Oncostatin M (OSM), a member of the interleukin-6 family, functions as a major mediator of cardiomyocyte remodeling under pathological conditions. Its involvement in a variety of human cardiac diseases such as aortic stenosis, myocardial infarction, myocarditis, cardiac sarcoidosis, and various cardiomyopathies make the OSM receptor (OSMR) signaling cascades a promising therapeutic target. However, the development of pharmacological treatment strategies is highly challenging for many reasons. In mouse models of heart disease, OSM elicits opposing effects via activation of the type II receptor complex (OSMR/gp130). Short-term activation of OSMR/gp130 protects the heart after acute injury, whereas chronic activation promotes the development of heart failure. Furthermore, OSM has the ability to integrate signals from unrelated receptors that enhance fetal remodeling (dedifferentiation) of adult cardiomyocytes. Because OSM strongly stimulates the production and secretion of extracellular proteins, it is likely to exert systemic effects, which in turn, could influence cardiac remodeling. Compared with the mouse, the complexity of OSM signaling is even greater in humans because this cytokine also activates the type I leukemia inhibitory factor receptor complex (LIFR/gp130). In this article, we provide an overview of OSM-induced cardiomyocyte remodeling and discuss the consequences of OSMR/gp130 and LIFR/gp130 activation under acute and chronic conditions.

This study compared long-term outcomes of biological and mechanical mitral valve replacement (MVR) in patients requiring replacement of the mitral valve where repair was not feasible. A single-centre registry of patients receiving MVR between 2005 and 2015 was established. Thirty-day mortality and long-term outcomes were analysed and compared. Three hundred twenty four patients underwent MVR (265 biological; 59 mechanical valves). Patients receiving biological valves were older (p < 0.001), had a higher log EuroSCORE (p < 0.001) and received less minimally invasive surgery (p < 0.001). Immediate procedural mortality was 1.9%, which only occurred in the biological valve group. At 30 days, 9.0% of patients had died, 4.0% experienced stroke, 8.0% received a pacemaker and 10.5% suffered an acute renal failure. The rate of re-thoracotomy (14.2%) was lower in the biological (12.5%) than in the mechanical valve group (22.0%; adjOR 0.45 [0.20–1.00]; p = 0.050). Frequent long-term complications were stroke (9.2%) and bleeding (4.8%), with bleeding complications being higher in the mechanical valve group (p = 0.009). During the follow-up period biological valves showed a numerically higher survival rate during the first years, which shifted after 3 years in favour of mechanical valves. At 10 years, survival rates were 62.4% vs. 77.1% in the biological and mechanical valve groups (p = 0.769). Hazard ratio after adjustment was 0.833 (95% CI 0.430–1.615). These data confirm that mechanical valve implantation is associated with an increased risk of bleeding. While there was a potential survival benefit during the first years after surgery for patients receiving a biological valves the difference became insignificant after a follow-up of 10 years.

The muscle-specific miR-1 and miR-133a RNAs lock cardiomyocytes in a differentiated state by suppressing OSMR/FGFR signaling.

Background: We aimed to find out how the concomitant performance of tricuspid valve repair (TVR) affects outcomes of patients undergoing mitral valve surgery (MVS). Methods: Single-centre, retrospective analysis of 1357 patients who underwent MVS between January 2005 and December 2015, including 1165 patients with isolated MVS and 192 patients with MVS plus TVR. We used propensity scores to match patients for baseline characteristics other than valve related parameters and arrived at a matched sample of 182 patients per group. Results: The overall procedure duration was longer in the MVS + TVR (224 min) versus the MVS group (176 min; p < 0.001), as were the duration of mechanical ventilation (13 vs. 11 h; p < 0.001), X-clamp (90.5 vs. 66 min; p < 0.001) and cardiopulmonary bypass time (136 vs. 95.5 min; p < 0.001). Rates of procedural complications were not different between groups with the exception of pacemaker rates which were 16.0% in the MVS + TVR group and 8.8% in the isolated MVS group (p = 0.037). There was no difference in death rates within 30 days, stroke, myocardial infarction or repeat MVS. The long-term survival rate was 60.8% in the MVS + TVR vs. 57.5% in the isolated MVS group (HR 1.048; 95%CI 0.737–1.492; p = 0.794). The rate of grade III/IV tricuspid regurgitation (TR) remained low after MVS + TVR during long-term follow-up while the rate of grade ≥ II TR increased slightly in the isolated MVS group. Conclusion: The data show that the concomitant performance of TVR in patients undergoing MVS is a safe and effective procedure with good long-term outcomes. Patients can undergo MVS + TVR with confidence as it improves their prognosis up to the level of patients undergoing isolated MVS.

Fetal and hypertrophic remodeling are hallmarks of cardiac restructuring leading chronically to heart failure. Since the Ras/Raf/MEK/ERK cascade (MAPK) is involved in the development of heart failure, we hypothesized, first, that fetal remodeling is different from hypertrophy and, second, that remodeling of the MAPK occurs. To test our hypothesis, we analyzed models of cultured adult rat cardiomyocytes as well as investigated myocytes in the failing human myocardium by western blot and confocal microscopy. Fetal remodeling was induced through endothelial morphogens and monitored by the reexpression of Acta2, Actn1, and Actb. Serum-induced hypertrophy was determined by increased surface size and protein content of cardiomyocytes. Serum and morphogens caused reprogramming of Ras/Raf/MEK/ERK. In both models H-Ras, N-Ras, Rap2, B- and C-Raf, MEK1/2 as well as ERK1/2 increased while K-Ras was downregulated. Atrophy, MAPK-dependent ischemic resistance, loss of A-Raf, and reexpression of Rap1 and Erk3 highlighted fetal remodeling, while A-Raf accumulation marked hypertrophy. The knock-down of B-Raf by siRNA reduced MAPK activation and fetal reprogramming. In conclusion, we demonstrate that fetal and hypertrophic remodeling are independent processes and involve reprogramming of the MAPK.