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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation Background Cardiogenic shock (CS) complicates 8% of acute myocardial infarctions and has a short-term mortality approaching 50%. Traditional mechanical circulatory support (MCS) have significant adverse event profiles related to their position within the circulation. PALVAD is an extra circulatory MCS designed to be implanted percutaneously. The dual balloon system provides cardiac support whilst sitting in the space between the pericardium and left ventricular (LV) free wall. The actuator (ACT) balloon augments CO through ECG gated LV systolic compression and the positioning balloon sits against the pericardium dissipating this force. Methodology Non-recovery experiments were conducted in eleven 40k-60g pigs. A percutaneous coronary balloon occlusion model was initially used (n = 3) following which an Esmolol infusion model (n = 8) was used due to increased stability when titrating for a low cardiac output state . A Millar catheter was placed in the LV for simultaneous pressure and volume measurements and a Transonic flow probe was placed around the internal carotid. The device was inserted percutaneously and operated for alternating on/off periods. The device was inserted into a saline perfused cadaver following which CT and MRI imaging was undertaken. CT images were reconstructed three dimensionally and analysed. Results PAL-VAD had a significant impact across all parameters with a mean increase of 42% ± 16.1 in CO, 42% ± 17.3 in stroke volume, 20% ± 15.5 in pressure and a 30% ± 18.5 in flow and a mean device actuation of 48mins. Cadaveric imaging confirmed appropriate device dimensions for human anatomy and a 32% reduction in LV volume was seen with ACT balloon inflation. Conclusions PALVAD performance in during a low CO state is promising. Recovery experiments, including histology assessment, are planned to further evaluate safety and efficacy with longer-term use. % Increase with PALVAD Parameter% IncreaseCardiac Output42Stroke Volume42Pressure20Flow30Abstract Figure.

Background Cardiogenic shock complicates around 8% of acute myocardial infarctions with a significant short term mortality of 35–50%. Traditional mechanical circulatory support can improve cardiac output (CO) however they have significant adverse event profiles related to their position within the circulation, including but not limited to infection, stroke and embolism. PALVAD is an extra circulatory left ventricular assist device, designed to be implanted percutaneously., It provides cardiac support whilst sitting outside the circulatory system in the space between the pericardium and left ventricular (LV) free wall. The dual balloon system connects to an external pumping system via a drive line. The actuator balloon augments CO through ECG gated LV systolic compression and the positioning balloon sits against the pericardial surface dissipating this force across a large surface. Purpose Assess device efficacy in a low CO state in a non-recovery porcine model. Understand device interactions with the left ventricle and pericardium in a cadaveric model. Methodology Non-recovery porcine model experiments were conducted in three 40k-50g pigs at a large animal catheterisation facility. An Esmolol infusion was titrated to create a low output state. A Millar catheter was placed in the LV for simultaneous pressure and volume measurements and a Transonic flow probe was placed around the internal carotid for flow measurements. The device was inserted percutaneously and operated for a total of 4.7 hrs. For cadaveric experiments the device was inserted into a Thiel embalmed saline perfused cadaver following which detailed CT and MRI imaging was undertaken. Results When target reduction in cardiac output was met PALVAD increased systolic pressure by 34%, stroke volume by 54%, CO by 53% and flow by 53%. There was no macroscopic evidence of epicardial or pericardial damage. Cadaveric imaging further informed optimal positioning of the device in relation to the LV free wall. Conclusions PALVAD performance during low CO state in non-recovery porcine experiments is promising. Further recovery experiments, including histology assessment, are planed to evaluate safety and efficacy with longer term use to guide optimisation towards the eventual aim of a first-in-man trial. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation Translational Research Grant

Background Cardiogenic shock (CS) is defined as hypotension despite adequate filling status with signs of organ hypoperfusion resulting from a primary cardiac disorder. It complicates 8% of acute myocardial infarctions and, despite the widespread availability of primary percutaneous coronary intervention, continues to have a high short term mortality of 35-50%. Traditional mechanical circulatory support (MCS) can improve cardiac output (CO) however these devices have significant adverse event profiles related to their position within the circulation. PALVAD is an extra circulatory left ventricular assist device, designed to be implanted percutaneously. It provides cardiac support whilst sitting outside the circulatory system in the space between the pericardium and left ventricular (LV) free wall. The dual balloon system connects to a currently external pumping system via a driveline. The actuator (ACT) balloon augments CO through ECG gated LV systolic compression and the positioning balloon sits against the pericardial surface dissipating this force across a large area. Due to its position outside the circulation the device avoids risks with traditional MCS such as clot generation or bleeding (if anticoagulation required), haemolysis and the risk of intravascular infection leading to endocarditis. Furthermore, by avoiding the need for surgical implantation PAL-VAD avoids the risk of general anaesthetic in critically ill patients with the potential to enable more widespread timely initiation of MCS targeting improved outcomes in CS. Purpose Assess device efficacy in a low CO state in a non-recovery porcine model. Understand device interactions with the left ventricle and pericardium in a cadaveric model. Methodology Non-recovery porcine model experiments were conducted in ten 40k-60g pigs at a large animal catheterisation facility. In 3 animals a closed chest coronary occlusion reperfusion technique was adopted. In 7 animals an Esmolol infusion was titrated to create a low output state. A Millar catheter was placed in the LV for simultaneous pressure and volume measurements and a Transonic flow probe was placed around the internal carotid for flow measurements. The device was inserted successfully percutaneously and operated for alternating periods of 5 minutes on and 1 minute off. For the cadaveric experiment, the device was inserted into a Thiel embalmed saline or contrast perfused cadaver following which detailed CT and MRI imaging was undertaken with the device in varying configurations. CT images were reconstructed three dimensionally and analysed using NX computer aided design (CAD) software. Results PAL-VAD had a significant impact across all target parameters with a mean increase of 44% ± 14.5 in CO, 43% ± 16.2 in stroke volume, 25% ± 14.7 in pressure and a 30% ± 18.5 in flow. There was no macroscopic evidence of epicardial or pericardial damage. Cadaveric imaging informed optimal positioning of the device in relation to the LV free wall and a 48% reduction in LV volume was seen when the ACT balloon was inflated. Conclusions PALVAD performance during a low CO state in non-recovery porcine experiments is promising. Further recovery experiments, including histology assessment, are planned to evaluate safety and efficacy with longer term use to guide optimisation prior to a first-in-man trial. Conflict of Interest Nil

The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis. In DSS-treated wild-type mice, the preneoplastic lesions which did not eventually evolve to adenomas resided in a colitic microenvironment characterized by a balanced upregulation of both BMP ligands, i.e., Bmp4/7 and BMP inhibitors, such as chordin, noggin, and gremlin-1. In the uPA-deficient tumor-promoting inflammatory microenvironment, however, there was a clear evidence for BMP pathway suppression. By contrast to DSS-treated wild-type controls, the inflammation-associated Bmp4 upregulation was abolished, and the BMP signaling suppression was further enhanced by a particularly high increase of gremlin-1 expression. These findings propose that BMP pathway suppression in colon cancer could be associated with very early stages of the preneoplasia-to-neoplasia sequence of events.

Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease in humans. The disease associated variants fall in a gene called Hedgehog interacting protein-like 1 (HHIPL1), which encodes an uncharacterised sequence homolog of a Hedgehog protein antagonist. Here, we present our investigation of HHIPL1 function and its role in atherosclerosis. Epitope tagged HHIPL1 protein is present in the media of HHIPLI transfected cells and immunoprecipitates with GFP tagged Sonic Hedgehog (SHH) protein, demonstrating that HHIPL1 is a secreted interactor of SHH. We measured HHIPL1 gene expression in different cardiovascular cell types and found that it is primarily expressed in aortic smooth muscle cells (AoSMCs). We performed siRNA knock-down of HHIPL1 in AoSMCs and observed a reduction of 32% (+/-11%) in proliferation (p = 0.002 at 72 h) and a reduction of 27% (+/-4%) in migration (p = 0.02 at 12 h). We went on to examine the role of Hhipl1 in atherosclerosis in vivo. In atherosclerotic mouse aortas Hhipl1 expression increased with disease progression (~2-fold increase at 6 weeks vs 32 weeks of age, p = 0.001). We crossed Hhipl1-/- mice onto Apoe-/-and Ldlr-/- atherosclerosis prone backgrounds. Hhipl1-/- mice displayed a reduction of 57% (+/-28%) in lesion area compared with controls on an Ldlr-/- background (en face aorta, n = 10 Hhipl1+/+; Ldlr-/-vs n = 19 Hhipl1-/-; Ldlr-/-, t-test p = 0.00007) and 49% (+/-28%) reduction on an Apoe-/- background (en face aorta, n = 9 Hhipl1+/+; Apoe-/- vs n = 17 Hhipl1-/-; Apoe-/-, t-test p = 0.0004). Our data represent the first experimental investigation of HHIPL1. We find that HHIPL1 is a proatherogenic protein that regulates smooth muscle cell proliferation and migration, presumably through its involvement in Hedgehog signalling. Ongoing analysis will further define the mechanisms through which HHIPL1 contributes to atherosclerosis.

Purpose omega 3 polyunsaturated fatty acids have anti-inflammatory properties and can be beneficial in the treatment of inflammatory diseases, such as ulcerative colitis. Dextran sodium sulphate (DSS) colitis in rats appears to mimic nearly all of the morphological characteristics and lesion distributions of ulcerative colitis. The purpose of the current study was to investigate the efficacy of omega 3 fatty acids in the treatment of experimental ulcerative colitis. Methods thirty-six Wistar rats were randomly assigned to group A or group B receiving 5% dextran sulfate sodium (DSS) in their drinking water for eight days. For the next eight days post-DSS, group A animals received tap-water, and group B animals were fed a nutritional solution containing high levels of omega 3 polyunsaturated fatty acids (ProSure®, Abbott Laboratories, Zwolle, Netherlands) once per day, administrated with a orogastric feeding tube. Results animals fed an omega 3 rich diet exhibited a statistically significant increase in hematocrit and hemoglobin levels, compared to animals drinking tap water, and a trend towards histopathological and clinical improvement, with the administration of omega 3 fatty acids ameliorating epithelial erosion by day 8 post-DSS, but no statistically significant difference was observed between group A and group B animals at 4 or 8 days post-DSS. Also, a statistically significant increase in neutrophil infiltration was observed, as depicted by myelohyperoxidase activity. Conclusion our findings support a positive role of omega 3 polyunsaturated fatty acids supplementation in an experimental model of ulcerative colitis despite the increased colonic neutrophil infiltration. Further studies are needed in order to investigate the role of increased neutrophils in colonic mucosa.

Urokinase-type plasminogen activator (uPA) participates in cancer-related biologic processes, such as wound healing and inflammation. The present study aimed to investigate the effect of uPA deficiency on the long-term outcome of early life episodes of dextran sodium sulfate (DSS)-induced colitis in mice. Wild-type (WT) and uPA-deficient (uPA(-/-)) BALB/c mice were treated with DSS or remained untreated. Mice were necropsied either 1 week or 7 months after DSS treatment. Colon samples were analyzed by histopathology, immunohistochemistry, ELISA, and real-time polymerase chain reaction. At 7 months, with no colitis evident, half of the uPA(-/-) mice had large colonic polypoid adenomas, whereas WT mice did not. One week after DSS treatment, there were typical DSS-induced colitis lesions in both WT and uPA(-/-) mice. The affected colon of uPA(-/-) mice, however, had features of delayed ulcer re-epithelialization and dysplastic lesions of higher grade developing on the basis of a significantly altered mucosal inflammatory milieu. The later was characterized by more neutrophils and macrophages, less regulatory T cells (Treg), significantly upregulated cytokines, including interleukin-6 (IL-6), IL-17, tumor necrosis factor-α, and IL-10, and lower levels of active transforming growth factor-β1 (TGF-β1) compared to WT mice. Dysfunctional Treg, more robust protumorigenic inflammatory events, and an inherited inability to produce adequate amounts of extracellular active TGF-β1 due to uPA deficiency are interlinked as probable explanations for the inflammatory-induced neoplasmatogenesis in the colon of uPA(-/-) mice.