Rat engineered heart tissue: a novel tool in the safety pharmacology toolkit?

Abstract

Adverse drug effects are a major problem in clinical practice and are responsible for more than 5 % of hospital admissions [16]. Drug-induced proarrhythmia is among the most severe adverse side effects with potentially fatal consequences. Over the last decades, several drugs have been taken off the market, or have been restricted in their application, due to concerns about proarrhythmic side effects [10]. Accordingly, cardiac safety testing is now mandatory before a new compound can be approved for clinical use. Many proarrhythmic compounds have been found to inhibit the rapid delayed-rectifier K-current (IKr) by blocking the underlying channel encoded by the human ether-a-go-go-related gene (hERG), resulting in excessive prolongation of cardiac repolarization, which has been associated with drug-induced ‘‘Torsade-de-Pointes’’ (TdP) arrhythmias. Consequently, current cardiac safety assays mainly involve in vitro screening of IKr inhibition (using drug-binding assays, fluorescent thallium flux assays, or automated patch-clamp), followed by in vivo analyses of QT-interval prolongation in large animal models and a ‘‘thorough QT study’’ in humans (reviewed in detail in [6, 8, 12, 17]). Although screening for IKr inhibition can be performed easily in high-throughput systems, it is now well accepted that evaluating IKr inhibition in non-cardiomyocytes only is insufficient to accurately predict the torsadogenic potential of novel compounds [6, 8]. In vivo studies in large animal models, on the other hand, show good (but not perfect) correlation with arrhythmogenic risk in patients, but their high costs, low throughput, and ethical concerns preclude their application for all but the most promising candidate compounds. It is unknown how many safe compounds with potential beneficial clinical use have been eliminated due to IKr inhibition as a result of the present ‘fail early, fail cheaply’ approach. Ectopic activity and reentry are well-established mechanisms for the initiation and maintenance of both atrial and ventricular arrhythmias. Although arrhythmias are intrinsically multicellular phenomena, and this aspect should be taken into account during cardiac safety testing, basic research has provided a wealth of information about the underlying molecular and cellular mechanisms promoting arrhythmias [5, 7, 14, 21]. Cardiac electrophysiology is controlled by a large number of ion channels and transporters, each of which is modulated by several signaling pathways. This system allows for various feed-back mechanisms and ensures that there is not a single point of failure. Accordingly, an acute insult to a single component is rarely sufficient to initiate and maintain an arrhythmia. Indeed, even in a monogenic disease in a large founder population with a dominant-negative mutation in the KCNQ1 gene, resulting in a pronounced reduction in the slow delayed-rectifier K-current, the clinical phenotype was extremely diverse [1]. Thus, other risk factors including a genetic predisposition, disease-related remodeling, neurohumoral factors, and drug effects can importantly influence the development and maintenance of cardiac arrhythmias [5, 7, 18]. This complexity also highlights the urgent need for novel integrative cardiac safety assays that can bridge the gap between available in vitro and in vivo systems and can provide a reliable assessment of potential proarrhythmic consequences of novel pharmacological compounds. This comment refers to the article available at doi:10.1007/s00395014-0436-7.