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The Bundesbank's balance sheet and those of other central banks in the eurozone are currently showing high "operating" losses due to the discrepancy between the low interest bearing securities holdings from bond purchases and the now higher interest bearing commercial bank deposits. However, the current accounting practice does not reflect the associated losses in value anywhere near the market level – even though, according to the PSPP ruling of the German Federal Constitutional Court, the sale of securities before final maturity should be the rule. Even under the current valuation practice, an equity gap cannot be ruled out in the future, which is generally seen as unproblematic for central banks. However, there are risks in the context of recapitalisation by the state. Within the eurozone, national and European requirements could make such capital injections necessary. [ABSTRACT FROM AUTHOR]

Aims Human induced pluripotent stem cell–derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in the human atrium. Data on the contribution of the slowly activating delayed rectifier currents (I Ks) to repolarization are lacking for both human atrium and hiPSC-aCM. Methods and results Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model I Ks contribution to action potential (AP) shape. Action potential was recorded by sharp microelectrodes. HMR-1556 (1 µM) was used to identify I Ks and to estimate I Ks contribution to repolarization. Less than 50% of hiPSC-aCM and aCM possessed I Ks. Frequency of occurrence, current densities, activation/deactivation kinetics, and voltage dependency of I Ks did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. β-Adrenoceptor stimulation with isoprenaline did not increase I Ks neither in aCM nor in hiPSC-aCM. In tissue from SR, block of I Ks with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultra-rapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031. Conclusion I Ks exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), I Ks does not appear to relevantly contribute to repolarization in hiPSC-aCM. [ABSTRACT FROM AUTHOR]

Little is known about the physical and mental health among police students. Based on data on Swedish police students' physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students' self-reported physical activity and mental health affect their perceived police ability differently in relation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession. [ABSTRACT FROM AUTHOR]

The trust placed in a central back is considered its most important asset – especially in turbulent times for monetary policy. In order to avoid any appearance of conflicts of interest, the European Central Bank (ECB) felt motivated to tighten its Code of Conduct for high-level officials at the beginning of 2023. However, an analysis of current self-disclosures by the members of the ECB's Governing Council on their financial investments indicates a lack of clarity in the new investment rules, which seems to result in inconsistent and partly contradictory disclosures – especially with regard to "legacy assets". The clarity and comprehensibility of the rules as well as their consistent implementation should therefore be reviewed in order to prevent an erosion of confidence in the ECB. [ABSTRACT FROM AUTHOR]

Models based on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are proposed in almost any field of physiology and pharmacology. The development of human induced pluripotent stem cell-derived cardiomyocytes is expected to become a step forward to increase the translational power of cardiovascular research. Importantly they should allow to study genetic effects on an electrophysiological background close to the human situation. However, biological and methodological issues revealed when human induced pluripotent stem cell-derived cardiomyocytes were used in experimental electrophysiology. We will discuss some of the challenges that should be considered when human induced pluripotent stem cell-derived cardiomyocytes will be used as a physiological model. [ABSTRACT FROM AUTHOR]

The heterozygous mutation c.155G > T in GNB2 clinically leads to sinus bradycardia and sinus node dysfunction. Here, patient-specific skin fibroblasts of the mutation carrier were used for Sendai virus reprogramming into human induced-pluripotent stem cells (hiPSC). For generating the isogenic control cell line, a CRISPR/Cas9-mediated HDR-repair of the hiPSCs was carried out. Both generated cell lines (GNB2 SV5528, GNB2 K26) maintained a normal karyotype, cell morphology, pluripotency in immunofluoresence and RT-qPCR analysis. Both hiPSC-lines showed differentiation potential into all three germ layers. Differentiated cardiomyocytes of this isogenic set may pave the way for investigating pharmacological rescue strategies for sinus node dysfunction. [ABSTRACT FROM AUTHOR]

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 ± 0.2 pA/pF and 3.2 ± 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 µM) markedly shortened the APD90 in EHT (by 26.6 ± 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 ± 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 ± 5.4%, p < 0.05) and EHT (by 20.8 ± 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a primary disorder of the cardiac muscle, characterized by dilatation of the left ventricle and contractile dysfunction. About 50% of DCM cases can be attributed to monogenic causes, whereas the etiology in the remaining patients remains unexplained. We report a family with two brothers affected by severe DCM with onset in the adolescent period. Using exome sequencing, we identified a homozygous premature termination variant in the MYZAP gene in both affected sibs. MYZAP encodes for myocardial zonula adherens protein—a conserved cardiac protein in the intercalated disc structure of cardiomyocytes. The effect of the variant was demonstrated by light and electron microscopy of the heart muscle and immunohistochemical and western blot analysis of the MYZAP protein in the heart tissue of the proband. Functional characterization using patient-derived induced pluripotent stem cell cardiomyocytes revealed significantly lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction. Weprovide independent support for the role of biallelic loss-of-function MYZAP variants in dilated cardiomyopathy. This report extends the spectrum of cardiac disease associated with dysfunction of cardiac intercalated disc junction and sheds light on the mechanisms leading to DCM. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 mM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1θmM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies. [ABSTRACT FROM AUTHOR]

The role and outcome of the muscarinic M2 acetylcholine receptor (M2R) signaling in healthy and diseased cardiomyocytes is still a matter of debate. Here, we report that the long isoform of the regulator of G protein signaling 3 (RGS3L) functions as a switch in the muscarinic signaling, most likely of the M2R, in primary cardiomyocytes. High levels of RGS3L, as found in heart failure, redirect the Gi-mediated Rac1 activation into a Gi-mediated RhoA/ROCK activation. Functionally, this switch resulted in a reduced production of reactive oxygen species (− 50%) in cardiomyocytes and an inotropic response (+ 18%) in transduced engineered heart tissues. Importantly, we could show that an adeno-associated virus 9-mediated overexpression of RGS3L in rats in vivo, increased the contractility of ventricular strips by maximally about twofold. Mechanistically, we demonstrate that this switch is mediated by a complex formation of RGS3L with the GTPase-activating protein p190RhoGAP, which balances the activity of RhoA and Rac1 by altering its substrate preference in cardiomyocytes. Enhancement of this complex formation could open new possibilities in the regulation of the contractility of the diseased heart. [ABSTRACT FROM AUTHOR]

Regulating cardiac relaxation: RBM20 is a cardiac splicing factor that regulates titin-based stiffness and thus cardiac filling. Using in silico, cell-, and animal-based screening, Radke et al. identified antisense oligonucleotides (ASOs) that down-regulated RBM20. Treating the titin N2B knockout mouse model of heart failure with preserved ejection fraction with RBM20 ASOs altered titin isoform expression, increased sarcomere length, improved ventricular filling and cardiac dimensions, and promoted expression of immune response and metabolism-associated genes. The authors further developed a human RBM20 ASO and showed that it could improve kinetics of relaxation in human engineered heart tissues in vitro, supporting RBM20-targeted ASOs as a potential therapeutic. Heart failure with preserved ejection fraction (HFpEF) is prevalent and deadly, but so far, there is no targeted therapy. A main contributor to the disease is impaired ventricular filling, which we improved with antisense oligonucleotides (ASOs) targeting the cardiac splice factor RBM20. In adult mice with increased wall stiffness, weekly application of ASOs over 2 months increased expression of compliant titin isoforms and improved cardiac function as determined by echocardiography and conductance catheter. RNA sequencing confirmed RBM20-dependent isoform changes and served as a sensitive indicator of potential side effects, largely limited to genes related to the immune response. We validated our approach in human engineered heart tissue, showing down-regulation of RBM20 to less than 50% within 3 weeks of treatment with ASOs, resulting in adapted relaxation kinetics in the absence of cardiac pathology. Our data suggest anti-RBM20 ASOs as powerful cardiac splicing regulators for the causal treatment of human HFpEF. [ABSTRACT FROM AUTHOR]