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Hypertension and/or aging impose stress on the heart with consecutive cardiac hypertrophy, inflammation and fibrosis, processes that lead to heart failure. Our group has previously shown that non-structural matrix proteins such as TSP-2 and SPARC are critical during hypertension, fibrosis, and age-related cardiac dysfunction. Osteoglycin (OGN) is a class III member of the small leucine rich proteoglycans, and was recently identified as a marker of increased left ventricular mass in a study using genomics in recombinant inbred hypertensive rat strains. Its precise biological role in cardiac remodeling, however, remains unclear. We hypothesize that OGN will influence cardiac hypertrophy and fibrosis and hence is critical in the cardiac response during hypertension and aging.We show in young adult mice (3 months old) that hypertension-induced pressure overload of the heart causes two phases of cardiac fibrosis, following 28 days of angiotensin-II (AngII) infusion. The first phase develops between days 3 to 7 after the AngII-treatment and consists of diffuse interstitially deposited loose fibers. During the second wave of fibrosis, which starts at 14 days, these loose fibers transition into more localized scars of denser collagens. Interestingly, the expression of OGN mRNA also shows a biphasic response, significantly decreasing prior to each phase of fibrosis, at day 1 (96% decrease, p=0.002) and day 14 (84% decrease, p=0.004) respectively. Moreover, hypertension causes exaggerated cardiac fibrosis (7.54±1.58 vs. 3.65±0.62 %, p=0.04) and increased heart weight to body weight ratios (6.39±0.31 vs. 5.42±0.17 mg/g, p=0.01) in young adult OGN null mice when compared to WT littermates, but no differences in the amount of infiltrating leukocytes (31.48±9.82 vs. 36.32±18.75 cells/mm2), after 28 days of AngII infusion. In addition, aging results in decreased cardiac function, as measured by ejection fraction, in 18 months versus 3 months old OGN null mice (42.65±2.74 vs. 58.05±1.37 %, p=0.0001), which is absent in WT mice (51.01±3.11 vs. 53.01±1.67 %, p=0.62). Furthermore, a follow-up study in WT and OGN null mice showed a decrease in stroke volume over time in the OGN null mice (39.30±2.90 μl at 6 months, 35.54±1.95 μl at 12 months and 31.13±1.29 μl at 18 months, p=0.04 between 6 and 18 months) but not in the WT mice (41.61±2.02 μl at 6 months, 39.04±1.95 μl at 12 months and 41.04±3.05 μl at 18 months). Collectively, these data suggest that OGN regulates cardiac fibrosis during pressure overload and is therefore important in the remodeling response to hypertension and aging. [ABSTRACT FROM AUTHOR]

To describe the prevalence of late graft dysfunction (LGD) in long-term survivors after heart transplantation (HTx) and determine baseline characteristics associated with the development of LGD. We retrospectively analysed pretransplant and 1-year characteristics of all adult patients who were transplanted in our centre and underwent right heart catheterization (RHC) 10 years post-HTx. LGD was defined as pulmonary capillary wedge pressure (PCWP) ≥15mmHg. Between 1989 and 2010, 310 patients were transplanted and underwent RHC 10 years post-HTx. A PCWP ≥ 15 mmHg was observed in 45% of the recipients, increasing to 57% 20 years after HTx. More than 95% of the recipients with LGD had a left ventricle ejection fraction > 50% on echocardiography. Table 1 shows the differences in pretransplant and first year characteristics between recipients with a PCWP < 15 mmHg and those with a PCWP ≥ 15 mmHg. In the first era (1987-1999) donor age was lower compared to the second post-transplantation era (2000-2010), with a median age of 30 (interquartile range (IQR) 21-39) and 38 (IQR 22-47) years, respectively (p<0.001). On univariate analysis donor age, PCWP 3 weeks post HTx, era and cyclosporine use were associated with LGD. On multivariate analysis, only donor age and PCWP 3 weeks post-HTx remained independently associated with LGD (table 2). Our analysis shows a high prevalence of LGD 10 years after HTx. Recipients receiving an older donor heart or having a higher PCWP 3 weeks post-HTx are at increased risk of developing LGD. The increased prevalence of LGD in the most recent era (58% versus 42%, p=0.001) might be explained by the higher donor age. [ABSTRACT FROM AUTHOR]

Background:Glioblastoma multiforme (GBM), a highly invasive primary brain tumour, remains an incurable disease. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), have central roles in GBM invasion. Anti-angiogenic therapies may stimulate GBM invasion via HGF/c-Met signalling. We aim to identify mediators of HGF-induced GBM invasion that may represent targets in a combination anti-angiogenic/anti-invasion therapeutic paradigm.Methods:Guanine nucleotide exchange factor expression was measured by microarray analysis and western blotting. Specific depletion of proteins was accomplished using siRNA. Cell invasion was determined using matrigel and brain slice assays. Cell proliferation and survival were monitored using sulforhodamine B and colony formation assays. Guanine nucleotide exchange factor and GTPase activities were determined using specific affinity precipitation assays.Results:We found that expression of Dock7, a GEF, is elevated in human GBM tissue in comparison with non-neoplastic brain. We showed that Dock7 mediates serum- and HGF-induced glioblastoma cell invasion. We also showed that Dock7 co-immunoprecipitates with c-Met and that this interaction is enhanced upon HGF stimulation in a manner that is dependent on the adaptor protein Gab1. Dock7 and Gab1 also co-immunoprecipitate in an HGF-dependent manner. Furthermore, Gab1 is required for HGF-induced Dock7 and Rac1 activation and glioblastoma cell invasion.Conclusions:Dock7 mediates HGF-induced GBM invasion. Targeting Dock7 in GBM may inhibit c-MET-mediated invasion in tumours treated with anti-angiogenic regimens. [ABSTRACT FROM AUTHOR]

To analyze our institutional outcomes in heart-lung transplantation (HLTx). We performed a single-center retrospective analysis of all patients who underwent HLTx at the University Hospitals Leuven (UZL) from 1991 to 2018 and compared our results to ISHLT registry data. 50 patients underwent HLTx in UZL. In-hospital mortality was 24% vs 72% in the ISHLT database (p<1.10-5). On average baseline characteristics of donors and receptors were comparable between UZL and ISHLT. Kaplan-Meier survival curves for both are depicted in figure 1. When considering the eras 1991-2003 and 2004-2018, 1-, 5, and 10-year survival rates of UZL were more favorable for the latter era; 15-year survival was significantly better for era 2004-2018, as depicted in figure 2. Over time, we observed an increase in cardiac-related indications with Eisenmenger syndrome being the most important (56% vs 25% in the ISHLT registry, p<1.10-5). Other forms of pulmonary arterial hypertension (PAH) were an important indication to perform HLTx (24% in both groups). The major cause of late mortality in our population was rejection (41.4%), more specifically chronic lung allograft dysfunction. Between 1991 and 2018, we performed 50 HLTx's. The most frequent indication was Eisenmenger syndrome, but with a twofold higher proportion in our population compared to the ISHLT registry. The proportion of other forms of PAH was comparable. While over time the indications shifted from pulmonary to cardiac conditions, our survival continues to improve. [ABSTRACT FROM AUTHOR]