Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog.

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and torsades de pointes (TdP, defined as ≥5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic atrioventricular block (CAVB) dog by dofetilide (IKr blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (≥3 TdPs/10 min) CAVB dogs underwent one mapping experiment and were observed for 10 min from the start of dofetilide infusion (0.025 mg/kg, 5 min). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARIs) on the intracardiac EGM, using the formula: [Formula: see text]. The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion before first 1) sEB (occurrence at 100 ± 35 s), 2) mEB (224 ± 96 s), and 3) non-self-terminating TdP (454 ± 298 s). STVARI increased from 2.15 ± 0.32 ms at BL to 3.73 ± 0.99 ms* before the first sEB and remained increased without further significant progression to mEB (4.41 ± 0.45 ms*) and TdP (5.07 ± 0.84 ms*) (*P < 0.05 compared with BL). SDR3D did not change from 31 ± 11 ms at BL to 43 ± 13 ms before sEB but increased significantly before mEB (68 ± 7 ms*) and to TdP (86 ± 9 ms*+) (+P < 0.05 compared with sEB). An increase in STV contributes to the initiation of sEB, whereas an increase in SDR is important for the perpetuation of non-self-terminating TdPs.NEW & NOTEWORTHY This study compared two well-established electrophysiological parameters, being temporal and spatial dispersion of repolarization, and provided new insights into their interplay in the arrhythmogenesis of torsades de pointes arrhythmias. Although it confirmed that an increase in temporal dispersion of repolarization contributes to the initiation of single ectopic beats, it showed that an increase in spatial dispersion of repolarization is important for the perpetuation of non-self-terminating torsades de pointes arrhythmias.

Comet 41P/Tuttle-Giacobini-Kresak, 45P/Honda-Mrkos-Pajdusakova, and 46P/Wirtanen: Water Production Activity over 21 Years with SOHO/SWAN.

In 2017, 2018, and 2019, comets 46P/Wirtanen, 45P/Honda-Mrkos-Pajdusakova, and 41P/Tuttle-Giacobini-Kresak all had perihelion passages. Their hydrogen comae were observed by the Solar Wind ANisotropies (SWAN) all-sky hydrogen Lyman-alpha camera on the SOlar and Heliospheric Observer (SOHO) satellite: comet 46P for the fourth time and comets 45P and 41P for the third time each since 1997. Comet 46P/Wirtanen is one of a small class of so-called hyperactive comets whose gas production rates belie their small size. This comet was the original target comet of the Rosetta mission. The Solar Wind ANisotropies (SWAN) all-sky hydrogen Lyman-alpha camera on the SOlar and Heliospheric Observer (SOHO) satellite observed the hydrogen coma of comet 46P/Wirtanen during the apparitions of 1997, 2002, 2008, and 2018. Over the 22 years, the activity decreased and its variation with heliocentric distance has changed markedly in a way very similar to that of another hyperactive comet, 103P/Hartley 2. Comet 45P/Honda-Mrkos-Pajdusakova was observed by SWAN during its perihelion apparitions of 2001, 2011, and 2017. Over this time period the activity level has remained remarkably similar, with no long-term fading or abrupt decreases. Comet 41P/Tuttle-Giacobini-Kresak was observed by SWAN in its perihelion apparitions of 2001, 2006, and 2017 and has decreased in activity markedly over the same time period. In 1973 it was known for large outbursts, which continued during the 2001 (2 outbursts) and 2006 (1 outburst) apparitions. However, over the 2001 to 2017 time period covered by the SOHO/SWAN observations the water production rates have greatly decreased by factors of 10-30 over corresponding times during its orbit.

The Future of Physiology: Cardiac Electrophysiology.

Is cardiac electrophysiology complete? What are the challenges that are to be met in cardiac electrophysiology and how can we best engage these? These questions will be addressed in view of the progressing subspecialization of the field. A suggested answer lies in multidisciplinary and extradisciplinary approaches.

Comet C/2017 S3 (PanSTARRS): Outbursts and Disintegration.

The Solar Wind ANisotropies (SWAN) all-sky hydrogen Lyman-alpha camera on the SOlar and Heliospheric Observer (SOHO) satellite observed the hydrogen coma of comet C/2017 S3 (PanSTARRS) for the last month of its activity from 2018 July 4 to August 4 and what appears to have been its final disintegration just 11 days before its perihelion on August 15. The hydrogen coma indicated water production had a small outburst on July 8 at a heliocentric distance of 1.1AU and then a much larger one on July 20 at 0.8 AU. Over the following two weeks the water production dropped by more than a factor of ten after which it was no longer detectable. The behavior is reminiscent of comet C/1999 S4 (LINEAR) in 2000, which had a few small outbursts on its inbound orbit and a major outburst at a heliocentric distance of about 0.8 AU, which was close to its perihelion, followed by its complete disintegration that was documented by several sets of observations including SWAN. C/2017 S3 (PanSTARRS) however had a much larger water production rate than C/1999 S4 (LINEAR). Here we estimate the size of the nucleus of C/2017 S3 just before its final outburst and apparent disintegration was estimated using the total amount of water produced during its last weeks for a range of values of the refractory/ice ratio in the nucleus. We also determine the size distribution of the disintegrating particles as the comet faded.

Aß42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells.

Amyloid-ß 42 [Aß1-42 (Aß42)] is one of the main Aß peptide isoforms found in amyloid plaques of brains with Alzheimer's disease (AD). Although Aß42 is associated with neurotoxicity, it might mediate several normal physiological processes during embryonic brain development and in the adult brain. However, due to the controversy that exists in the field, relatively little is known about its physiological function. In the present work, we have analyzed the effects of different concentrations of monomeric Aß42 on cell death, proliferation, and cell fate specification of human neural stem cells (hNSCs), specifically the hNS1 cell line, undergoing differentiation. Our results demonstrate that at higher concentrations (1 µM), Aß42 increases apoptotic cell death and DNA damage, indicating that prolonged exposure of hNS1 cells to higher concentrations of Aß42 is neurotoxic. However, at lower concentrations, Aß42 significantly promotes cell proliferation and glial cell specification of hNS1 cells by increasing the pool of proliferating glial precursors, without affecting neuronal differentiation, in a concentration-dependent manner. At the molecular level, these effects could be mediated, at least in part, by GSK3ß, whose expression is increased by treatment with Aß42 and whose inhibition prevents the glial specification induced by Aß42. Since the cellular and molecular effects are known to appear decades before the first clinical symptoms, these types of studies are important in discovering the underlying pathophysiological processes involved in the development of AD. This knowledge could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.

Effects of ECG Signal Processing on the Inverse Problem of Electrocardiography.

The inverse problem of electrocardiography is ill-posed. Errors in the model such as signal noise can impact the accuracy of reconstructed cardiac electrical activity. It is currently not known how sensitive the inverse problem is to signal processing techniques. To evaluate this, experimental data from a Langendorff-perfused pig heart (n=1) suspended in a human-shaped torso-tank was used. Different signal processing methods were applied to torso potentials recorded from 128 electrodes embedded in the tank surface. Processing methods were divided into three categories i) high-frequency noise removal ii) baseline drift removal and iii) signal averaging, culminating in n=72 different signal sets. For each signal set, the inverse problem was solved and reconstructed signals were compared to those directly recorded by the sock around the heart. ECG signal processing methods had a dramatic effect on reconstruction accuracy. In particular, removal of baseline drift significantly impacts the magnitude of reconstructed electrograms, while the presence of high-frequency noise impacts the activation time derived from these signals (p<0.05).

Mechano-electric coupling, heterogeneity in repolarization and the electrocardiographic T-wave.

Stretch influences repolarization by mechano-electric coupling (MEC) and contributes to arrhythmogenesis. Although there is an abundance of research on electrophysiological effects of MEC, it is still unclear how MEC translates to the ECG. We aim to provide an overview of the MEC research focused on the ECG and the underlying changes in electrophysiology. In addition, we present new data on the effect of left ventricular pressure on the electrocardiographic T-wave. We show that an increase in left ventricular pressure leads to prolonged QT-intervals with increased amplitudes of the STT-segment. This corresponds to a prolongation in repolarization and an increased interventricular dispersion of repolarization. MEC is dependent on timing, intensity and modality of stretch and these three factors should be taken into account to analyse the effects of MEC on the heart and on the ECG. In addition, the deformation of the heart itself should be considered, since it influences the amplitude of the STT-segment. Because the electrocardiographic T-wave represents heterogeneity in repolarization, left ventricular pressure increases may have significant influence on the inducibility of (re-entrant) arrhythmias.

The pro- or antiarrhythmic actions of polyunsaturated fatty acids and of cholesterol.

In this review, the pro- and anti-arrhythmic effects of a diet rich in fish oil fatty acids and of hypercholesterolemia will be discussed in relation to two major mechanisms of arrhythmogenesis (triggered activity and re-entry). Whereas a diet rich in fish oil is pro-arrhythmic in relation to re-entry based arrhythmias (as occur in acute myocardial ischemia) and anti-arrhythmic in relation to triggered activity based arrhythmias (as occur in heart failure), the reverse is true for hypercholesterolemia. Changing the lipid composition of cardiomyocytes likely has powerful pro- or anti-arrhythmic consequences, depending on the mechanism of arrhythmias, and has corresponding therapeutic potential.

Electrophysiological changes in heart failure and their implications for arrhythmogenesis.

Heart failure is the final common pathway of various cardiac pathologies and is associated with sudden cardiac death, mostly caused by ventricular arrhythmias. In this paper we briefly review the electrophysiological remodeling and the alterations in intracellular calcium handling, and the resulting arrhythmogenic mechanisms associated with heart failure. Intercellular uncoupling and fibrosis are identified as a major arrhythmogenic factors. Diet and ventricular wall stretch are discussed as modulating factors. Finally, emphasis is placed on the hitherto poorly studied aspects of right ventricular failure. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.

Noninvasive detection of epicardial and endocardial activity of the heart.

Determining electrical activation of the heart in a noninvasive way is one of the challenges in cardiac electrophysiology. The ECG provides some, but limited information about the electrical status of the heart. This article describes a method to determine both endocardial and epicardial activation of the heart of an individual patient from 64 electrograms recorded from the body surface. Information obtained in this way might be helpful for the treatment of arrhythmias, to assess the effect of drugs on conduction in the heart and to assess electrical stability of the heart.

Chronic inhibition of the Na+/H+ - exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling.

BACKGROUND AND PURPOSE: Increased activity of the Na+/H+ -exchanger (NHE-1) in heart failure underlies raised [Na+]i causing disturbances of calcium handling. Inhibition of NHE-1, initiated at the onset of pressure/volume overload, prevents development of hypertrophy, heart failure and remodelling. We hypothesized that chronic inhibition of NHE-1, initiated at a later stage, would induce regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. EXPERIMENTAL APPROACH: Development of heart failure in rabbits was monitored electrocardiographically and echocardiographically, after one or three months. Cardiac myocytes were also isolated. One group of animals were treated with cariporide (inhibitor of NHE-1) in the diet after one month. Cytoplasmic calcium, sodium and action potentials were measured with fluorescent markers and sarcoplasmic reticulum calcium content by rapid cooling. Calcium after-transients were elicited after rapid pacing. Sodium channel current (INa) was measured using patch-clamp techniques. KEY RESULTS: Hypertrophy and heart failure developed after one month and progressed during the next two months. After one month, dietary treatment with cariporide was initiated. Two months of treatment reduced hypertrophy and heart failure, duration of action potential QT-interval and QRS, and restored sodium and calcium handling and the incidence of calcium after-transients. In cardiac myocytes, parameters of INa were not changed by cariporide. CONCLUSION AND IMPLICATIONS: In rabbit hearts with hypertrophy and signs of heart failure one month after induction of pressure/volume overload, two months of dietary treatment with the NHE-1 inhibitor cariporide caused regression of hypertrophy, heart failure and ionic and electrophysiological remodelling.

[Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure.

OBJECTIVE: Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX (DeltaG(exch)). METHODS: The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of DeltaG(exch) were calculated. RESULTS: With increasing stimulation frequency, 0.2-3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch) decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of DeltaG(exch) decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. CONCLUSIONS: [Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode DeltaG(exch) secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode DeltaG(exch) may account for increased contribution of NCX to e-c coupling in HF.

Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model.

OBJECTIVE: Cytosolic sodium ([Na+]i) is increased in heart failure (HF). We hypothesize that up-regulation of Na+/H+-exchanger (NHE) in heart failure is causal to the increase of [Na+]i and underlies disturbance of cytosolic calcium ([Ca2+]i) handling. METHODS: Heart failure was induced in rabbits by combined volume and pressure overload. Age-matched animals served as control. [Na+]i, cytosolic calcium [Ca2+]i and cytosolic pH (pH(i)) were measured in isolated left ventricular midmural myocytes with SBFI, indo-1 and SNARF. SR calcium content was measured as the response of [Ca2+]i to rapid cooling (RC). Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin. NHE and Na+/K+-ATPase activity were inhibited with 10 micromol/l cariporide and 100 micromol/l ouabain, respectively. RESULTS: At all stimulation rates (0-3 Hz) [Na+]i and diastolic [Ca2+]i were significantly higher in HF than in control. With increasing frequency [Na+]i and diastolic [Ca2+]i progressively increased in HF and control, and the calcium transient amplitude (measured as total calcium released from SR) decreased in HF and increased in control. In HF (at 2 Hz), SR calcium content was reduced by 40% and the calcium gradient across the SR membrane by 60%. Fractional systolic SR calcium release was 90% in HF and 60% in control. In HF the rate of pH(i) recovery following acid loading was much faster at all pH(i) and NHE dependent sodium influx was almost twice as high as in control. In HF cariporide (10 micromol/l, 5 min) reduced [Na+]i and end diastolic [Ca2+]i to almost control values, and reversed the relation between calcium transient amplitude and stimulation rate from negative to positive. It increased SR calcium content and SR membrane gradient and decreased fractional systolic SR depletion to 60%. Cariporide greatly reduced the susceptibility to develop calcium after-transients. In control animals, cariporide had only minor effects on all these parameters. Increase of [Na+]i with ouabain in control myocytes induced abnormal calcium handling as found in HF. CONCLUSIONS: In HF up-regulation of NHE activity is causal to increased [Na+]i and secondarily to disturbed diastolic, systolic and SR calcium handling. Specific inhibition of NHE partly normalized [Na+]i, end diastolic [Ca2+]i, and SR calcium handling and reduced the incidence of calcium after-transients. Chronic treatment with specific NHE inhibitors may provide a useful future therapeutic option in treatment of developing hypertrophy and heart failure.

Monophasic action potentials and Ca2+ transients in ischaemically preconditioned rabbit ventricular muscle.

BACKGROUND: ATP-sensitive K+ (KATP) channels play an important role in the protective mechanism underlying ischaemic preconditioning. Ample evidence indicates, however, that action potential shortening is not a prerequisite for the cardioprotective effect of preconditioning. METHODS: Monophasic action potential duration (MAPD), tissue resistance, intracellular Ca2+ (Indo-1) and mechanical activity were simultaneously assessed in arterially perfused rabbit papillary muscles. We studied four experimental protocols preceding sustained ischaemia: 1. control perfusion (n=6), 2. ischaemic preconditioning (PC; n=4), 3. pretreatment with a KATP channel blocker, glibenclamide (15 µmol/1), prior to ischaemic preconditioning (PC+glib; n=3), 4. glibenclamide pretreatment only (Glib; n=2). RESULTS: In the PC group an increase in the diastolic Ca2+ level and a prolongation of the Ca2+ transient just prior to the induction of sustained ischaemia correlate to the postponement of the onset of irreversible ischaemic damage, as established by a rise in [Ca2+]i, electrical uncoupling and contracture. Glibenclamide antagonised these changes in the Ca2+ transient and the cardioprotection induced by preconditioning. MAPD was equal in all experimental groups. CONCLUSIONS: Prolongation of the Ca2+ transient and increase of diastolic [Ca2+]i just prior to the induction of sustained ischaemia and not action potential shortening are involved in the cardioprotective effect of ischaemic preconditioning. Therefore, a glibenclamide-sensitive mechanism, other than the sarcolemmal KATP channels, is involved in the protective effect of ischaemic preconditioning. Changes in Ca2+ metabolism may play a crucial role in ischaemic preconditioning.

Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis.

BACKGROUND: Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. METHODS AND RESULTS: High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. CONCLUSIONS: The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

K(ATP) channel opening during ischemia: effects on myocardial noradrenaline release and ventricular arrhythmias.

Cardioprotection by K(ATP) channel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. K(ATP) channel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of K(ATP) channel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and K+-selective electrodes were inserted in the left ventricular free wall. Cromakalim (3 microM) or glibenclamide (3 microM) was added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim (n = 16) prevented the second rise of extracellular [K(+)] in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. control 941 +/- 278; p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr dry wt vs. control 1,460 +/- 433; p < 0.05), but after 30 min of ischemia, the difference in noradrenaline release was no longer significant (cromakalim 2,703 +/- 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.08). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation (mean +/- SEM onset after 12.5 +/- 1.6 min ischemia vs. control 16.2 +/- 0.7 min; p < 0.05). Noradrenaline release occurred only in cromakalim-treated hearts with early-onset arrhythmias whereas no noradrenaline release was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K(ATP) channel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of K(ATP) openers during myocardial ischemia.