Marcel A.G. van der Heyden

• Ph.D.
• Professor (Associate) at University Medical Center Utrecht

Introduction Lupin beans are the seeds of plants from the Fabaceae family. These beans are rich in protein and used for human consumption for several millennia. Their popularity is still increasing. Some species produce beans with high alkaloid contents, specifically of spartaine and lupanine. Without proper processing, consuming these beans can re...

Scientific integrity has been increasingly challenged by scientific misconduct and paper mills, resulting in an increase in retractions. Naunyn–Schmiedeberg’s Archives of Pharmacology has been significantly impacted by fraudulent submissions, resulting in numerous retractions. By analyzing retraction notes and utilizing a post-publication surveilla...

Background and Purposes Reduced inward rectifier potassium channel (Kir2.1) functioning is associated with heart failure and may cause Andersen‐Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen–Tawil Syndrome patients are treated with β‐adrenoceptor antagonists (β‐blockers) or sodium channel block...

Introduction The mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination. Methods Five independent groups of goats were investigated: (1) spon...

The functioning of the human heart relies on complex electrical and communication systems that coordinate cardiac contractions and sustain rhythmicity. One of the key players contributing to this intricate system is the KIR2.1 potassium ion channel, which is encoded by the KCNJ2 gene. KIR2.1 channels exhibit abundant expression in both ventricular...

Introduction Medical undergraduate students receive limited education on scholarly publishing. However, publishing experiences during this phase are known to influence study and career paths. The medical bachelor Honours Program (HP) at Utrecht University initiated a hands-on writing and publishing course, which resulted in nine reviews published i...

Background: The rapid delayed rectifier potassium current (IKr) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small current density. Interestingly, the i...

Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rat...

Aims An automated method for determination of short-term variability of repolarization (STV) on intracardiac electrograms (STV-ARIauto) has previously been developed for arrhythmic risk monitoring by cardiac implantable devices, and has proved effective in predicting ventricular arrhythmias (VA) and guiding preventive high-rate pacing (HRP) in a ca...

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular...

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been l...

Expression and activity of inwardly rectifying potassium (KIR) channels within the heart are strictly regulated. KIR channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. Impaired KIR2.1 functi...

Background A preclinical model standardized at different remodeling stages after AV block induction in awake state is suitable for the evaluation of improved cardiac devices. We studied exercise-induced cardiorespiratory parameters at three different timepoints after inducing AV block in dogs. Methods Mongrel dogs (n = 12) were placed on a treadmi...

The use of pre-workout supplements has become increasingly popular, including the use of supplements containing synephrine. Synephrine might stimulate weight loss and improve sports performance by its proposed adrenergic properties. However, with its increasing popularity, numerous cases of adverse events related to synephrine use have been reporte...

Background The phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential...

Introduction Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic ef...

Alteration of the inward rectifier current IK1, carried by KIR2.1 channels, affects action potential duration, impacts resting membrane stability and associates with cardiac arrhythmias. Congenital and acquired KIR2.1 malfunction frequently associates with aberrant ion channel trafficking. Cellular processes underlying trafficking are intertwined w...

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with t...

Background Recreational use of nitrous oxide (N2O) is associated with many side effects, of which neurological complications are most common. Nitrous oxide abuse is also associated with psychiatric symptoms, but these have received less attention so far. Vitamin B12 deficiency may play a role in the development of these psychiatric symptoms. Aims T...

Publications baring falsified and fabricated images appear frequently in the primary literature. Industrialized forms of image forgery as practiced by the so-called paper mills worsen the current situation even further. Good education and awareness within the scientific society are essential to create an environment in which honesty and trust are t...

Context The black mamba (Dendroaspis polylepis) is, due to its extremely toxic venom, one of the most dangerous snake species in Sub-Saharan Africa. A D. polylepis bite is a medical emergency and requires adequate action to prevent severe complications. However, there are no comprehensive reviews available based on clinical cases, and no readily ac...

The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (IK1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis that the co-culturing...

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ITN Networks PersonalizeAF: Personalized Therapies for Atrial Fibrillation. A Translational Approach, No. 860974; CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, No. 633196; MAESTRIA: M...

Ventricular cardiac arrhythmia is a life threating condition arising from abnormal functioning of many factors in concert. Animal models mirroring human electrophysiology are essential to predict and understand the rare pro‐ and anti‐arrhythmic effects of drugs. This is very well accomplished by the canine chronic atrioventricular block (CAVB) mode...

Introduction Torsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP. Methods Dofetilide (25 μg/kg per 5 min)...

Inward rectifier potassium ion channels (IK1-channels) of the Kir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. IK1-channel loss-of-function, either congenital or acquired, has been associated with cardi...

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 ch...

This work presents drug-likeness and the cardiotoxicity profiles of six potent pentamidine analogs 1–6 and three new compounds 7–9 as chemotherapeutics for therapy of Pneumocystis jiroveci pneumonia. A combination of experimental and computational approaches was used in the cardiotoxicity examination. The hERG trafficking and functionality of the h...

The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney...

Cardiac manifestation of Lyme borreliosis occurs in 0.3-4% of patients with Lyme disease in Europe. Lyme carditis has a variable clinical presentation with cardiac death as one of its endpoints. The most common cardiac manifestation is atrioventricular conduction block (AV block). We reviewed all published Lyme cases presenting with AV block within...

Background and Purpose Kv11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia...

Background: Electronic cigarettes (e-cigarettes), the smokeless alternative to conventional tobacco cigarettes, have become increasingly popular. E-cigarettes vaporise e-liquid, a solution of highly concentrated nicotine, propylene glycol (PG) and vegetable glycerine (VG). With the popularity of e-cigarettes, e-liquid refills have become easily acc...

KIR2.1 potassium channels, producing inward rectifier potassium current (I K1 ), are important for final action potential repolarization and a stable resting membrane potential in excitable cells like cardiomyocytes. Abnormal KIR2.1 function, either decreased or increased, associates with diseases such as Andersen-Tawil syndrome, long and short QT...

KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodil...

Cantú syndrome (CS) is caused by dominant gain‐of‐function mutation in ATP‐dependent potassium channels. Cellular ATP concentrations regulate potassium current thereby coupling energy status with membrane excitability. No specific pharmacotherapeutic options are available to treat CS but IKATP channels are pharmaceutical targets in type II diabetes...

KATP channels consist of four Kir6.x pore-forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodil...

Background The inward rectifier inhibitor pentamidine analogue 6 (PA‐6) is effective in cardioversion of goats with persistent rapid pacing induced atrial fibrillation (AF) and is not proarrhythmic in dogs with experimental chronic 3rd‐degree AV block. Efficacy and safety in the clinical setting are unknown. Hypothesis That PA‐6 would be effective...

Table S1 Hemodynamic effects of GS967 in sinus rhythm dogs.

Data S1 Identification of dogs for animal and cellular experiments.

Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na+/K+-transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated...

Background and purpose: Enhanced late sodium current (late INa) in heart failure and long QT syndrome type 3 is proarrhythmic. GS-458967 (GS967) is a selective and potent late INainhibitor. This study aimed to evaluate the antiarrhythmic effect of late INainhibition by GS967 in the chronic atrioventricular block (CAVB) dog model sensitive to Torsa...

Hyperkalemia is a metabolic disturbance of the potassium balance that can cause potentially fatal cardiac arrhythmias. Kidney dysfunction and renin-angiotensin-aldosterone system inhibiting drugs are notorious for their tendency to induce hyperkalemia by decreasing the excretion of potassium. The role of dietary potassium intake in inducing hyperka...

Degradation of cellular material by lysosomes is known as autophagy, and its main function is to maintain cellular homeostasis for growth, proliferation and survival of the cell. In recent years, research has focused on the characterization of autophagy pathways. Targeting of autophagy mediators has been described predominantly in cancer treatment,...

Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as IKr(rapid delayed rectifie...

Background The inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient...

Gold open access provides free distribution of trustworthy scientific knowledge for everyone. As publication modus, it has to withstand the bad reputation of predatory journals and overcome the preconceptions of those who believe that open access is synonymous with poor quality articles and high costs. Gold open access has a bright future and will...

Objectives This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. Background The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the in...

Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and contribute to a wide range of physiological processes. Kir4.1 channel expression is found in the brain, inner ear, eye, and kidney. Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy,...

Preclinical drug screens are not based on human physiology, possibly complicating predictions on cardiotoxicity. Drug screening can be humanised with in vitro assays using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, in contrast to adult ventricular cardiomyocytes, iPSC-CMs beat spontaneously due to presence of th...

Figure S2 Electrophysiological parameters in cAVB dogs (n = 9) upon high dose bolus (2.5 mg.kg−1 10 min−1) infusion up to 30 min following start of infusion. QRS and QTc values are derived from ECG recordings. LVMAP80 values are derived from monophasic action potential recordings from the left ventricle.

Figure S4 Amino acid alignment of human (Hs, Homo sapiens), dog (Cf, Canis familiaris) and goat (Ch, Capra hircus) Kir2.1, Kir2.2 and Kir2.3 amino acid sequences in single letter code. Non‐identical residues with respect to the human sequence are depicted in white font on a black background. Transmembrane region 1 and 2, selectivity filter, G‐loop,...

Data S1 Supplementary Methods.

Figure S1 Electrophysiological parameters in sinus rhythm dogs (n = 4) upon low dose bolus (0.5 mg.kg−1 10 min−1) (A) or high dose bolus (2.5 mg.kg−1 10 min−1) (B) up to 30 min following start of infusion. RR, PQ, QRS, QTc values are derived from ECG recordings. LVMAP80 and STVlv are derived from monophasic action potential recordings from the left...

Figure S3 PA‐6 mediated inhibition (50 and 200 nM) of human (Hs, Homo sapiens) and fish (Bb, Blicca bjoerkna (white bream)) IKir2.1 determined by patch‐clamp electrophysiology in the inside‐out orientation. Percentage amino acid sequence identity between Hs and Bb is 82.9%.

Background and purpose: Inward rectifier current (IK1 ) density increases in atrial fibrillation (AF), shortening effective refractory period and thus promotes atrial reentry. Pentamidine-Analogue 6 (PA-6) is a selective and potent IK1 inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, in established large animal models....

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. KIR 2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1 ), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarr...

Short-term variability (STV), to quantify beat-to-beat variability of repolarization (BVR), is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed, but also in vulnerable patients with heart failure...

Context: Zinc chloride (ZnCl2)-based smoke bombs and screens are in use since the Second World War (1939-1945). Many case descriptions on ZnCl2 smoke inhalation incidents appeared since 1945. Objective: We provide a comprehensive overview of the clinical symptoms and underlying pathophysiology due to exposure to fumes from ZnCl2 smoke producing...

We read with great interest the excellent paper by Varghese (2016) who describes an in silico approach to study the consequences of reciprocal regulation of expression of the sodium current (INa) and the inward rectifier potassium current (IK1) in the ventricle for cardiac excitability and conduction. The in silico approach follows the experimental...

Introduction: The arrhythmia Torsade de Pointes (TdP) is responsible for >5% of all sudden cardiac deaths. However, the mechanism(s) underlying the TdPs is under debate. Clinical and experimental data suggest that TdP may be driven either by focal sources or by moving reentry. One way to study the mechanisms of TdP is to use the electrically remode...

Recently, the Journal of Cardiovascular Pharmacology retracted two papers for figure irregularities. In an attempt to reduce the number of such cases in future, we provide insights in a number of existing control mechanisms for scientists, editors, reviewers and readers, in the process of scholarly publication. We encourage case-based education usi...

Aim In healthy hearts, ventricular gap junctions are mainly composed by Connexin43 (Cx43) and localize in the intercalated disk, enabling appropriate electrical coupling. In diseased hearts, Cx43 is heterogeneously downregulated whereas activity of calmodulin/calcium-calmodulin protein kinase II (CaM/CaMKII) signaling increases. It is unclear if Ca...

Background: Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrh...

Acute excessive alcohol consumption is associated with heart rhythm disorders like atrial fibrillation but also premature ventricular contractions, collectively known as the "holiday heart syndrome". More rarely but clinically significant are reports of atrioventricular (AV) conduction disturbances in binge drinkers with no underlying heart disease...

Background: Skeletal myoblast (SkMB) transplantation has been conducted as a therapeutic strategy for severe heart failure. However, arrhythmogenicity following transplantation remains unsolved. We developed an in-vitro model of myoblast transplantation with "patterned" or "randomly-mixed" co-culture of SkMBs and cardiomyocytes enabling subsequent...

Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed hERG channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this...

The cardiac action potential arises and spreads throughout the myocardium as a consequence of highly organized spatial and temporal expression of ion channels conducting Na(+), Ca(2+) or K(+) currents. The cardiac Na(+) current is responsible for the initiation and progression of the action potential. Altered Na(+) current has been found implicated...

Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and association...

Potassium inward rectifier KIR2.1 channels contribute to the stable resting membrane potential in a variety of muscle and neuronal cell-types. Mutations in the KIR2.1 gene KCNJ2 have been associated with human disease, such as cardiac arrhythmias and periodic paralysis. Crystal structure and homology modelling of KIR2.1 channels combined with funct...

Introduction: The methoxamine-sensitized rabbit model is widely used to screen drugs for proarrhythmic properties, especially repolarization-dependent TdP arrhythmias. With the change of anesthesia and/or sensitizing agent, conduction disturbances have been reported as well. Therefore, we compared currently available in-house anesthetics in order...

Protein kinase A (PKA) is in vertebrates localized to specific locations in the cell via A-kinase anchoring proteins (AKAPs). The regulatory subunits of the four PKA isoforms (RIα, RIβ, RIIα and RIIβ) each form a homo-dimer and their dimerization domain interacts with a small helical region present in each of the over 40 so far reported AKAPs. This...

Pronounced beat-to-beat variability in cardiac repolarization duration (BVR) is associated with increased arrhythmic risk in patients, animal models and isolated cardiomyocytes. However, the mechanisms linking an enhanced BVR to arrhythmogenicity is unknown and may differ between single cells and the intact heart, since cellular coupling is known t...

Purpose: In healthy hearts, ventricular gap junctions are composed by Connexin43 proteins (Cx43) and are localized in the intercalated disk (ID) where they enable appropriate electrical and metabolic coupling. During pathophysiological conditions, Cx43 is heterogeneously downregulated whereas the activity of CaM/CaMKII signaling increases. It is un...