In previous experiments we have demonstrated that expression of the transcription factors E2F2 and E2F4 is sufficient to induce proliferation of isolated primary cardiomyocytes from newborn rats and mice. We now wanted to analyse whether E2F2 or E2F4 are also able to promote cell cycle progression of adult cardiomyocytes in vivo, which unlike cardiomyocytes from newborn rodents lack the ability to undergo cell proliferation. E2F2 or E2F4 was expressed in hearts of mice at different developmental stages using adenoviral vectors. Effects regarding proliferation, hypertrophy, and apoptosis were analysed on histological sections, and quantitative assessment of cell cycle regulatory genes was performed by real-time PCR (polymerase chain reaction) and western blot. We found that both E2F2 and E2F4 can stimulate hypertrophic cell growth of cardiomyocytes. However, only directed expression of E2F2 but not of E2F4 was sufficient to induce proliferation of cardiomyocytes. Expression of E2F2 in vivo did not increase the percentage of apoptotic cardiomyocytes but down-regulated the expression of the pro-apoptotic genes caspase-6 and apaf-1. Further analysis of the cell cycle regulatory machinery revealed that expression of E2F2 caused a strong induction of cyclin A and E while the expression of cyclin-dependent kinase inhibitors (CKIs) such as p21 was not affected. We conclude that a limited induction of cardiomyocyte cell proliferation can be achieved by E2F2-mediated stimulation of cyclin A and E expression without a reduction of CKIs.

In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs. This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality. Patients had a median age of 84 [IQR 82–87] years and a mean CFS of 4.75 (± 1.6 standard-deviation) points. More than half of the patients (53.6%) were classified as frail (CFS ≥ 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival. The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany. The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807 ) on May 1, 2017.

Various strategies have been devised to reduce the clinical consequences of myocardial infarction, including acute medical care, revascularization, stem cell transplantations, and more recently, prevention of cardiomyocyte cell death. Activation of embryonic signaling pathways is a particularly interesting option to complement these strategies and to improve the functional performance and survival rate of cardiomyocytes. Here, we have concentrated on bone morphogenetic protein 2 (BMP-2), which induces ectopic formation of beating cardiomyocytes during development in the mesoderm and protects neonatal cardiomyocytes from ischemia-reperfusion injury. In a mouse model of acute myocardial infarction, an i.v. injection of BMP-2 reduced infarct size in mice when given after left anterior descending artery ligation. Mice treated with BMP-2 are characterized by a reduced rate of apoptotic cardiomyocytes both in the border zone of the infarcts and in the remote myocardium. In vitro, BMP-2 increases the frequency of spontaneously beating neonatal cardiomyocytes and the contractile performance under electrical pacing at 2 Hz, preserves cellular adenosine triphosphate stores, and decreases the rate of apoptosis despite the increased workload. In addition, BMP-2 specifically induced phosphorylation of Smad1/5/8 proteins and protected adult cardiomyocytes from long-lasting hypoxia-induced cellular damage and oxidative stress without activation of the cardiodepressant transforming growth factor-β pathway. Our data suggest that BMP-2 treatment may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by improving the contractility of cardiomyocytes and preventing cardiomyocyte cell death.

Background: Infective endocarditis (IE) requires multidisciplinary management. We established an endocarditis team within our hospital in 2011 and a state-wide endocarditis network with referring hospitals in 2015. We aimed to investigate their impact on perioperative outcomes. Methods: We retrospectively analyzed data from patients operated on for IE in our center between 01/2007 and 03/2018. To investigate the impact of the endocarditis network on referral latency and pre-operative complications we divided patients into two eras: before (n = 409) and after (n = 221) 01/2015. To investigate the impact of the endocarditis team on post-operative outcomes we conducted multivariate binary logistic regression analyses for the whole population. Kaplan–Meier estimates of 5-year survival were reported. Results: In the second era, after establishing the endocarditis network, the median time from symptoms to referral was halved (7 days (interquartile range: 2–19) vs. 15 days (interquartile range: 6–35)), and pre-operative endocarditis-related complications were reduced, i.e., stroke (14% vs. 27%, p < 0.001), heart failure (45% vs. 69%, p < 0.001), cardiac abscesses (24% vs. 34%, p = 0.018), and acute requirement of hemodialysis (8% vs. 14%, p = 0.026). In both eras, a lack of recommendations from the endocarditis team was an independent predictor for in-hospital mortality (adjusted odds ratio: 2.12, 95% CI: 1.27–3.53, p = 0.004) and post-operative stroke (adjusted odds ratio: 2.23, 95% CI: 1.12–4.39, p = 0.02), and was associated with worse 5-year survival (59% vs. 40%, log-rank < 0.001). Conclusion: The establishment of an endocarditis network led to the earlier referral of patients with fewer pre-operative endocarditis-related complications. Adhering to endocarditis team recommendations was an independent predictor for lower post-operative stroke and in-hospital mortality, and was associated with better 5-year survival.