyroid carcinomas and 40 matched lymph nodes with metastatic papillary thyroid carcinomas. We found altered endothelin axis mRNA expression in several clinicopathologic parameters with increased endothelin 1 expression in thyroid papillary carcinoma showing stromal calcification, cancers in men, and primary cancers with lymph node metastases. Increased endothelin receptor A mRNA expression was noted in the larger cancers. There is a significant correlation between expression of endothelin receptor A and endothelin 1 in papillary thyroid carcinoma. Both endothelin receptor A and endothelin 1 mRNA expressions were significantly higher in metastatic carcinoma in the lymph node than in primary thyroid cancer. The metastatic carcinoma in the lymph node had increased expression compared with matched primary thyroid carcinoma. Expressions of endothelin 1 and endothelin receptor A were also documented as being high at the protein level. Our results indicate that in thyroid cancer, endothelin 1 and endothelin receptor A are associated with growth in advanced stages and lymph node metastases, likely through known angiogenic linkages. Targeting the endothelin axis may be useful in planning angiogenesis therapy for thyroid cancer.

Impact of community pharmacist intervention discussing patients’ beliefs to improve medication adherence

Background Adherence to evidence based medicines in patients who have experienced a myocardial infarction remains low. Individual’s beliefs towards their medicines are a strong predictor of adherence and may influence other factors that impact on adherence. Objective To investigate if community pharmacists discussing patients’ beliefs about their medicines improved medication adherence at 12 months post myocardial infarction. Setting This study included 200 patients discharged from a public teaching hospital in Queensland, Australia, following a myocardial infarction. Patients were randomised into intervention (n = 100) and control groups (n = 100) and followed for 12 months. Method All patients were interviewed between 5 to 6 weeks, at 6 and 12 months post discharge by the researcher using the repertory grid technique. This technique was used to elicit the patient’s individualised beliefs about their medicines for their myocardial infarction. In the intervention group, patients’ beliefs about their medicines were communicated by the researcher to their community pharmacist. The pharmacist used this information to tailor their discussion with the patient about their medication beliefs at designated time points (3 and 6 months post discharge). The control group was provided with usual care. Main outcome measure The difference in non-adherence measured using a medication possession ratio between the intervention and control groups at 12 months post myocardial infarction. Results There were 137 patients remaining in the study (intervention group n = 72, control group n = 65) at 12 months. In the intervention group 29 % (n = 20) of patients were non-adherent compared to 25 % (n = 16) of patients in control group. Conclusion Discussing patients’ beliefs about their medicines for their myocardial infarction did not improve medication adherence. Further research on patients beliefs should focus on targeting non-adherent patients whose reasons for their non-adherence is driven by their medication beliefs.