Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here, we describe a methodology to unravel the ionic determinants of intersubject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, because of their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology, and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude, and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide.cardiac electrophysiology | computational biology | mathematical modeling | systems biology | drug B iological variability is exhibited at all levels in all organs of living organisms. It manifests itself as differences in physiological function between individuals of the same species and often more drastically by significant differences in the outcome of their exposure to pathological conditions. Thus, healthy cardiac cells of the same species and location exhibit a qualitatively similar response to a stimulus, i.e., the action potential (AP). However, significant quantitative intersubject differences exist in AP morphology and duration, which may explain the different individual response of each of the cells (and patients) to disease or drug action.The variability underlying the physiological and pathological responses of different individuals has often been ignored in experimental and theoretical research, ultimately hampering the extrapolation of results to a population level. Experimentalists often average the results obtained in different preparations to reduce experimental error, therefore also averaging out the effects of intersubject variation and resulting in an important loss of information. T...
Transmembrane influx of extracellular calcium through specific calcium channels is now accepted to have an important role in the excitation-contraction coupling of cardiac and smooth muscle. The importance of such slow calcium channels has been underlined by the development of specific calcium channel blocking agents, the 'calcium antagonists', typified by verapamil, nifedipine and diltiazem. These drugs have been used to investigate the properties of slow calcium channels in a variety of tissues. We have found that small modifications to the nifedipine molecule produce other dihydropyridine derivatives (see Fig. 1) with effects diametrically opposite to those of the calcium antagonists: cardiac contractility is stimulated and smooth muscle is contracted. These effects are competitively antagonized by nifedipine. Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel. In contrast to nifedipine, however, the new compounds promote--instead of inhibiting--the influx of Ca2+ ions. We report here the properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate), one of the most potent of these novel compounds.
beta-Adrenergic challenges trigger TdP in a reproducible manner in this model of drug-induced LQT1. Paradoxical prolongation and increased temporal and spatial dispersion of repolarization precipitate TdP. Incremental LV systolic aftercontractions precede TdP, suggesting abnormal cellular Ca(2+) handling contributes to the arrhythmogenic mechanism.
Background and purpose: The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K þ current (I Kr ), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a 'first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here. Experimental approach: hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits. Key results: 576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC 50 , 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 mM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts. Conclusion and implications:The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an B15-25% incidence of death.
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