It is now well-established that a number of prescription medications are linked to a low, but significant risk of alterations to the QT interval of the electrocardiogram and with an associated dangerous arrhythmia called torsades de pointes. For such drugs, arrhythmias tend to occur in overdose or in the presence of risk factors such as electrolyte abnormalities or impaired drug metabolism. Despite structural and therapeutic differences, drugs linked to this unwanted cardiotoxicity usually share a common feature: an ability to produce pharmacological inhibition of a specific ion channel in the heart called “hERG” (Hancox et al, 2008, Pharmacology and Therapeutics, 119, 118-132). The link between drug induced arrhythmia and hERG is sufficiently strong that all new pharmaceuticals are evaluated for their propensity to inhibit this ion channel and affect the process of ventricular repolarization.
Awareness of the need to evaluate drugs for QT interval prolongation has been high since the latter part of the 1990s. However, many drugs – including some over the counter medications – were developed and introduced before that time. As pharmacovigilance data have emerged, cardiac pharmacology studies have been undertaken. The aim of this project is to increase understanding of potential effects on cardiac electrophysiology of selected over-the-counter medications. The project will provide a thorough training in in vitro approaches to cardiac drug safety evaluation. The appointed PhD student will learn cellular electrophysiological and pharmacological approaches for the mechanistic study of how drugs interact with the hERG potassium channel, both on their own and in the presence of factors that may exacerbate unwanted effects (such as electrolyte abnormalities and drug combinations). They will also learn methods for interrogating potential drug effects on other cardiac ion channels and on ventricular repolarization, using stem-cell derived cardiomyocytes.
The appointed PhD student will join a lively, committed and supportive research team and undertake a project that has clear translational relevance.