Objective To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. Methods Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. Results Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. Conclusions The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development

Endothelial cells (EC) form a unique signal-transducing surface in the vascular system. The abundance of ion channels in the plasma membrane of these nonexcitable cells has raised questions about t...

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.4.1415

Ion channels and their functional role in vascular endothelium.

We calculated the wavelength of the atrial impulse in chronically instrumented conscious dogs by measuring both conduction velocity and refractory period: wavelength = refractory period X conduction velocity. Implantation of multiple stimulating and recording electrodes allowed wavelength determination at four different areas: the right and left parts of Bachmann's bundle and the free walls of the right and left atria. During programmed electrical stimulation, three types of arrhythmias were observed: rapid repetitive responses, atrial flutter, and atrial fibrillation. During normal rhythm, the wavelength of the atrial impulse varied between 14 and 18 cm. Premature beats had a shorter wavelength, depending on the degree of prematurity. Premature beats that evoked rapid repetitive responses showed a critical shortening of the wavelength below 12.3 cm. Episodes of atrial flutter were induced at a wavelength below 9.7 cm, while fibrillation occurred at wavelengths shorter than 7.8 cm. We correlated the induction of these arrhythmias with the values of refractory period, conduction velocity, and wavelength during control and during administration of several drugs. Intravenous administration of acetylcholine shortened the wavelength by 30-40%, mainly because of refractory period shortening. Both propafenone and lidocaine had strong but opposite effects on refractoriness and conduction and, consequently, little effect on the wavelength. Quinidine markedly prolonged the refractory period, but prolongation of wavelength was less because of a simultaneous decrease in conduction velocity. d-Sotalol also increased refractory period, but because it had no appreciable effect on conduction velocity, this drug was the most effective in prolongation of wavelength. Linear discriminant analysis of the data showed that the refractory period and the conduction velocity each were poor parameters to predict the occurrence of the different arrhythmias (predictive value 48% and 38%, respectively). The combination of both properties, however, as expressed in the wavelength, was a more reliable index that predicted the induction of the different arrhythmias correctly in 75% of the cases. We conclude that the wavelength is a useful parameter for evaluating antiarrhythmic drugs.

Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.

Background The importance of barriers in atrial flutter has been demonstrated in animals. We used activation and entrainment mapping, guided by intracardiac echocardiography (ICE), to determine whether the crista terminalis (CT) and eustachian ridge (ER) are barriers to conduction during typical atrial flutter in humans. Methods and Results In eight patients, ICE was used to guide the placement of 20-pole and octapolar catheters along the CT and interatrial septum and a roving catheter to nine sites: just posterior (1) and anterior (2) to the CT along the lateral right atrium, at the fossa ovalis (3), and just posterior and anterior to the ER at the low posterolateral (4 and 5), low posterior (6 and 7), and low posteromedial (8 and 9) right atrium. Entrainment was performed, and each site was considered within the flutter circuit if the postpacing interval–flutter cycle length (PPI−FCL) and the stimulus time–activation time (stim time−act time) were <10 msec. Split potentials were recorded along the CT wi...

Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter. Activation and entrainment mapping guided by intracardiac echocardiography.

Available models of circus movement reentry in cardiac muscle and of drug action on reentrant arrhythmias are based on continuous medium theory, which depends solely on the membrane ionic conductances to alter propagation. The purpose of this study is to show that the anisotropic passive properties at a microscopic level highly determine the propagation response to modification of the sodium conductance by premature action potentials and by sodium channel-blocking drugs. In young, uniform anisotropic atrial bundles, propagation of progressively earlier premature action potentials continued as a smooth process until propagation ceased simultaneously in all directions. In older, nonuniform anisotropic bundles, however, premature action potentials produced either unidirectional longitudinal conduction block or a dissociated zigzag type of longitudinal conduction (a safer type of propagation, similar to transverse propagation). Directional differences in the velocity of premature action potentials demonstrated that anisotropic propagation was necessary for a reentrant circuit to be contained within an area of 50 mm2, even with very short refractory periods. Quinidine produced Wenckebach periodicity, which disappeared after acetylcholine shortened the action potential. Quinidine also produced use-dependent dissociated zigzag longitudinal conduction in the older, nonuniform anisotropic bundles but not in the young, uniform anisotropic bundles. The electrophysiological consequence was that propagation events differed in an age-related manner in response to the same modification of the sodium conductance. The electrical events at microscopic level showed that conditions leading to obliteration of side-to-side electrical coupling between fibers (e.g., aging and chronic hypertrophy) provide a primary mechanism for reentry to occur within very small areas (1-2 mm) due to a variety of propagation phenomena that do not occur in tissues with tight electrical coupling in all directions.

Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation.

Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly.

The circus movement theory of flutter has been supported by numerous theoretical, experimental, and clinical studies, but there has been little consideration of the possible participation of the specialized conduction pathways of the atria. In the present work we have studied experimental atrial flutter in relation to the behavior of these pathways, in response to elevated potassium and to surgical interruption. Application of trains of ttimuli at frequencies appropriate to Induce a self-sustained flutter revealed that (1) flutter can be more easily induced by stimuli applied to the left atrial insertion of Bachmann+-s bundle than to the body of the right atrium, (2) flutter can be initiated by appropriate trains of stimuli without the creation of an artificial obstacle, and (3) flutter exhibits the same characteristic behavior, with or without artificial obstacles. Doses of potassium that elevate the plasma concentration to 9.5 mM/liter cause total inactivation of atrial myocardium without suppressing flutter waves as recorded from the vicinity of the intemodal pathways. Section of the middle internodal pathway reduces the frequency of experimental flutter, section of both the middle and posterior pathways prevents the establishment of flutter. The results suggest that the specialized intemodal pathways play an important role in the genesis and maintenance of circus movement flutter.

Participation of atrial specialized conduction pathways in atrial flutter.

The search for a digitalis substitute II milrinone (Win 47203) its action on the heart-lung preparation of the dog

Studies were carried out on the actions of semisynthetic cardiac glycosides compounded from digitoxigenin and one molecule of glucose. In one (AY-22, 248) the position of attachment of the lactone ring to the steroid nucleus is similar to that of the naturally occurring glycosides, i.e. , through the C-3 atom of the lactone. In the other (AY-22, 241), the point of attachment is the C-2 atom of the lactone. Their actions have been compared with those of dihydro-ouabain (DHO) and ouabain in the failing heart of the dog heart-lung preparation and in the intact anesthetized dog. Among the four glycosides, we found important differences in potency and reversibility. When administered by continuous infusion in the dog heart-lung preparation. AY-22, 241, DHO and AY-22, 248, produced positive inotropic effects when the cumulative doses were smaller percentages of the lethal doses than was the case with ouabain. The fraction of the lethal dose with inotropic effect was smallest with AY-22, 241 and increased, in ascending order, with DHO, AY-22, 248 and ouabain. With respect to the reversibility of a toxic effect (ventricular tachycardia) in the anesthetized dog, upon discontinuance of the drug, the effect of AY-22, 241 is most rapidly dissipated, followed by DHO, AY-22, 245 and ouabain in that order. These results suggest that the new semisynthetic cardiac glycoside with the unique lactone linkage retains the qualitative effects of the classical cardiac glycosides but differs in its dynamics of action: i.e. , there is lower potency, more rapid onset of action, quick reversibility of toxic effects and a greater margin between therapeutic and toxic doses.

Gustavo Pastelín

Papers

Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly.

Participation of atrial specialized conduction pathways in atrial flutter.

The search for a digitalis substitute II milrinone (Win 47203) its action on the heart-lung preparation of the dog

The influence of the position of attachment of the lactone ring to the steroid nucleus on the action of cardiac glycosides

Vasodilator activity of the aqueous extract of Viscum album.