The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis

LM has received grants by the Faculty of Medicine at the RWTH Aachen University (START 15/14 and START 46/16) and the Deutsche Forschungsgemeinschaft (DFG, MA 7082/1–1). This work was supported by the Immunohistochemistry and Confocal Microscopy Unit, a core facility of the Interdisciplinary Centre for Clinical Research (IZKF) Aachen, within the Faculty of Medicine at the RWTH Aachen University and the RWTH centralized Biomaterial Database (RWTH cBMB) of the University Hospital RWTH Aachen. We are very grateful to Antons Martincuks M.Sc. and Professor Gerhard Müller-Newen for live-cell imaging. This work was supported, in part, by the University of Turin (ex-60% 2015A and B) and by the William Harvey Research Foundation and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit that is supported and funded by the National Institute for Health Research. This work also contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences supported by the Barts and The London Charity (Award 753/1722)

Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart

Heart failure (HF) is characterized by molecular and cellular defects which jointly contribute to decreased cardiac pump function. During the development of the initial cardiac damage which leads to HF, adaptive responses activate physiological countermeasures to overcome depressed cardiac function and to maintain blood supply to vital organs in demand of nutrients. However, during the chronic course of most HF syndromes, these compensatory mechanisms are sustained beyond months and contribute to progressive maladaptive remodeling of the heart which is associated with a worse outcome. Of pathophysiological significance are mechanisms which directly control cardiac contractile function including ion- and receptor-mediated intracellular signaling pathways. Importantly, signaling cascades of stress adaptation such as intracellular calcium (Ca2+) and 3′-5′-cyclic adenosine monophosphate (cAMP) become dysregulated in HF directly contributing to adverse cardiac remodeling and depression of systolic and diastolic function. Here, we provide an update about Ca2+ and cAMP dependent signaling changes in HF, how these changes affect cardiac function, and novel therapeutic strategies which directly address the signaling defects

Ionic mechanisms limiting cardiac repolarization-reserve in humans compared to dogs.

The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50–100 nmol l−1 dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l−1 BaCl2) and IKs block (1 μmol l−1 HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ∼30% larger and ∼29% smaller in human, and Na+–Ca2+ exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKsα-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human–canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study

Background: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. Objective: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. Methods: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. Results: Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+ /Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. Conclusion: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds - ERDF - FEDER), (ii) the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119), and (iii) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Gómez García, JF.; Cardona, K.; Romero Pérez, L.; Ferrero De Loma-Osorio, JM.; Trénor Gomis, BA. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study. PLoS ONE. 9(9). https://doi.org/10.1371/journal.pone.0106602S9

Excitation - contraction coupling in heart muscle The roles of L-type Ca channels, Na/Ca exchange and membrane potential

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