Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment.

The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell-tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

MitraClip in CRT non-responders with severe mitral regurgitation.

BACKGROUND: Severe mitral regurgitation (MR) ≥ 3+ and left ventricular dyssynchrony in heart failure patients are markers of CRT non response. The MitraClip (MC) implantation is a therapy for MR ≥ 3+ in patients with high surgical risk of mitral valve reconstruction. METHODS AND RESULTS: We investigated 42 patients with CRT and MR ≥ 3+ who received an MC device at our center. One and two year mortality rates were compared with the predicted mortality by Seattle Heart Failure Model (SHFM) and meta-analysis global group in chronic heart failure (MAGGIC), using the baseline characteristics of patients at the time of MC implantation. The median time interval between CRT and MC implantation was 20.1 (4.5-43.3) months. In 19 patients we observed a functional regurgitation with normal leaflets and in 23 patients a degenerative mechanism for mitral regurgitation. There was no change in mean QRS duration by biventricular pacing or MC implantation. The use of MC led to significant reductions in: median N-terminal pro-brain natriuretic peptide (NT-proBNP) level (pg/ml) from 3923 to 2636 (p = 0.02), tricuspid regurgitation pressure gradient (TRPG) from 43 to 35 mmHg (p = 0.019) and in left ventricular end-diastolic volume (LVEDV) by MC (p = 0.008). At the 2 year follow-up interval the all-cause mortality was 25%. CONCLUSION: MC implantation leads to an improvement of NT-proBNP level, TRPG and LVEDV in both functional and degenerative MR but does not influence QRS duration. Two year all-cause mortality was 25% and did not differ significantly from that predicted by SHFM and MAGGIC.

Patient selection criteria and midterm clinical outcome for MitraClip therapy in patients with severe mitral regurgitation and severe congestive heart failure.

AIMS: The implantation of a MitraClip (MC) is a new treatment modality for severe mitral regurgitation (MR) in patients whose condition is inoperable or who are at high conventional operative risk. This study reports the follow-up data of patients implanted with an MC in our heart centre to find selection criteria for this procedure in patients with severe congestive heart failure. METHODS AND RESULTS: This study included 163 implantation procedures in 157 patients between March 2009 and November 2012. The severe MR was caused by functional or organic valve disease. The patients had no surgical treatment option or dramatically increased surgical operative risk due to reduced LVEF or concomitant diseases. Three (2%) implantation procedures were unsuccessful. Eleven (7%) patients died during the first 30 days after MC implantation, and 9 (6%) additional patients died during the first 6 months, both groups mainly due to severe, therapy-resistant end-stage heart failure. The 111 patients who were followed up showed significant improvement in NT-proBNP, LVEF, NYHA class, 6 min walk test, and quality of life. Ten (6%) patients needed conventional heart surgery despite high operative risk due to persistent symptomatic MR after MC implantation. CONCLUSION: The interventional implantation of an MC is a new treatment for severe MR with acceptable periprocedural risk and results in clinical improvement in the majority. Patients with end-stage heart failure and an NT-proBNP value >10 000 pg/mL have a high mortality despite MC implantation, and their treatment should be based on a very individualized decision. Based on this experience, a clinical algorithm for patient selection is proposed.