Cardiac arrhythmias electrophysiology

The side-effects of cardiac glycosides are mostly caused by electrophysiological/neuronal phenomena. Gastro-intestinal adverse reactions are probably triggered by effects on the central nervous system. Various types of cardiac arrhythmias are caused by the influence of the drugs on nodal tissues in the heart. The risk of arrhythmia is strongly enhanced by low plasma potassium concentrations. 

One of the most important chronic alterations in the heart is the chronic phase after myocardial infarction. The postinfarction period is known to be associated with an increased risk for sudden cardiac death and for the occurrence of cardiac arrhythmia. Changes in conduction properties have been identified [Dillon et al., 1988], although the cells exhibit normal or near normal action potential characteristics [Wit and Janse, 1992]. Thus, cellular electrophysiology does not explain the complete pathophysiology of the arrhythmogenic substrate. Thus, other factors, for example structural changes and passive electrical properties, have to be taken into account. 

This is not to say that cardiotoxicity is not seen with biopharmaceuticals. Cardiomyopathy is now a well-recognized complication of trastuzumab and and has been reported with bevacizumab treatment, in particular in combination with other cytotoxic cancer therapies [20]. Myocarditis and pericarditis are a well-documented complications of vaccinia immunization [21], and could also complicate use of a pox-virus vector for other therapeutics. In 1995 Genetics Institute suspended phase 2 cancer trials of Interleukin-12 for serious tox-icities including cardiac arrhythmia. However, such toxicities are best detected by incorporation of biomarkers for myocardial damage such as troponin-T into preclinical and early clinical studies, and continual ECG monitoring for arrhythmia in preclinical and early clinical studies, not by in vitro explorations of electrophysiology. 

Surawicz, B. (1995). Electrophysiologic Basis of ECG and Cardiac Arrhythmias. Williams and Wilkins, Baltimore. 

Because the half-life of ATI-2001 in human plasma was found to be only 12 min (203), which may be too short to allow long-term management of cardiac arrhythmias, esters with longer or more branched side chains were also examined. These modifications were found to markedly alter the magnitude and time course of the induced electrophysiological effects, and the sec-butyl and isopropyl esters were considered to merit further investi-... 

Baumert M, Porta A, Vos MA et al (2016) QT interval variability in body surface ECG measurement, physiological basis, and clinical value position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology. Europace 18 925-944 Behere SP, Weindfing SN (2015) Inherited arrhythmias The cardiac channelopathies. Ann Pediatr Cardiol 8 210-220... 

The anticipated outcome from this change in paradigm is the development of a non-clinical, standardised in vitro assay that determines the effects of drugs on the major cardiac ion channels and provide an assessment of the potential to precipitate clinical proarrhythmia, obviate conduct of the clinical TQT study and facilitate more efficient drug discovery efforts. In order to understand the fundamentals of this novel paradigm, it is important to review fundamental cardiac electrophysiology including basic ion channel biophysics as well as review some fundamental cardiac arrhythmia mechanisms to achieve this alternate approach. 

Wit, A. L., Hoffman, B. F. and Rosen, M. R.(1975) Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac electrophysiology effects of beta adrenergic receptor stimuiation and biockade. Part B. Amer. Heart J., 90, 665. 

Electrophysiology and pharmacology of cardiac arrhythmias. IV. Cardiac antiarrhythmic and toxic effects of digitalis. Amer. Heart J., 89, 391. 

Napolitano, C., Schwartz, P.J., Brown, A.M., Ronchetti, E., Bianchi, L., Pinnavaia, A., Acquaro, G. and Priori, S.G. (2000) Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. Journal of Cardiovascular Electrophysiology, 11, 691-696. 

Therapeutic plasma concentrations of TCAs have clinically significant antiarrhythmic activity (420). Imipramine and nortriptyline (and probably other TCAs) share electrophysiological properties characteristic of type I (A, B) compounds (e.g., quinidine, procainamide, disopyramide) and can even be used in cardiac patients free from depression, exclusively for the control of arrhythmia (421). 

Schoenmakers M, Ramakers C, van Opstal JM et at. (2003) Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog. Cardiovascular Research 59 351-359 Van Opstal JM, Leunissen JDM, Wellens HJJ, Vos MA (2001) Azimilide and dofetilide produce similar electrophysiolog-ical and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias. European Journal of Pharmacology 412 67-76... 

The purpose of this chapter is to review the principles involved in both normal and abnormal cardiac conduction and to address the pathophysiology and treatment of the more commonly encountered arrhythmias. Certainly, many volumes of complete text could be (and have been) devoted to basic and clinical electrophysiology. Therefore, this chapter briefly addresses those principles necessary for clinicians. 

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