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Background: Secondary mitral regurgitation (MR) worsens in 10-15 % of heart failure (HF) patients receiving cardiac resynchronization therapy (CRT). Transcatheter edge-to-edge repair (TEER) with Mitra-Clip (Abbot Vascular, Santa Clara, CA, USA) therapy is associated with improved survival and decreased rates of hospitalization for HF in selected patients with secondary MR. Data on TEER outcomes in CRT-non-responders are limited. The purpose of this meta-analysis was to evaluate outcomes of mitral TEER with Mitra-Clip in CRT-non-responders., Methods: Cochrane, Scopus, MEDLINE, and EMBASE were searched for studies discussing outcomes of Mitra-Clip in CRT non-responders. Two reviewers were independently involved in screening studies and extracting relevant data. Individual study incidence rate estimates underwent logit transformation to calculate the weighted summary proportion under the random effect model., Results: A total of eight reports met the inclusion criteria (439 patients). Mitra-Clip improved MR grade to ≤2+ in 83.8 % and 86.8 % of CRT non-responders at six months and one year, respectively. Symptomatic improvement (New York Heart Association class ≤II) was also found in 71 % and 78.1 % of CRT non-responders at six months and one year, respectively. The pooled overall incidence estimates of mortality at 30 days, 6 months, 1 year, and 2 years were 3.6 %, 9.2 %, 17.8 %, and 25.9 %, respectively., Conclusion: TEER with Mitra-Clip in patients with significant secondary MR who do not respond to CRT was associated with MR improvement, alleviation of symptoms, and mortality rates similar to those in the COAPT trial., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest., (Published by Elsevier Ltd.)

Background & Aims: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies., Methods: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia., Results: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN., Conclusions: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations., Impact and Implications: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)