József Simkó

Proarrhythmic Potential of Antimicrobial Agents

Several antiarrhythmic and non-cardiovascular drug therapies including antimicrobial agents have been implicated as the causes for QT interval prolongation, torsades de pointes (TdP) ventricular tachycardia and sudden cardiac death. Most of the drugs that have been associated with the lengthening of the QT interval or development of TdP can also block the rapidly activating component of the delayed rectifier potassium current (IKr) in the ventricular cardiomyocytes. This article presents a review of the current literature on the QT interval prolonging effect of antimicrobials based on the results of the in vitro, in vivo studies and case reports. Our observations were derived from currently available Medline database. As we found, the most frequently QT interval prolonging antimicrobials are erythromycin, clarithromycin, fluoroquinolones, halofantrine, and pentamidine. Almost every antimicrobial-associated QT interval prolongation occurs in patients with multiple risk factors of the following: drug interactions, female gender, advanced age, structural heart disease, genetic predisposition, and electrolyte abnormalities. In conclusion, physicians should avoid prescribing antimicrobials having QT prolonging potential for patients with multiple risk factors. Recognition and appropriate treatment of TdP are also indispensable.

Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration‐dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts.

Myocardial adrenergic innervation in patients with vasovagal syncope measured with 123I-MIBG uptake.

BackgroundData about biochemical abnormalities (catecholamines) during vasovagal syncope (VVS) are available, but adrenergic myocardial structural damage may be hypothesized as well. AimTo study the global and regional adrenergic myocardial innervations in patients with VVS that was shown by head-up tilt table testing. Patients and methodsFifteen adult patients with VVS were studied. The age of patients was 44±18 years (17–73), nine were female and six were male. According to the tilt test results, five patients had cardioinhibition, six patients had vasodepressor syncope and four patients suffered from mixed-type VVS. Ischemic heart diseases were excluded by normal 99mTc-MIBI rest–stress dipyridamol single-photon emission computed tomography (SPECT) results. A control group was formed from six healthy adult volunteers. To investigate cardiac sympathetic innervations 250–370 MBq iodine-123 meta-iodobenzylguanidine (123I-MIBG) was used. Fifteen minutes after the intravenous administration of 123I-MIBG early, and 2–3 h later, delayed planar myocardial and tomographic (SPECT) scintigraphies were performed. The heart-to-mediastinum count ratio (H/M) was calculated for both early and delayed images, together with the decay-corrected change rates. The regional 123I-MIBG uptake was visualized on SPECT slices and polar map images. The regional uptake was considered pathological below 50% compared with normal uptake sites. ResultsDelayed H/M ratios significantly depended on group (analysis of variance: P=0.005), whereas early H/M values did not. Although the decay-corrected myocardial MIBG uptake increased in time in controls, less wash-in or even wash-out could be observed in the VVS groups; however, difference from the controls was significant only in the vasodepressor group (Dunnetts t-test: P<0.05). All patients had regional 123I-MIBG uptake deficit in different regions. ConclusionIn our patients with VVS, global 123I-MIBG deficit was present frequently, and all patients had regional adrenergic nerve function deficit. These alterations may play a role in causing clinical symptoms and have importance in staging and treatment planning.

Can the electrophysiological action of rosiglitazone explain its cardiac side effects

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90% level of repolarization (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90. In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC50 value for this inhibition was 25.2±2.7 μM for the transient outward K+ current (Ito), 72.3±9.3 μM for the rapid delayed rectifier K+ current (IKr), and 82.5±9.4 μM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.

Atrial fibrillation and the autonomous nervous system

The autonomic nervous system has a crucial role in the genesis, maintenance and abruption of atrial fibrillation. The substrate and trigger mechanism of atrial fibrillation can be influenced by the changing autonomic tone. The authors summarize the current knowledge on the relationship between autonomic nervous system and atrial fibrillation. The special neuroanatomical status and the role of autonomic reflexes and baroreflex in the initiation, maintenance, and termination of arrhythmia are reviewed. Furthermore, the mechanism and consequences of autonomic effect of the curative radiofrequency catheter ablation of pulmonary vein with atrial vagal neuroablation are discussed. At the end we also summarize the pharmacologic therapy of atrial fibrillation. Classification of atrial fibrillation, as either vagal or adrenergic, has only limited impact on current management.

Molecular and genetic background of sudden cardiac death

Despite recent findings on the functional, structural and genetic background of sudden cardiac death, the incidence is still relatively high in the entire population. A thorough knowledge on susceptibility, as well as pathophysiology behind the development of malignant arrhythmias will help us to identify individuals at risk and prevent sudden cardiac death. This article presents a review of the current literature on the role of altered intracellular Ca2+ handling, acute myocardial ischaemia, cardiac autonomic innervation, renin-angiotensin-aldosterone system, monogenic and complex heritability in the pathogenesis of sudden cardiac death.

Sinus node dysfunction due to psychotropic agents' combination.

Background: Although sinus node dysfunction is primarily related to degenerative fibrosis of nodal tissue in the elderly, it may occur at any age secondary to other cardiac abnormalities or extrinsic causes. Pharmacologic agents including psychotropic drug therapy may also play a role. Method: We present the case of a 53-year-old woman with bipolar affective disorder in whom antipsychotic agents were suspected of inducing sinus node dysfunction. Result: The combination of psychotropic agents including lithium, quetiapine and carbamazepine (first occasion) or escitalopram (second occasion) has been implicated as a cause for sinus node dysfunction. Conclusion: Patients with severe mental illness usually require long-term psychotropic drug therapy, often in combination. This may enhance efficacy but also involves an increased risk of adverse effects including cardiotoxicity.