M. A. G. van der Heyden

Drugs and trafficking of ion channels: a new pro‐arrhythmic threat on the horizon?

Tuning of functional expression levels of the ion channels that make up the cardiac action potential (AP) is crucial for preserving correct AP duration (APD) and QTc times. Many compounds inhibit human ether‐à‐go‐go related gene (hERG)‐mediated delayed rectifier currents and thus prolong cardiac repolarization that may cause life‐threatening arrhythmias like Torsades de Pointes. An increasing number of drugs are found to inhibit hERG function by a dual mechanism of short‐term channel block and long‐term trafficking defects that operate over different time and concentration scales. In safety screens at present used by pharmaceutical companies, the short‐term effect of channel block is covered. In contrast, specific screening for long‐term trafficking defects is not common, with the consequent risk of drugs that disturb trafficking entering the market. Whether that poses another pro‐arrhythmic threat for the patients treated has to be determined, but is not unlikely.

Regulatory Roles of the Ubiquitin-Proteasome System in Cardiomyocyte Apoptosis

Cardiovascular disease is the leading cause of death in the western world. The major contributor of all cardiovascular deaths is myocardial infarction, which often progresses into end-stage heart failure. The loss of cardiomyocytes is a key problem in the development of cardiovascular disease. Two main processes mediate cardiomyocyte loss: necrosis and apoptosis. In contrast to necrosis, apoptosis is a well regulated process essential in normal development and tissue homeostasis. Tight regulation of this process is crucial, especially in post mitotic cells lacking regenerative capacity, like cardiomyocytes. The ubiquitin-proteasome system, accounting for 80 to 90% of intracellular protein degradation, appears to be involved in the regulation of apoptosis. In this process, regulation is performed through the degradation of pro- and anti-apoptotic proteins involved in cell cycle control and specific apoptotic pathways. On the one hand, disturbances in this normally well regulated process are associated with a number of cardiovascular diseases. On the other hand, proteasomal dysfunction may result from ischemia, hypertrophy and heart failure, and a number of cardiomyopathies. This paper reviews the current knowledge on the role of the ubiquitin-proteasome system-mediated regulation of cardiomyocyte apoptosis in cardiovascular disease. Finally, within the ubiquitin-proteasome system new molecular targets for treatment of cardiovascular disease are suggested.

Fraud and misconduct in science: the stem cell seduction: Implications for the peer-review process.

Scientific misconduct and fraud occur in science. The (anonymous) peer review process serves as goalkeeper of scientific quality rather than scientific integrity. In this brief paper we describe some limitations of the peer-review process. We describe the catastrophic facts of the ‘Woo-Suk Hwang fraud case’ and raise some ethical concerns about the issue. Finally, we pay attention to plagiarism, autoplagiarism and double publications. (Neth Heart J 2009;17:25-9.)

Barium toxicity and the role of the potassium inward rectifier current.

Abstract Introduction. Barium is a stable divalent earth metal and highly toxic upon acute and chronic exposure. Barium is present in many products and involved in a number of industrial processes. Barium targets the potassium inward rectifier channels (IRCs) of the KCNJx gene family. Extracellular barium enters and strongly binds the potassium selectivity filter region resulting in blockade of the potassium conducting pore. IRCs are involved in numerous physiological processes of the human body and the most barium sensitive IRCs are highly expressed in all muscle types. Objective. Our purpose was correlate to the clinical outcome of acute barium poisoning in man to current knowledge on IRC function. Methodology. The primary literature search was performed using Medline, Scopus and Google Scholar using search terms “barium AND poisoning”; “barium AND intoxication”; “barium AND case report” and retrieved publications from 1945 through 2012. Additional case reports were retrieved based on the reference lists of the primary hits. Duplicate publications, or publications presenting identical cases were omitted. A total of 39 case reports on acute barium poisoning containing 226 human subjects were identified for review. Results. BaCO3 was the most frequent source and food the most frequent mode of poisoning. Patients suffered from gastrointestinal (vomiting, diarrhea), cardiovascular (arrhythmias, hypertension), neuromuscular (abnormal reflexes, paralysis), respiratory (respiratory arrest/failure) and metabolic (hypokalemia) symptoms. Severe hypokalemia (< 2.5 mM) was observed from barium serum concentrations greater than or equal to 0.0025 mM. Review of the ECG outcomes demonstrated ventricular extrasystoles, ST changes and profound U-waves to be associated strongly with poisoning. Most common treatment modalities were gastric lavage, oral sulfates, potassium i.v. and cardiorespiratory support. 27 patients (12%) died from barium poisoning. Conclusions. Barium is a potent, non-specific inhibitor of the potassium IRC current and affects all types of muscle at micromolar concentrations. Gastrointestinal symptoms frequently occur early in the course of barium poisoning. Hypokalemia resulting from an intracellular shift of potassium and the direct effect of barium at the potassium channels explain the cardiac arrhythmias and muscle weakness which commonly occur in barium poisoning. Treatment of barium poisoning is mainly supportive. Orally administered sulfate salts to form insoluble barium sulfate in the intestinal tract and potassium supplementation have potential but unproven benefit.

Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.

Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied.

Inhibition of Cardiac Inward Rectifier Currents by Cationic Amphiphilic Drugs

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004–2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region.

Adrenergic regulation of conduction velocity in cultures of immature cardiomyocytes

During cardiac maturation, increased exposure of the heart to circulating catecholamines correlates with increased conduction velocity and growth of the heart. We used an in vitro approach to study the underlying mechanisms of adrenergic stimulation induced changes in conduction velocity. By combining functional measurements and molecular techniques, we were able to demonstrate that the increased conduction velocity after β-adrenergic stimulation is probably not caused by changes in intercellular coupling. Instead, RT-PCR experiments and action potential measurements have shown an increased excitability that may well explain the observed increase in conduction velocity. Apart from being relevant to cardiac maturation, our findings are relevant in the context of stem cells and cardiac repair. Preconditioning of stem cell derived cardiomyocytes may help to enhance electrical maturation of de novo generated cardiomyocytes and consequently reduce their proarrhythmogenic potential. (Neth Heart J 2008;16:106-9.)

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