Empowering translation of new ideas - A EIT Health ClinMed Summer School overview

Translational research training is crucial to convert academic research ideas into efficient real-life solutions. In this paper a summer school supported by EIT Health is presented. Its main goal is to integrate clinical knowledge in the development of new medical devices, from ideas to post-market approval, in the clinics. Students were immersed in clinical centres where they had close contacts and engaged discussions with clinicians and patients to identify and assimilate clinical unmet needs. From this immersive stage resulted innovative solutions that were further investigated with the support of plenary lectures and by interaction with experts of the medical field, from clinicians to Medtech company representatives. This experience proved to have a positive impact on the student’s understanding of the clinical development life cycle from research findings or new ideas into medical devices.This work received funding from EIT-Health campus call (Project Grant Agreement n°18497). This research was supported by a Marie Curie ITN fellowship within the 7th European Community Framework Programme (Grant Number: 676338).Not peer reviewe

Empowering translation of new ideas - A EIT Health ClinMed Summer School overview

Translational research training is crucial to convert academic research ideas into efficient real-life solutions. In this paper a summer school supported by EIT Health is presented. Its main goal is to integrate clinical knowledge in the development of new medical devices, from ideas to post-market approval, in the clinics. Students were immersed in clinical centres where they had close contacts and engaged discussions with clinicians and patients to identify and assimilate clinical unmet needs. From this immersive stage resulted innovative solutions that were further investigated with the support of plenary lectures and by interaction with experts of the medical field, from clinicians to Medtech company representatives. This experience proved to have a positive impact on the student’s understanding of the clinical development life cycle from research findings or new ideas into medical devices.This work received funding from EIT-Health campus call (Project Grant Agreement n°18497). This research was supported by a Marie Curie ITN fellowship within the 7th European Community Framework Programme (Grant Number: 676338).Not peer reviewe

Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure.

BackgroundConsiderable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.Methods and resultsImmunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared with non-β-AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIδC transgenic mice were treated with the β1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n≥29; P<0.001), attenuated the development of cardiac hypertrophy (-14±6% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (-70±22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A-dependent phospholamban and ryanodine receptor 2 phosphorylation (-42±9% for P-phospholamban-S16 and -22±7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n≥11). The lack of CaMKII modulation by β-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol.ConclusionsChronic β-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of β-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to β-AR blockade

Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure

Background Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive -adrenoceptor (-AR) stimulation. Recent studies indicate a significant cross talk between -AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental -AR signaling in HF. In this study, we investigated the effect of chronic -AR blocker treatment on CaMKII activity in human and experimental HF. Methods and Results Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with -AR blockers revealed no difference in CaMKII activity when compared with non--AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIC transgenic mice were treated with the (1)-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n29; P<0.001), attenuated the development of cardiac hypertrophy (-146% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (-70 +/- 22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A-dependent phospholamban and ryanodine receptor 2 phosphorylation (-42 +/- 9% for P-phospholamban-S16 and -22 +/- 7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n11). The lack of CaMKII modulation by -AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol. Conclusions Chronic -AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of -AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to -AR blockade

A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure