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Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology., Author summary Advances in the understanding of functional alterations at genetic, epigenetic or protein expression and the expanding knowledge in mechanisms modulating ion channel kinetics and thus the cells’ bioelectric properties have arisen as promising cancer biomarkers and oncological targets. Our hidden Markov-based in-silico cell model represents the electrophysiology behind proliferation of the A549 cell line, explaining the cell’s rhythmic oscillation from hyperpolarized to depolarized states of the membrane potential, able to trigger the transition between cell cycle phases. The model enables the prediction of membrane potential changes over the cell cycle provoked by targeted modulation of specific ion channels, leading to cell cycle promotion or interruption. We are encouraged that the availability of this first cancer cell model will provide profound insight into possible roles and interactions of ion channels in tumor development and progression, and may aid in the testing of research hypotheses in lung cancer electrophysiology.

to the editor: Cell membrane capacitance C m is a fundamental property of excitable cells. It scales with the cell surface area and is therefore used for cell size estimation and most important for normalizing currents and conductances. Consequently, proper knowledge of C m is also crucial for

Objective : The left human atrium plays an important role in initiation of atrial fibrillation (AF) and the hyperpolarization activated cation current ( I f) is a candidate for contributing to abnormal automaticity. However, electrophysiological data concerning I f are not available in this cardiac region and we therefore investigated I f in human left atrial tissue. Methods : Human atrial myocytes were isolated from the left atrial appendage (LAA) and the left atrial wall (LAW) obtained from patients undergoing open heart surgery. I f was measured with the whole-cell patch-clamp technique. Results : I f densities between −70 and −110 mV were found to be significantly higher in LAA than in LAW cells. Furthermore, in the group of LAA cells the half maximal activation potential ( V 1/2) was found to be less negative ( V 1/2 of −84.3±1.9 mV, n =14/9) compared to LAW cells ( V 1/2 of −97.8±2.1 mV, n =28/9). Beta-adrenergic receptor stimulation with isoproterenol (1 μM) caused an acceleration of current activation and a V 1/2 shift to more positive potentials in cells of both regions (LAA: 8.8±2.3 mV, n =6/4 and LAW: 8.9±2.6 mV, n =6/4). Simulations using a mathematical model of the human atrial myocyte demonstrated that I f was able to induce spontaneous activity in the model at a regular rhythm due to the interplay of I f, Na+/Ca2+ exchange current and Ca2+ release of the sarcoplasmic reticulum (SR). Conclusions : Our study revealed the presence of I f in left atrial myocytes and showed that I f parameters depend on atrial region. I f current densities were sufficient to convert the mathematical model of a quiescent human atrial cell into a “pacemaker cell”. These data support the hypothesis of I f as a contributor to abnormal automaticity in human atrial tissue.

Objective : It was our aim to investigate effects of human LDL, copper-, or AAPH-oxidized over different periods of time to different degrees (ox-LDL), on viability and electrophysiological parameters of isolated ventricular myocytes of guinea pigs. Methods : Guinea pig ventricular myocytes were incubated with ox-LDL or native LDL (at 0.5 mg/ml) for 12 h, and afterwards myocyte damage, action potentials, and transmembrane ion currents were studied (at 37 °C). Results : Ox-LDL was found to induce severe myocyte damage, whereas native LDL had no effect. Myocyte damage was dependent on the content of total lipid hydroperoxides in both copper-oxidized and AAPH-oxidized LDL. Incubation with ox-LDL led to intense contractile and electrophysiological effects including prolongation of action potential duration, depolarization of resting membrane potential, spontaneous activity, generation of afterdepolarizations, and modification of transmembrane ion currents (e.g. inward rectifier, calcium, and background currents). Conclusions : Ox-LDL induced cell damage and irregular electrical activity in ventricular myocytes. These effects were dependent on the lipid hydroperoxide content of ox-LDL and were similar to oxidative stress (OS) induced by various OS-generating systems. The observed effects may play a role for functional cardiac abnormalities in patients with increased ox-LDL levels.

I(f) was shown to be present in adult human atrial and ventricular myocytes but data obtained from infant myocytes are lacking. We have studied I(f) in isolated ventricular myocytes from children undergoing surgical correction of tetralogy of Fallot (TOF; n = 5; mean age: 15.3 months). All recordings were made with the patch clamp technique in the whole cell mode at a temperature of 36-37 degrees C. A modified Tyrode solution containing 25 mM KCl was used to amplify I(f). Considering I(f) to be present when its current density at -120 mV was greater than 0.5 pA/pF, I(f) could be found in 28 out of 32 myocytes (88%). The mean current density was -2.01 +/- 0.3 pA/pF (mean +/- S.E.M.). First current activation occurred at -70 mV and I(f) could be reversibly inhibited by superfusing the myocytes with CsCl (2 mM). Half maximal activation (V(1/2)) of I(f) was at -80.3 +/- 1.0 mV (n = 28). Beta-adrenergic receptor stimulation with isoproterenol (1 microM) caused an acceleration of current activation and a shift of V(1/2) by 7.88 +/- 1.8 mV (n = 10) to less negative potentials. This study provides first evidence that the hyperpolarization-activated pacemaker current I(f) is present in infant human ventricular myocytes. Our results suggest that I(f) in ventricle of infants suffering from TOF has similar properties as I(f) in adult ventricle.