Inflammation as a Risk Factor in Cardiotoxicity: An Important Consideration for Screening During Drug Development

Abstract

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…Although these approaches can abolish AF and VF, they have no impact on the development and/or recurrence of these arrhythmias. The current antiarrhythmic drugs can also be pro-arrhythmic by overdose or adverse interaction with cardiac disease status [1,9], and this supports the theory that prevention of cardiac arrhythmia development is the best approach in reducing cardiac arrhythmic burden. This has inspired ongoing search for novel approaches which prevent or at least attenuate pro-arrhythmic factors and conditions.…”

Hesperidin protects against cisplatin-induced cardiotoxicity in mice by regulating the p62–Keap1–Nrf2 pathway

“…48 Under pathological conditions, oxidative stress can activate the transcription of various proinflammatory cytokines, and the release of cytokines during the inflammatory process can also induce systemic changes including cardiac damage. 49,50 Inflammatory responses can, in turn, increase oxidative stress. 51 Oxidative stress is also an important inducer of programmed cell death.…”