No abstract

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.

Multiple myeloma (MM) is an incurable plasma cell disorder representing 10% of all hematologic malignancies. Cancer is a known risk factor for venous thromboembolism (VTE). Patients with MM are at a particularly high risk of developing VTE owing to patient characteristics (e.g. previous history of VTE), disease characteristics, and treatment characteristics including use of the immunomodulatory agents (IMIDs). Unfortunately, standard criteria to identify the patients most at risk for developing VTE in MM while receiving IMIDs are unknown. We sought to assess the incidence of VTE and its associated risk factors in MM patients receiving IMID therapy. A retrospective cohort study including 1680 consecutive patients with multiple myeloma treated at our centre between January 01, 1995 and January 26, 2016 was conducted. The annual incidence of VTE on immunomodulatory agents including thalidomide, lenalidomide, and pomalidomide was derived. Univariate incidence ratio analyses of VTE for different risk factors was performed including: previous history of VTE, concomitant use of dexamethasone, and ≥/< 6 months after IMID initiation. A total of 309 MM patients treated with an immunomodulatory agent were identified. Nineteen patients were excluded (incomplete data, lost to follow). Of the remaining 290 patients, the mean age was 67.9 and 42.4% were female. Twenty-seven VTE events were recorded. The overall risk ratio was 6.1 for the development of VTE. Patients with a personal history of VTE had an increased risk of suffering a VTE while on IMID therapy (IRR 5.4; CI, 1.9-13.6). The time from the initiation of the IMID therapy (less than 6 months) also increased the risk of developing a VTE (IRR 51.7; CI,19.4-160.1). The concomitant use of dexamethasone was not associated with a statistically significant increased risk (IRR 1.7; CI, 0.3-69.5). Incidence risk ratios for these risk factors are depicted in Table 1. Our results suggest that a personal history of VTE and the time from the initiation of the IMID (less than 6 months) are associated with an increased risk of VTE in MM patients receiving IMID therapy. This may be helpful in determining which multiple myeloma patients treated with an IMID agent warrant more aggressive thromboprophylaxis. Further prospective studies are needed to determine the optimal agent, intensity, and duration of thromboprophylaxis in patients with MM on IMID therapy. Disclosures McCurdy: Celgene: Honoraria.