Marieke Veldkamp - Academia.edu (original) (raw)

Papers by Marieke Veldkamp

Europace, Jul 12, 2023

Opioids are associated with an increased risk of sudden cardiac death due to life-threatening car... more Opioids are associated with an increased risk of sudden cardiac death due to life-threatening cardiac arrhythmias: • Tramadol reduced current of Nav1.5 channels in a fully-available state in a dosedependent manner and caused gating changes at lethal concentrations. • These effects were mirrored by reductions in the action potential upstroke velocity and reduction in action potential amplitude. • Fentanyl and codeine had no effects on Nav1.5 channels in a fully-available state at lethal concentrations.

Circulation, Oct 28, 2008

Netherlands Heart Journal, Nov 10, 2017

Background Monosodium glutamate (MSG), also referred to as Vetsin or E621, is a flavour enhancer ... more Background Monosodium glutamate (MSG), also referred to as Vetsin or E621, is a flavour enhancer frequently used in Asian cuisine and abundantly present in the famous Chinese dish Peking duck. MSG is notorious for triggering the onset of the so-called 'Chinese restaurant syndrome' (CRS), a complex of unpleasant symptoms, which might include flushing, sweating and the onset of atrial fibrillation (AF). This study aims to determine the effects of MSG on the occurrence of AF. Methods We conducted a placebo self-controlled singlearm study in the Academic Medical Centre in Amsterdam. We included paroxysmal AF patients who reported a consistent onset of AF upon MSG intake. During three admissions, participants were subsequently administered: placebo, 1.5 g and 3 g MSG. If AF was recorded after the Both Van den Berg and Neefs are first author of the manuscript, as they have written the manuscript together. S.P.J. Krul and J.R. de Groot contributed equally to the manuscript. All authors have contributed to the conception of the study, have either drafted or critically reviewed the manuscript and all have approved the final version of the manuscript.

Circulation, Jun 6, 2000

Background-The ionic mechanism underlying the transient inward current (I ti), the current respon... more Background-The ionic mechanism underlying the transient inward current (I ti), the current responsible for delayed afterdepolarizations (DADs), appears to be different in ventricular myocytes and Purkinje fibers. In ventricular myocytes, I ti was ascribed to a Na ϩ-Ca 2ϩ exchange current, whereas in Purkinje fibers, it was additionally ascribed to a Cl Ϫ current and a nonselective cation current. If Cl Ϫ current contributes to I ti and thus to DADs, Cl Ϫ current blockade may be potentially antiarrhythmogenic. In this study, we investigated the ionic nature of I ti in single sheep Purkinje and ventricular myocytes and the effects of Cl Ϫ current blockade on DADs. Methods and Results-In whole-cell patch-clamp experiments, I ti was induced by repetitive depolarizations from Ϫ93 to ϩ37 mV in the presence of 1 mol/L norepinephrine. In both Purkinje and ventricular myocytes, I ti was inward at negative potentials and outward at positive potentials. The anion blocker 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid (DIDS) blocked outward I ti completely but inward I ti only slightly. The DIDS-sensitive component of I ti was outwardly rectifying, with a reversal close to the reversal potential of Cl Ϫ currents. Blockade of Na ϩ-Ca 2ϩ exchange by substitution of extracellular Na ϩ by equimolar Li ϩ abolished the DIDS-insensitive component of I ti. DIDS reduced both DAD amplitude and triggered activity based on DADs. Conclusions-In both Purkinje and ventricular myocytes, I ti consists of 2 ionic mechanisms: a Cl Ϫ current and a Na ϩ-Ca 2ϩ exchange current. Blockade of the Cl Ϫ current may be potentially antiarrhythmogenic by lowering DAD amplitude and triggered activity based on DADs.

Nature Biomedical Engineering, 2022

Instrument Ploidy assessment: FACSCanto II (BD Biosciences). Purity assessment: Accuri C6 (BD Bio... more Instrument Ploidy assessment: FACSCanto II (BD Biosciences). Purity assessment: Accuri C6 (BD Biosciences). Software Ploidy assessment: FACSDiva 8.0 (BD Biosciences, used for acquisition), WinList 8 and ModFit LT 5.0 (both from Verity Software House, used for analysis). Purity assessment: Accuri C6 software v1.0.264 (BD Biosciences, used for acquisition and analysis). Cell population abundance Ploidy assessment: minimum of 30,000 single cell events. Purity assessment: 5,000-20,000 gated events per condition. Gating strategy Cell debris was excluded on the basis of size and scatter characteristics. Detailed strategies for both flow cytometric studies are provided (including visual support) in Supplementary Fig. 2 and Supplementary Fig. 4. Tick this box to confirm that a figure exemplifying the gating strategy is provided in the Supplementary Information.

Cardiovascular Drugs and Therapy, 2019

Purpose Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac e... more Purpose Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. Methods The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). Results A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity...

Science Translational Medicine, May 22, 2019

Catheter ablation for atrial fibrillation induces intracardiac neural damage characterized by gli... more Catheter ablation for atrial fibrillation induces intracardiac neural damage characterized by glial S100B release, which promotes nerve sprouting.

Journal of Molecular and Cellular Cardiology

Circulation, 2001

Background Animal studies have shown that the Ca 2+ -activated Cl − current ( I Cl(Ca) ) and the ... more Background Animal studies have shown that the Ca 2+ -activated Cl − current ( I Cl(Ca) ) and the Na + /Ca 2+ exchange current ( I Na/Ca ) contribute to the transient inward current ( I ti ). I ti is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of I ti and DADs in human cardiac cells. Methods and Results Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology. I ti s were elicited in the presence of 1 μmol/L norepinephrine by trains of repetitive depolarizations from −80 to +50 mV. DADs were induced in the presence of 1 μmol/L norepinephrine at a stimulus frequency of 1 Hz. I ti currents were inwardly directed over the voltage range between −110 and + 50 mV. Neither the Cl − channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid nor changes in [Cl − ] i affected I ti or DAD amplitude. This excludes an important r...

Heart Rhythm

BACKGROUND Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. T... more BACKGROUND Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. The effect of EAT secretome (EATs) on cardiac electrophysiology remains largely unknown. OBJECTIVE The purpose of this study was to investigate the arrhythmogenicity of EATs and its underlying molecular and electrophysiological mechanisms. METHODS We collected atrial EAT and subcutaneous adipose tissue (SAT) from 30 patients with atrial fibrillation (AF), and EAT from 3 donors without AF. The secretome was collected after a 24-hour incubation of the adipose tissue explants. We cultured neonatal rat ventricular myocytes (NRVMs) with EATs, subcutaneous adipose tissue secretome (SATs), and cardiomyocytes conditioned medium (CCM) for 72 hours. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested arrhythmia inducibility. RESULTS Incubation of NRVMs with EATs decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K 1 current I K1 by 35% compared to incubation with CCM, resulting in a depolarized resting membrane of cardiomyocytes. EATs decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 or Gja1 expression in comparison to CCM, and their resting potential was not depolarized. Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. Computer modeling of human left atrium revealed that the electrophysiological changes induced by EATs promote sustained reentrant arrhythmias if EAT partially covers the myocardium. CONCLUSION EAT slows conduction, depolarizes the resting potential, alters electrical cell-cell coupling, and facilitates reentrant arrhythmias.

Rationale: The SCN10A gene encodes the neuronal sodium channel isoform NaV1.8. Several recent gen... more Rationale: The SCN10A gene encodes the neuronal sodium channel isoform NaV1.8. Several recent genome-wide association studies have linked SCN10A to PR interval and QRS duration, strongly suggesting an as-yet unknown role for NaV1.8 in cardiac electrophysiology. Objective: To demonstrate the functional presence of SCN10A/Nav1.8 in intracardiac neurons of the mouse heart. Methods and Results: Immunohistochemistry on mouse tissue sections showed intense NaV1.8 labeling in dorsal root ganglia and intracardiac ganglia and only modest NaV1.8 expression within the myocardium. Immunocy-tochemistry further revealed substantial NaV1.8 staining in isolated neurons from murine intracardiac ganglia but no NaV1.8 expression in isolated ventricular myocytes. Patch-clamp studies demonstrated that the NaV1.8 blocker A-803467 (0.5–2 mol/L) had no effect on either mean sodium current (INa) density or INa gating kinetics in isolated myocytes but significantly reduced INa density in intracardiac neurons...

$Research paper thumbnail of Neurokinin-3 receptor activation selectively prolongs atrial refractoriness by inhibition of a background K+ channel$

Nature Communications

The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardia... more The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardiac ANS produces various neuropeptides, among which the neurokinins, whose actions on atrial electrophysiology are largely unknown. We here demonstrate that the neurokinin substance-P (Sub-P) activates a neurokinin-3 receptor (NK-3R) in rabbit, prolonging action potential (AP) duration through inhibition of a background potassium current. In contrast, ventricular AP duration was unaffected by NK-3R activation. NK-3R stimulation lengthened atrial repolarization in intact rabbit hearts and consequently suppressed arrhythmia duration and occurrence in a rabbit isolated heart model of atrial fibrillation (AF). In human atrial appendages, the phenomenon of NK-3R mediated lengthening of atrial repolarization was also observed. Our findings thus uncover a pathway to selectively modulate atrial AP duration by activation of a hitherto unidentified neurokinin-3 receptor in the membrane of atrial myocytes. NK-3R stimulation may therefore represent an anti-arrhythmic concept to suppress re-entry-based atrial tachyarrhythmias, including AF.

Cardiovascular Research

Time for primary review: 41 days Aims Selective inhibition of cardiac late sodium current (I NaL)... more Time for primary review: 41 days Aims Selective inhibition of cardiac late sodium current (I NaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of I NaL , in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD þ/induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD þ/- .

Nature communications, Jan 27, 2017

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibri... more The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental...

Circulation, Nov 25, 2014

Background and Aim: Selective inhibition of cardiac late sodium current (INa,L) is an emerging ta... more Background and Aim: Selective inhibition of cardiac late sodium current (INa,L) is an emerging target in the treatment of ventricular arrhythmias. The electrophysiological effects of GS967, a potent INa,L inhibitor, were investigated in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from human SCN5A -1795insD induced pluripotent stem cells (iPSC-CMs) and mice carrying the homologous mutation Scn5a -1798insD. Methods and Results: On patch-clamp analysis, isolated mouse Scn5a -1798insD cardiomyocytes and human SCN5A -1795insD iPSC-CMs showed decreased peak INa and action potential (AP) upstroke velocity (Vmax) and increased INa,L and AP duration at 90% repolarization (APD90) as compared to wild-type. GS967 (50-300 nM) significantly decreased APD90 in mouse Scn5a -1798insD cardiomyocytes by 8±2% (mean±SEM) at 50 nM (n=7), 13±3% at 100 nM (n=11) and 20±5% at 300 nM (n=6) (all p <0.01 vs. control), without affecting Vmax. GS967 (300 nM) selectively inhibited INaL in mouse Scn5a -1798insD cardiomyocytes (GS967-sensitive current of 0.7±0.1 pA/pF, n=6), but had no effect on peak INa . Furthermore, GS967 (100 nM) suppressed fast (5 Hz) pacing-induced afterpotentials and triggered activity. In human SCN5A -1795insD iPSC-CMs (n=6), GS967 (300 nM) significantly reduced APD90 without affecting the resting membrane potential or Vmax. In Langendorff-perfused, isolated mouse Scn5a -1798insD hearts (n=5), GS967 (300 nM) had no effect on ventricular activation time or conduction velocity (as assessed by epicardial mapping). Conclusion: Selective inhibition of INaL by GS967 attenuated AP prolongation and prevented pro-arrhythmic activity in mouse Scn5a -1798insD cardiomyocytes and human SCN5A-1795insD iPSC-CMs, thus suppressing the gain-of-function features of this overlap syndrome mutation. Importantly, these beneficial actions of GS967 occurred in the absence of deleterious effects on sodium channel availability or cardiac conduction, despite a pre-existing decrease in peak INa. Thus, selective inhibition of INa,L constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced INaL, even in overlap syndromes whereby peak INa is decreased.