| Zugriffsnummer | 20135 |
| Dokumenttyp | Zeitschriftenartikel |
| Sprache | Englisch |
| Titel | Safety pharmacology and prolongation of the QT interval |
| Autor(in); Institution |
Cavero, Icilio; Lucca, ITALY
Yan, Gan-Xin; Main Line Heart Center, Lankenau Institute for Medical Research, Philadelphia, PA, USA
Lux, Robert; Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, USA
Steinhoff, Uwe; 8.2, Biosignale, PTB-Berlin
|
| Quelle/Jahr | Journal of Electrocardiology: 40 (2007), 1/1, S58 - S61 |
| ISSN | 0022-0736 |
| DOI | |
| Verlag | Naperville, Ill. [u.a.]: Elsevier |
| Freie Schlagworte | safety pharmacology ; magnetocardiography ; QT interval |
| Zusammenfassung | The presently implemented guidelines on the non-clinical evaluation of QT interval prolongation require among other tests a large number of measurements in intact animals during the drug development process. While there is an ongoing discussion about the relation between prolonged repolarization and the proarrhythmic potential of a drug, it remains nevertheless necessary to investigate drug induced alterations of cardiac repolarization in animals. Established measurement protocols rely on electrocardiography (ECG) using external leads in anesthetized animals and on telemetric ECG devices with internal leads for studies in conscious animals. Magnetocardiography (MCG) as a contactless noninvasive method provides an alternative approach to asses cardiac electric function. MCG uses sensitive magnetic field sensors out-side the body to detect minute changes in magnetic field that are caused by the electrical currents in the heart. Thus the generators producing the MCG signal are the same currents that give rise to the electric potential differences measured by the ECG [1]. A multichannel MCG device can therefore be considered to be another lead system, containing the same information on cardiac intervals as the established multilead ECG methods. Since the magnetic field sensors do not require body contact, measurements in conscious animals become feasible. Several recent reports have shown that sufficient MCG signal amplitudes can be recorded from dogs, rabbits, hamsters, and guinea pigs [2,3]. Other MCG studies beyond QT prolon-gation assessment were performed on rats and mice [4,5]. In order to clarify the relation between QT intervals determined from ECG or MCG, we pe-formed simultaneous measurements of both modalities in 11 anesthetized guinea pigs. For the magnetic measurements, we used a commercially available magnetoencephalograph (Eagle Technology, Inc., Japan). Isoproterenol and d,l-sotalol were applied as test sub-stances in the anesthetized animals, since those drugs are known to induce different altera-tions of the normal repolarization mechanisms. MCG without drug interference was also performed in the awake animals and enabled a re-producible QT interval determination over 5 minutes using Bazett’s correction formula. In the anesthetized guinea pigs, the typical increase of heart rate after isoproterenol and the decrease after sotalol application could be followed on a beat by beat basis for 20 minutes of recording time. QTc prolongation after sotalol and QTc shortening after isoproterenol were reflected in MCG and ECG as expected. A statistical comparison of PQ, QRS, QT and QTc intervals demonstrated the equivalence of ECG and MCG results. Furthermore, the use of a multichannel MCG system enabled the construction of magnetic field maps during depolari-zation and repolarization process. The value of these maps in the context of safety pharma-cology is subject of further research. In conclusion, we have demonstrated the equivalence of MCG and ECG for assessing car-diac interval durations in anesthetized guinea pigs. The feasibility of reproducible measure-ments in conscious animals was shown. More than 100 biomagnetic measurement devices similar to the one used in this study are installed world-wide and might at once be utilized for small animal MCG. Especially for measuring the heart function of conscious animals MCG might be useful, because no prepa-ration of the animals is required besides the adaptation to baseline levels after animal han-dling. The development of dedicated animal MCG systems, that are optimized in size and sensor location, is currently on its way [6]. 1.Fenici R, Brisinda D, Meloni AM. Clinical application of magnetocardiography. Expert Rev Mol Di-agn. 2005;5(3):291-313. 2.Brazdeikis A, Chu CW, Cherukuri P, Litovsky S, Naghavi M. Changes in magnetocardiogram pat-terns of infarcted-reperfused myocardium after injection of superparamagnetic contrast media. Neurol Clin Neurophysiol. 2004; 2004:16. 3.Steinhoff U, Knappe-Grueneberg S, Schnabel A, Trahms L, Smith F, Langley P, Murray A, Koch H. Magnetocardiography for pharmacology safety studies requiring high patient throughput and reli-ability. J Electrocardiol. 2004;37(Suppl):187-92. 4.Brisinda D, Caristo ME, Fenici R. Contactless magnetocardiographic mapping in anesthetized Wis-tar rats: evidence of age-related changes of cardiac electrical activity. Am J Physiol Heart Circ Physiol. 2006;291(1):H368-78. 5.Steinhoff U, Wilhelm C, Wiekhorst F, Lee SY, Ackermann R, Bader M, Schurig T, Contactless magnetocardiographic characterization of knock-out mice. Folia Cardiologica. 2005;12(D):396-8 6.Wiekhorst F, Jurgons R, Eberbeck D, Sander T, Steinhoff U, Hartwig S, Alexiou C, Trahms L. SQUID system with integrated superconducting shield for monitoring of drug targeting with mag-netic nanoparticles in animals. Biomed Tech. 2005;50(1/1):609-10 |
