Fibrosis is a common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor4,5, but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesized that downstream effectors of TGFβ1 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 TGFβ1 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.

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Background Whether mitral valve repair (MVRep) during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. Methods and Results Patients with ejection fraction ≤ 35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy (MED) with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary endpoint was mortality. Of 1212 randomized patients, 435 (36%) had none/trace, 554 (46%) mild, 181 (15%) moderate, and 39 (3%) severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace, 114 (44%) with mild and 58 (50%) in moderate-severe MR. In patients with moderate-severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (HR vs. MED 1.20, 95% CI 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (HR vs. MED 0.62, 95% CI 0.35–1.08). After adjustment for baseline prognostic variables, the HR for CABG with mitral surgery vs. CABG alone was 0.41 (95%CI 0.22–0.77; p=0.006). Conclusions While these observational data suggest that adding MVRep to CABG in patients with LV dysfunction and moderate-severe MR may improve survival compared with CABG alone or MED alone, a prospective randomized trial would be necessary to confirm the validity of these observations.