Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based “double‐negative” nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

Aims We investigated whether cooling instituted by total liquid ventilation (TLV) improves cardiac and mitochondrial functions in rabbits submitted to lethal myocardial ischemia. Methods Rabbits were instrumented with a coronary artery occluder and myocardial ultrasonic crystals for assessment of segment length shortening. Two weeks later they were reanesthetized and underwent either a normothermic 30-min coronary artery occlusion (CAO) (Control group, n=7) or a comparable CAO with cooling initiated after 5-min of occlusion. Cooling was initiated by a 10-min hypothermic TLV episode and then maintained by ice-filled cold blanket put over the skin (Hypo-TLV group, n=6). A last group underwent normothermic TLV during CAO (Normo-TLV group, n=6). Wall motion was measured in the conscious state over 3 days of reperfusion before infarct size evaluation and histology. Additional experiments were done in anesthetized rabbits for myocardial sampling at the end of the ischemic period (electron microscopy and mitochondrial studies). Results The cooling procedure induced a rapid decrease in heart temperature to a target 32–34°C. Post-ischemic contractile dysfunction and infarct sizes were significantly decreased in Hypo-TLV vs Control and Normo-TLV (e.g., 4±1, 39±2 and 42±5% of region at risk for infarct sizes, respectively). Mitochondrial function was improved by Hypo-TLV regarding ADP-stimulated respiration and calcium-induced opening of mitochondrial permeability transition pore (mPTP). Histology and electron microscopy revealed also better preservation of lung and cardiomyocyte ultrastructure in Hypo-TLV as compared to Control, respectively. Conclusion Institution of hypothermia by TLV during ischemia not only reduces infarct size but also abolishes most consequences of ischemia such as post-ischemic contractile dysfunction and calcium-induced opening of mPTP.

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