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.

Background Mitral regurgitation is a frequent valvular disease, with an increasing prevalence. We analysed the long-term outcomes of mitral valve repair procedures conducted over the last 10 years in our clinic using almost exclusively two different annuloplasty ring types. Methods A single-centre, retrospective analysis of mitral valve surgeries conducted between January 2005 and December 2015 for patients undergoing first-line mitral valve repair with either open (Cosgrove) or closed (CE Physio / Physio II) annuloplasty (OA or CA, respectively) rings. Results In total, 1120 patient documentations were available of which 528 underwent OA and 592 patients CA. The median age of patients was 64.0 years and 41.1% were female. The majority of these patients underwent the procedure because of degenerative valve disease. Rates of successful repair were about 90%, 72 h procedural mortality was 0.6% and the rate of re-intervention was 0.6% within the first 30 days. Functional (mitral regurgitation, left ventricular ejection fraction, left ventricular end-diastolic and systolic diameter and New York Heart Association class) as well as hard outcomes were comparable. 77.7 and 74.4% of patients were alive at the 10-year follow-up in the OA and CA groups, respectively. Upon multivariable adjustment, the hazard ratio was 0.926 (95% CI: 0.642–1.3135; p = 0.681). Conclusions The functional outcome and survival rates up to 10 years after mitral valve repair were comparable using open and closed annuloplasty rings. Whether this means these rings are interchangeable or a carefully selection of the best-for-the-patient devices will be subject of future investigations.

Background Mitral valve (MV) surgery has traditionally been performed by conventional sternotomy (CS), but more recently minimally invasive surgery (MIS) has become another treatment option. The aim of this study is to compare short- and long-term results of MV surgery after CS and MIS. Methods This study was a retrospective propensity-matched analysis of MV operations between January 2005 and December 2015. Results Among 1357 patients, 496 underwent CS and 861 MIS. Matching resulted in 422 patients per group. The procedure time was longer with MIS than CS (192 vs. 185 min; p = 0.002) as was cardiopulmonary bypass time (133 vs. 101 min; p < 0.001) and X-clamp time (80 vs. 71 min; p < 0.001). ‘Short-term’ successful valve repair was higher with MIS (96.0% vs. 76.0%, p < 0.001). Length of hospital stay was shorter in MIS than CS patients (10 vs. 11 days; p = 0.001). There was no difference in the overall 30-day mortality rate. Cardiovascular death was lower after MIS (1.2%) compared with CS (3.8%; OR 0.30; 95%CI 0.11–0.84). The difference did not remain significant after adjustment for procedural differences (aOR 0.40; 95%CI 0.13–1.25). Pacemaker was required less often after MIS (3.3%) than CS (11.2%; aOR 0.31; 95%CI 0.16–0.61), and acute renal failure was less common (2.1% vs. 11.9%; aOR 0.22; 95%CI 0.10–0.48). There were no significant differences with respect to rates of stroke, myocardial infarction or repeat MV surgery. The 7-year survival rate was significantly better after MIS (88.5%) than CS (74.8%; aHR 0.44, 95%CI 0.31–0.64). Conclusion This study demonstrates that good results for MV surgery can be obtained with MIS, achieving a high MV repair rate, low peri-procedural morbidity and mortality, and improved long-term survival.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, requiring lifelong anticoagulation or interventional, transseptal left atrial appendage (LAA) occluder implantation to minimize stroke risk. Incomplete LAA closure post implantation is a frequent observation. Incomplete LAA occlusion after transseptal occluder implantation necessitates anticoagulation in cases of persistent AF to minimze risk of embolism and/or apoplexy. Patients with contraindications to lifelong anticoagulation therapy are challenging to treat and alternative options are needed. We present a case of a patient with persistent AF who underwent frustraneous LAA occluder implantation. The patient's anatomy necessitated surgical closure of the LAA, which was accomplished with an LAA clip 4 weeks after implantation. The patient was discharged in excellent clinical status 5 days after the surgery. No further complications were observed within the following year.

Background Minimally invasive mitral valve surgery is standard of care in many centres and it is commonly associated with the need for cardiopulmonary bypass. Conventional external aortic clamping (exoclamping) is not always feasible, so endoaortic clamping (endoclamping) has evolved as a viable alternative. The aim of this study is to compare endoclamping (Intraclude ™ , Edwards Lifesciences) with exoclamping (Chitwood) during minimally invasive mitral valve procedures. Methods This single-centre study included 822 consecutive patients undergoing minimally invasive mitral valve procedures. The endoclamp was used in 64 patients and the exoclamp in 758. Propensity-score (PS) matching was performed resulting in 63 patients per group. Outcome measures included procedural variables, length of intensive care unit (ICU) and hospital stay, major adverse cardiac and cerebrovascular events (MACCE) and repeat surgery. Results The mean age was similar in the two group (62.2 [endoclamp] vs. 63.5 [exoclamp] years; p = 0.554), as were the cardiopulmonary bypass (145 vs. 156 min; p = 0.707) and the procedure time (203 vs. 211 min; p = 0.648). The X-clamp time was significantly shorter in the endoclamp group (88 vs. 99 min; p = 0.042). Length of ICU stay (25.0 vs. 23.0 h) and length of hospital stay (10.0 vs. 9.0 days) were slightly longer in the endoclamp group, but without statistical significance. There were nominal but no statistically significant differences between the groups in the rates of stroke, vascular complications, myocardial infarction or repeat mitral valve surgery. The conversion rate to open sternotomy approach was 2.4% without difference between groups. The estimated 7-year survival rate was similar for both groups (89.9% [endoclamp]; 84.0% [exoclamp]) with a hazard ratio of 1.291 (95% CI 0.453–3.680). Conclusions Endoaortic clamping is an appropriate and reasonably safe alternative to the conventional Chitwood exoclamp for patients in which the exoclamp cannot be used because the ascending aorta cannot be safely mobilised.

Minimally invasive cardiac surgery (MICS) via right lateral mini thoracotomy is the gold standard treatment approach for mitral and tricuspid valve disorders. Other selected procedures (e.g. transapical aortic valve implantation, MIDCAB) require a left lateral mini thoracotomy for surgical access. Advantages of MICS over complete sternotomy are well known, but access-related complications post MICS, such as pulmonary herniation, are often underestimated/overlooked. In males, a pulmonary herniation in the proximity of the former thoracotomy is often clinically visible, especially when the intrathoracic pressure rises (e.g. during coughing). In females, clinical symptoms may be hidden by the breast and patients often have unspecific complaints or occasional pain when coughing, making identification of a lung herniation more difficult. Chest computed tomography is the diagnostic tool of choice for pulmonary herniations. Using a series of 20 patients with pulmonary herniation post MICS, we report our findings in diagnosis and treatment of this condition.

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.

Resection (triangular or quadrangular) is considered the gold standard for the treatment of posterior leaflet prolapse and loop implantation a more recent alternative. We aimed to compare the long‐term outcomes of triangular or quadrangular resection vs loop implantation.

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.

Clinicians can feel confident about performing mitral repair/replacement in patients who have previously undergone mammoplasty. It may also have applications in performing atrial septal defect closure, Maze procedures for atrial fibrillation, and tricuspid valve surgery in patients with breast implants.

Journal of Cardiac SurgeryVolume 33, Issue 12 p. 806-807 IMAGES IN CARDIAC SURGERY Angiosarcoma of the right atrium with extension to the superior and inferior vena cavae Ayse Cetinkaya MD, Corresponding Author a.cetinkaya@kerckhoff-klinik.de Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, Germany Correspondence Ayse Cetinkaya MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Benekestraße 2-8, 61231 Bad Nauheim, Germany. Email: a.cetinkaya@kerckhoff-klinik.deSearch for more papers by this authorWojtek Skwara MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorStefan Hein MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorPeter Bramlage MD, orcid.org/0000-0003-4970-2110 Institute for Pharmacology and Preventive Medicine, Cloppenburg, GermanySearch for more papers by this authorMarkus Schönburg MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorManfred Richter MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this author Ayse Cetinkaya MD, Corresponding Author a.cetinkaya@kerckhoff-klinik.de Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, Germany Correspondence Ayse Cetinkaya MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Benekestraße 2-8, 61231 Bad Nauheim, Germany. Email: a.cetinkaya@kerckhoff-klinik.deSearch for more papers by this authorWojtek Skwara MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorStefan Hein MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorPeter Bramlage MD, orcid.org/0000-0003-4970-2110 Institute for Pharmacology and Preventive Medicine, Cloppenburg, GermanySearch for more papers by this authorMarkus Schönburg MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this authorManfred Richter MD, Department of Cardiac Surgery, Kerckhoff-Heart Center Bad Nauheim, Bad Nauheim, GermanySearch for more papers by this author First published: 11 December 2018 https://doi.org/10.1111/jocs.13964Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume33, Issue12December 2018Pages 806-807 RelatedInformation

Objectives: Aim of this study was to compare the outcomes (30 days) after biological (B) versus mechanical (M) mitral valve replacement (MVR) in case mitral valve repair was not feasible.

OBJECTIVES We studied the role of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in fibrosis formation in the transition from hypertrophy to heart failure (HF) as well as the cellular source of MMPs and TIMPs. BACKGROUND Human pressure-overloaded hearts are characterized by a significant increase in cardiac fibrosis. However, the contribution of the proteolytic/antiproteolytic system in aortic stenosis (AS) during hypertrophy progression has not yet been elucidated. METHODS Three groups of AS patients (I: EF 50%, n 12; II: EF 50% to 30%, n 10; III: EF 30%, n 12) undergoing aortic valve replacement and seven controls were studied. Tissue samples were investigated by immunoconfocal microscopy, Western blotting, and zymography. RESULTS Quantitative analysis by immunoconfocal microscopy and Western blotting showed an upregulation of MMP-1, -2, -3, -9, -13, and -14 in group I and further increases in later stages. Tissue inhibitors of metalloproteinase-1 and -2 were enhanced and TIMP-4 was decreased in comparison to control. Gelatinolytic activity of MMP-2 significantly (p 0.05) increased 1.2-fold (group I), 1.5-fold (group II), and 1.6-fold (group III) over control. The level of collagen I was significantly upregulated in all AS groups. Immunoconfocal microscopy showed that MMPs and TIMPs are produced predominantly by fibroblasts. The number of proliferating fibroblasts was significantly elevated during the transition to HF (0.67 n/mm-control, 5.03-group III, p 0.05). CONCLUSIONS In human hearts a continuous turnover of the extracellular matrix occurs during the progression from compensated hypertrophy to HF that is characterized by the upregulation of MMPs and inadequate inhibition by TIMPs. The altered balance between proteolysis/ antiproteolysis with accompanying proliferation of fibroblasts results in fibrosis progression. (J Am Coll Cardiol 2004;44:1609–18) © 2004 by the American College of ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.07.023

The phosphatonin fibroblast growth factor 23 (FGF23) is increasingly recognized as a heart failure marker. Accumulating evidence indicates furthermore that the failing heart itself is the major source of circulating FGF23 through the activation of the oncostatin M (OSM) receptor (Oβ). Since Oβ activation orchestrates a variety of regenerative processes in the myocardium such as macrophage infiltration through the secretion of Reg3 proteins by cardiomyocytes we asked whether OSM is able to potentiate the release of FGF23 through the induction of synergistically acting cytokine receptors. In order to determine synergistically acting receptors we performed proteome and transcriptome profiling of adult mouse hearts 4 days after myocardial infarction and compared the results with data obtained from OSM stimulated adult cardiomyocytes. Promising candidates were furthermore analyzed by RT-PCR, confocal microscopy (CM) and Western blots (WB). Levels of FGF23 were determined by ELISA. By comparison of the transcriptome and proteome data of infarcted hearts and OSM stimulated cultured cardiomyocytes the interleukin (Il) 4 receptor (Il4R) and its coreceptor Il13Rα1 appeared to be the most promising candidates. The Il4R increased 6.04-fold (p<0.001) and Il13Rα1 3.7-fold (p<0.02) in OSM treated cultures. Similarly, comparison of the remote with the cardiac infarct zone revealed a 2.94-fold increase of Il4R (p<0.001) and a moderate increase of Il13Rα1 after 4 days in the remote zone. Our observations were verified by Western blot analysis and confocal microscopy. In addition, treatment of mice with OSM (60 ng/g body weight) for 4 days increased the Il4R receptor more than 3-fold (p<0.01) in the heart. Importantly, IL4R activation in culture massively enhanced the release of FGF23 from 680±35 pg/ml in OSM stimulated cardiomyocytes to 3701±113 pg/ml (n=6; p<0.001). In contrast, the increase of FGF23 to 101±2 pg/ml (n=2) after Il4R activation was only mild in comparison to controls (3.3±0.8pg/ml). While Oβ signaling is crucial for the cardiac release of FGF23 during heart failure the involvement of the Il4R in the Oβ/FGF23 axis is highly likely and is presently under investigation in an Il4R knock-out strain.

ObjectivesWe used immuhistochemistry and Western blot to study fibrillar and non-fibrillar collagens, collagen metabolism, matricellular proteins and regulatory factors of the ECM remodeling in left ventricular (LV) septum biopsies from 3 groups of patients with aortic valve stenosis (AS): (AS-1,n = 9): ejection fraction (EF) > 50%; AS-2,(n = 12): EF 30%–50%; AS-3,(n = 9): EF < 30%). Samples from 8 hearts with normal LV function served as controls.ResultsIn comparison with controls, fibrillar collagens I and III were progressively upregulated from compensated (AS-1) toward decompensated hypertrophy (AS-3). The collagenIII/collagen I ratio decreased 2-fold in the AS-2 and AS-3 groups as compared with AS-1 and controls. Non-fibrillar collagen IV was upregulated only in AS-3 patients, whereas collagen VI progressively increased from AS-1 to AS-3 group. Collagen synthesis in AS-3 was shifted to collagen I, while the maturation/degradation level was shifted to collagen III. RECK was downregulated only in AS-3 patients. Matricellular proteins tenascin and osteopontin were increased in all AS patients. However, thrombospondin 1, 4 and CTGF were increased only in AS-3. Only AS-3 patients were characterized by increased levels of TGFβ1 and downregulation of TGFβ3, TGFβ-activated kinase1 and Smad7. In contrast, Smad3 gradually increased from AS-1 toward AS-3. Similar trend of changes was observed for TNFα-R1 and TNFα-R2, whereas TNFα was diminished only in AS-2 and AS-3.ConclusionsDistinct changes in fibrillar collagen turnover, non-fibrillar collagens, matricellular proteins and the key regulatory profibrotic and anti-fibrotic factors of the myocardial ECM remodeling are involved in the transition from compensated to decompensated LV hypertrophy and HF in human patients with AS.

Objectives: Conventional aortic valve replacement (AVR) is a standard procedure with low morbidities and mortalities. Aim of this study was to analyze the outcome of conventional AVR in all comers when high-risk patients were treated using transcatheter aortic valve implantation (T-AVI) in parallel.

Cardiomyocyte remodeling, which includes partial dedifferentiation of cardiomyocytes, is a process that occurs during both acute and chronic disease processes. Here, we demonstrate that oncostatin M (OSM) is a major mediator of cardiomyocyte dedifferentiation and remodeling during acute myocardial infarction (MI) and in chronic dilated cardiomyopathy (DCM). Patients suffering from DCM show a strong and lasting increase of OSM expression and signaling. OSM treatment induces dedifferentiation of cardiomyocytes and upregulation of stem cell markers and improves cardiac function after MI. Conversely, inhibition of OSM signaling suppresses cardiomyocyte remodeling after MI and in a mouse model of DCM, resulting in deterioration of heart function after MI but improvement of cardiac performance in DCM. We postulate that dedifferentiation of cardiomyocytes initially protects stressed hearts but fails to support cardiac structure and function upon continued activation. Manipulation of OSM signaling provides a means to control the differentiation state of cardiomyocytes and cellular plasticity.

OBJECTIVES:We studied fibrosis, collagen metabolism, MMPs/TIMPs and cytokine expression in various forms of human heart failure (HF) by quantitative immunofluorescent microscopy, Western blot, zymography, RT-PCR and in situ hybridization. In explanted human hearts with HF due to either dilated (DCM, n=6) or ischemic (ICM-BZ-borderzone, ICM-RZ-remote zone, n=7) or inflammatory (myocarditis, MYO, n=6) cardiomyopathy and 8 controls MMP2, 8, 9, 19, and TIMP1, 2, 3, 4 as well as procollagens I and III (PINP, PIIINP), mature collagen III (IIINTP) and the cross-linked collagen I degradation product (ICTP) were measured.RESULTS:In comparison with controls, MMPs and TIMPs were significantly upregulated ranging (from highest to lowest) from ICM-BZ, DCM, ICM-RZ, MYO for all MMPs with the exception of MMP9 (highest in DCM), and for TIMPs from ICM-BZ, ICM-RZ, DCM and MYO. MMP2 and 9 were activated in all groups. The TIMP/MMP ratio was 1.3 for control, 1.9 in ICM-BZ (TIMP>MMP) and lowered to 1.0 in the other groups. Collagen I/collagen III ratio correlated significantly with the decrease in LVEDP. PINP was higher than ICTP in all groups. PIIINP elevation was present in DCM and ICM-RZ and IIINTP was up to 4-fold augmented in all groups. Fibrosin mRNA was upregulated in ICM-BZ, activin A in MYO but FGF1 and FGF2 remained unchanged. ANP mRNA was increased in all groups.CONCLUSIONS:Although different degrees of severity of collagen metabolism, MMP/TIMP imbalance and cytokine expression in diverse forms of HF are present, the end product is collagen deposition. These findings suggest multiple mechanisms acting alone or in concert in fibrosis development in HF.