Indirect modulation of cardiac ion channels and implications for preclinical safety assessment

Ion channels play essential roles in excitation, contraction and repolarisation of the heart¹. Given their fundamental contributions to cardiac electrical activity, it is not surprising that mutations in the genes encoding various cardiac ion channels result in multiple cardiac arrhythmia syndromes, some of which are associated with prolongation of the QT interval and sudden cardiac death². In particular, drug-induced inhibition of IKr, the rapid component of the delayed rectifier potassium current (a.k.a. hERG current), has been linked to acquired long QT syndrome Type 2 (LQT2) and potentially fatal arrhythmias in humans^2-5.

In the last two decades, several drugs were withdrawn from the market or received black box FDA labelling due to reported clinical cases of QT interval prolongation, ventricular arrhythmias and sudden death. Other drugs were denied regulatory approval due to their potential for QT prolongation^5,6. Furthermore, off-target activity of drugs on cardiac ion channels has been shown to be associated with increased mortality in patients with underlying cardiovascular diseases⁷. In light of the increasing importance of ion channel interactions for cardiac safety, regulatory authorities published guidelines for preclinical (International Conference on Harmonisation, ICH S7B) and clinical assessment (ICH E14) of QT interval prolongation. Since clinical arrhythmia risk is a major criterion for compound termination, preclinical profiling for off-target cardiac ion channel interactions early in the drug discovery process has become common practice in the pharmaceutical industry^8,9.

The first step in the preclinical evaluation of small molecule QT prolongation liability is an in vitro assessment of ion channel activity based on patch clamp electrophysiology studies in recombinant expression systems. This is typically followed by an in vivo telemetry study in non-rodent species^8,9. Patch clamp assays have been extensively validated, and recent technological advances in automated electrophysiology systems have allowed their implementation in the early lead optimisation stage of drug discovery to help identify potential cardiac liabilities. However, patch clamp assays using heterologously expressed recombinant channels are acute functional assessments and are best used to detect direct, rather than indirect, modulation of the channel protein.

Indirect modulation of cardiac ion channels may significantly contribute to QT interval prolongation and help explain discrepancies between in vitro and in vivo data^10,11,12. One of the most studied examples of indirect channel modulation is drug-induced inhibition of hERG channel trafficking to the plasma membrane^13,14. hERG channel trafficking inhibition has been proposed as a contributing mechanism for the delayed QT interval prolongation observed with arsenic trioxide and pentamidine treatments in animals and humans^15,16. There are numerous other possible mechanisms (e.g., transcriptional, translational and post-translational) that could influence expression and functional properties of cardiac ion channels.

Despite copious literature indicating potential mechanisms for indirect ion channel modulation, contribution of these mechanisms to QT interval prolongation and/or arrhythmogenesis is not well understood. In this brief review, we discuss selected indirect channel modulation mechanisms, their link to QT prolongation, and potential pre-clinical strategies for early detection. We focus on ventricular repolarisation, a critical process in cardiac electrical activity during which irregularities can result in dangerous clinical arrhythmias. Special attention is given to in silico hypotheses for non-hERG off-target interactions based on predictive chemogenomic methods and how they can help the design of follow-up studies. Cardiac ion channel trafficking is not covered and readers are referred to recent review articles^13,14.

Effects of glucose concentration on ventricular repolarisation

Changes in blood glucose levels have been shown to prolong the heart rate corrected QT interval (QTc) and, under certain circumstances, cause ventricular arrhythmias in healthy subjects and dogs^17-19. Type I and II diabetes are also associated with increases of both QT interval duration and dispersion in patients of both genders and a wide range of age groups^20-22. QTc prolongation and ECG abnormalities occur during nocturnal hypoglycaemia in patients with type 1 diabetes and investigators suggest these findings may help explain the ‘dead in bed’ syndrome18. Diabetes is strongly associated with sympatho – adrenal neuropathy, which may be responsible for increased QTc and QT dispersion due to elevated plasma concentrations of catecholamines seen during hypo- and hyperglycemia episodes²³. However, conflicting data exists, as QTc prolongation was also seen in diabetic patients without autonomic neuropathy²⁴. In studies of identical twins, QTc prolongation did not correlate with duration of diabetes or autonomic dysfunction²⁴. Additionally, insulin levels had very little influence on QT dispersion²⁵.

The hERG channel is modulated by extracellular glucose levels and it is plausible that impairment of hERG function may contribute to the ECG changes observed in hypo- and hyperglycemia²⁶. Zhang et al studied the hERG channel in HEK 293 cells and showed that IKr amplitude decreased in response to extracellular glucose concentration changes in both directions²⁶. The authors proposed that intracellular ATP generated by glucose metabolism acted as a substrate for protein kinase mediated channel phosphorylation and was therefore essential for the normal function of the channel. When hypoglycemia was reproduced by complete inhibition of glycolysis and oxidative phosphorylation by 2-deoxy-D-glucose substitution for glucose, IKr was diminished due to the depletion of intracellular ATP. Hyperglycemia again decreased IKr by overproduction of reactive oxygen species (ROS), by-products of oxidative glucose metabolism. Superoxide anion (O2 -) is the major ROS produced by hyperglycemia^27,28 and acute elevations in glucose levels also depresses cells natural antioxidant defenses²⁹. Excessive ROS decrease ATP production by inhibiting glycolysis and may contribute to the hERG channel inhibition in hyperglycemia^30,31. In addition to their effects on IKr, hypo- and hyperglycemia can also potentiate the effects of IKr blockers such as dofetilide, further increasing their QT prolonging effects and the risk of proarrhythmia³².

In healthy subjects, glucose ingestion and subsequent increased plasma insulin levels has been shown to cause ECG changes including increased QT dispersion³³. In patients with congenital long QT syndrome, insulin-induced QT interval prolongation was associated with T wave changes, suggesting that glucose-induced insulin secretion can influence repolarisation^34,35. Although serum K+ levels were unchanged in this study, it is possible that insulin decreases K+ concentration in the extracellular space, thereby activating the Na+/K+ pump and hyperpolarising the transmembrane potential³⁶. Insulin has also been shown to stimulate the L-type Ca2+ current in isolated rat ventricular myocytes in a concentration dependent manner³⁷.

Overall, these investigations clearly implicate a role for plasma glucose and insulin levels in modulating cardiac ion channels and ventricular repolarisation. During drug development, these effects may not be detected until in vivo studies or, in some cases, until clinical studies because routine patch clamp studies are not designed to screen for indirect effects.

Plasma potassium levels and QTc

Serum K+ levels play a key role in the ventricular repolarisation: hypokalemia increases the cardiac action potential duration and prolongs QTc by decreasing IKr^11,38. Initially the effects of low extracellular K+ were attributed to the accelerated inactivation of the channel^39-41. However, more recent studies also suggested that extracellular K+ controls cell surface density of the hERG channel by modifying its gating state^42,43. Massaeli et al showed that in low extracellular K+ media, hERG channels entered a novel nonconducting state, which was different from the inactivated or drug-blocked state. The nonconducting channels were subsequently internalised and degraded, decreasing the number functional channels⁴².

In humans, hypokalemia can occur secondary to numerous drug treatments or disease processes, and is a major risk factor for arrhythmia^11,44. Furosemide is a loop diuretic and by inhibiting the Na-K-2Cl symporter in the renal loop of Henle, it can cause electrolyte imbalances (e.g. hypokalemia and hypo – magnesaemia) even at moderate doses, and thus produce QTc prolongation both in man and dogs. This highlights the critical role serum K+ levels play in modulation of cardiac ion channels and ventricular repolarisation^11,41,44. Analogous to the furosemide scenario, small molecules could affect ventricular repolarisation indirectly by producing hypokalemia; they would appear clean in patch clamp studies but cause QT interval prolongation in vivo.

Effects of autonomic tone on ventricular repolarisation

Drugs could also indirectly induce QTc prolongation by influencing autonomic tone in isolation or in combination with other direct or indirect ion channel effects^45-47. Ventricular arrhythmias are occasionally precipitated by physical or emotional stress suggesting a link between increased adrenergic stimulation and cardiac ion channel activity⁴⁸. IKs has been shown to be regulated by α and β adrenergic stimulation via protein kinase A and C, which may explain the increased incidence of ventricular arrhythmias in LQTS-1 patients⁴⁹. It has been shown that hERG/IKr is inhibited by α and β adrenergic stimulation which may be of importance in LQTS-2 where hERG currents are already impaired due to underlying gene mutations^48,50-52. Chen et al have recently reported post-translational regulation of the hERG channel that may pertain to the electrical remodelling observed in chronic cardiac diseases⁵³. In their experiments, prolonged α adrenergic stimulation influenced the balance of hERG channel synthesis and degradation via multiple signalling pathways involving PKC and PKA. There are also intriguing examples from clinical medicine linking autonomic mechanisms with cardiac repolarisation. A recent clinical report linked elevated catecholamines to profound ECG repolarisation changes in acute states of myocardial stunning, mimicking myocardial infarction⁵⁴. Smith et al investigated how autonomic blockade might affect QT prolongation and found that autonomic block in the presence of the IKr blocker ibutilide resulted in exaggeration of drug-induced QT prolongation⁵⁵, further strengthening the connection between autonomic modulation and repolarisation. In sum, there is a growing body of evidence establishing the importance of autonomic effects in cardiac safety.

In silico hypotheses for non hERG off-targets, based on predictive chemogenomics methods and how it can help design of follow-up studies

Predicting compound activity against a single target has always been a major objective in the field of cheminformatics. A substantial quantity of in vitro activity data has accumulated in public (Pubchem, chEMBL) and commercial (GVK, Wombat) chemogenomics databases over recent years. The systematic annotation of assays, targets, compounds and activities in these databases has allowed for large scale modelling and poly-pharmacology predictions that use chemical structure alone to rank the order of the most likely targets that might be modulated by a compound⁵⁶. These predictions could be viewed as an inexpensive and rapid method for generating preliminary off-target interaction hypotheses when a candidate molecule possesses a QTc prolongation liability. Analysing model predictions for overlap with biologically relevant targets (as described above) that might explain the QTc liability or predict other potential safety risks would be the natural extension of this dataset and its most relevant application. Any identified overlaps or safety risks could then drive the design of future studies to elucidate mechanisms or mitigate risks. Since model predictions are based on published in vitro data, most follow up assays to confirm in silico off-target hypotheses should be available for investigative studies⁵⁷.

Beyond direct cardiac ion channel interactions

In summary, several complex mechanisms including modulation of cardiac ion channels and autonomic tone may influence ventricular repolarisation and these factors should be taken into consideration when interpreting in vivo results⁴⁵. In vitro patch clamp assays using heterologously expressed recombinant channels are widely used in the pharmaceutical industry during drug development. Modern automated electrophysiology technologies have enabled early phase, large scale implementation of these assays, allowing the screening of thousands of compounds. These assays, however, are likely to detect only direct modulation of channel proteins. Although pivotal to early screening, cardiac safety issues may stem from several other factors beyond direct cardiac ion channel modulation, as discussed above.

Figure 1 Cardiac safety schematic integrating indirect ion channel modulation analysis

A schematic of how indirect ion channel modulation might fit into an overall drug development safety analysis strategy is illustrated in Figure 1 above. In a chronic in vivo model, if QTc prolongation is seen for a late stage compound that does not directly block cardiac ion channels, human metabolites could be synthesised and tested in patch clamp assays. Determining the concentrations of the parent compound and its metabolite(s) in cardiac tissue together with pharmacokinetic/ pharmacodynamic (PK/PD) modelling of QTc prolongation could be instrumental in understanding the mechanisms involved⁵⁸. Predictive in silico methods can be helpful to propose off-target hypotheses that could be tested in relevant in vitro assays. For example, cardiac ion channel trafficking assays could be used to test whether the compound blocks the channel trafficking to the surface membrane⁵⁹. An important point to consider is that trafficking assays testing the channel protein expression on the cell surface may fail to identify compounds affecting channel maturation or degradation. In such cases, follow up patch clamp assays using longer incubation with the compound of interest may be implemented.

Additional pre-clinical assays could be run on a case-by-case basis at various stages of the process, including after the compound is tested in man. If the mechanism of effect is identified, relevant assays could be incorporated into the discovery phase for back up activities to try to remove the liabilities. This approach is likely to reduce the chances of having to halt progression of a compound late in the discovery phase after considerable resource investments. Early detection of these effects using in vitro methods, however, is challenging and the translatability of these effects from in vitro to in vivo and preclinical species to human is not yet well defined either.

It is vital to recognise that unexpected QTc prolongation could occur in preclinical telemetry studies or in human trials even with compounds showing no known direct effects on cardiac ion channels. A prudent strategy to avoid such unpleasant findings may be to invest more time and resources early in candidate profiling to identify the potential mechanisms responsible for QTc prolongation and design targeted experiments to help clarify impact or even abort development. A notable caveat to this strategy, however, is that the degree of safety risk incurred due to indirect cardiac ion channel modulation is usually difficult to quantify. Moreover, in vitro assays to characterise each potential mechanism with sufficient specificity and throughput may not always be available. Developing tools to accurately predict cardiac arrhythmia risks during drug development continues to challenge our field, whether addressing direct or indirect ion channel modulation. Awareness that indirect mechanisms can have a meaningful impact on safety is an important step forward.

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About the Authors

Gül Erdemli

Gül Erdemli obtained an MD from Hacettepe University, Medical School, Ankara, Turkey and a PhD in Pharmacology from the same university. She did her postdoctoral studies at McGill University in Montreal, Institute of Neurology and Neurosurgery in London and Cardiff University until establishing her lab at University of Liverpool as a lecturer. In 2003, she joined Organon Laboratories / Schering Plough Research Institute in UK (now a part of Merck Research Laboratories) as the electrophysiology team leader. In October 2008, she joined Novartis Institutes for BioMedical Research and is the Head of Ion Channel Group in Cambridge, Massachusetts. Her group is responsible for in vitro cardiac ion channel safety profiling and supports ion channel drug discovery projects.

Contact the Author
email: [email protected]

Dmitri Mikhailov

Dmitri Mikhailov holds an MSc in Physics & Applied Math and a PhD in Structural Biology with the focus on using NMR and modelling to study interactions between proteins and natural products. After a post-doctorate at Harvard in 1998-99, Dmitri joined SGI Life Sciences where he was a Bioinformatics Application Scientist responsible for major academic and biopharmaceutical client collaborations. In 2003, Dmitri joined Novartis in Cambridge, US to establish Advanced Scientific Computing team responsible for developing global scientific web tools. Since 2007, Dmitri’s focus has been on safety assessment and using informatics approaches to manage early drug safety risks and to explore drug repositioning opportunities.

Albert Kim

Albert M Kim earned a bachelor’s degree in Biomedical Engineering at Harvard University and attended medical school at UCLA. As a member of the medical scientist training program there, he earned his M.D. and a Ph.D. in Physiology. He then completed an internal medicine residency at Brigham and Women’s Hospital in Boston, a cardiology fellowship at Massachusetts General Hospital in Boston and a cardiac electrophysiology fellowship at UCSF. He joined the UCSF faculty as a clinician-scientist in 2008 where his research focused on new therapies for atrial fibrillation. He was recruited to the Novartis Institutes for Biomedical Research in 2009 where he now serves as a Senior Translational Medicine Expert in cardiovascular medicine and is an active member of the Translational Cardiovascular Advisory Team. He also practices clinical electrophysiology at the West Roxbury VA Hospital.