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Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.

s S201 Methods: On April 1, 2014, we started using the protocol for prevention of pump thrombosis. The key points included checking for hypercoagulable state at the baseline and raising INR goals to 2.5-3.5 for patients with such state or for those with spikes in lactatedehydrogenase (LDH), full dose aspirin (325 mg) and dipyridamole 25 mg three times a day for patients without history of bleeding, coverage with low molecular weight heparin when INR drops below therapeutic, and admission with immediate full work-up for pump thrombosis when LDH exceeds 600 IU/mL for HeartMate II or 400 IU/mL for Heartware (LDH spikes). Comparison for LDH spikes was made between first three months of the year (before the protocol), second three months (transition), and third quarter (on the protocol). The comparison was done with chi square test. Results: In the 1st quarter of 2014, we followed 33 patients (5 with Heartware), and 7 (20.6) had LDH spikes. In the 2nd quarter, there were 37 patients (8 with Heartware) with 6 (15.7%) having LDH spikes. In the third quarter, there were 37 patients (10 with Heartware) with 2 LDH spikes (5.1%, p= 0.05 for the difference between the 1st and the 3rd quarter). The distribution of LDH values is shown on figure 1. There was one clinical pump thrombosis in each of the first two quarters and none in the third quarter. There was no increase in bleeding events or decrease in hematocrit after the protocol was started. Conclusion: Targeted higher level of anticoagulation in LVAD patients decreases the rate of LDH spikes used as a surrogate indicator of pump thrombosis.

Purpose: Position of the inflow cannula (IC) within the left ventricle may affect optimal function of the LVAD and contribute to the risk of complications. We evaluated the intraventricular position of the IC in Heartmate II (HM2) and Heartware (HW) LVADs. Methods: A single-center retrospective review of the most recent cardiac CT (CCT) of all continuous flow LVAD implants between 10/2006 and 9/2013 was performed. CT acquisitions were completed on a 64 or 256 slice platform using ECG gated helical technique. Measurements were performed in standard 2-chamber and short-axis views. Fisher’s exact and Wilcoxon-MannWhitney tests were used to determine statistical difference between groups. Results: A total of 195 patients underwent LVAD implants (101 HM2, 94 HW). At least one CCT was performed on 63 patients. Mean LV end diastolic diameter was 63 ± 11 mm. Apical tip of the IC was more frequently in contact with anterior wall in the HM2 patients (15/24, 62%) compared to HW pumps (5/38, 13%, p< 0.001). Basal tip did not abut the anterior wall in any patient. Septal wall contact was 25% vs. 5 % (p= 0.05) and lateral wall contact was 29% vs. 25% (p= 0.7) in HM2 and HW pumps, respectively. In the total population, the IC was angulated towards the mitral annulus plane (median 33 degrees, IQR 22, 46) and formed a 77-degree horizontal angle in the short axis (IQR 57, 95, figure 1). Angle of the IC was significantly different between HM2 and HW LVADs (table 1). Conclusion: Significant variation exists among patients and between two different types of continuous-flow LVAD with regards to intraventricular position of the inflow cannula. Clinical significance of these variations remains to be determined.