IL-11 is a crucial determinant of cardiovascular fibrosis.

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is a complication reported in patients post left ventricular assist device (LVAD) implantation that is associated with high mortality rates. Thalidomide is an anti-angiogenic compound that may offer a potential option for management of refractory LVAD-related GIB. METHODS: A single-center, retrospective review was conducted from January 2009 to October 2016 at a tertiary cardiology center. It included LVAD patients initiated on thalidomide for refractory GIB. RESULTS: All patients (n = 11) were started on thalidomide 50 mg nocte and there was resolution of GIB in all patients except one (90.9%) during initial thalidomide treatment.The median duration of thalidomide therapy was 98 days (interquartile range: 34-215). The dose of thalidomide was reduced for 2 patients due to adverse effects. Thalidomide therapy was discontinued in 6 patients due to cessation of GIB (n = 4) and adverse effects (n = 2). Reported adverse effects included LVAD thrombosis (n = 2), somnolence (n = 1), neuropathy (n = 1), constipation (n = 1), and transaminitis (n = 1).Recurrent GIB occurred in 4 patients (45.4%) post-discontinuation of thalidomide therapy, which led to the re-initiation of therapy. CONCLUSIONS: Thalidomide appears to be a safe and effective option for management of refractory LVAD-related GIB. Monitoring for recurrent GIB should be performed closely following cessation of thalidomide therapy.

"Burnt out" dilated hypertrophic cardiomyopathy causing acute LVAD thrombosis.

Case report illustrates obstruction encountered in a patient with end-stage dilated hypertrophic cardiomyopathy (HCM) who underwent LVAD implantation. The morphology reversed in early postoperative period to HCM. Pump replacement required coring of the ventricular muscle. Dilated end-stage hypertrophic cardiomyopathy can revert back to the original morphology on decompression.