Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

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.

Rapid cooling of the heart with total liquid ventilation prevents transmural myocardial infarction following prolonged ischemia in rabbits.

Study Aim: Total liquid ventilation (TLV) with cooled perfluorocarbons has been demonstrated to induce an ultrafast cardioprotective cooling in rabbits. However, it remains unknown whether this technically challenging strategy would be actually more potent than a conventional external cooling after a prolonged ischemia inducing transmural myocardial infarction.

Methods: Anesthetized rabbits were randomly submitted to 60min of coronary artery occlusion (CAO) under normothermic conditions (Control group, n=7) or with cooling started at the 5th min of CAO (target left atrial temperature: 32 degrees C).

Chronic heart rate reduction with ivabradine improves systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term increase in FKBP12/12.6 expression.

Aims: To investigate the adaptations of left ventricular function and calcium handling to chronic heart rate reduction with ivabradine in the reperfused heart.

Methods And Results: Rabbits underwent 20 min coronary artery occlusion followed by 3 weeks of reperfusion. Throughout reperfusion, rabbits received ivabradine (10 mg/kg/day) or vehicle (control).

Relation of the ischaemic substrate to left ventricular remodelling by cardiac magnetic resonance at 1.5 T in rabbits.

Objectives: Contrast-enhanced cardiac magnetic resonance (CMR) for infarct sizing has been validated in large animals, but studies and follow-up are restricted. We sought to (1) validate CMR for assessment of myocardial area at risk (MAR) and infarct size (IS) in a rabbit model of reperfused myocardial infarction (MI); (2) analyse the relation between ischaemic substrates and subsequent left ventricular (LV) remodelling.

Methods: Experimental reperfused acute MI was induced in 16 rabbits.

[Heart rate reduction: beneficial effects in heart failure and post-infarcted myocardium].

Heart rate (HR) is an independent predicting factor of cardiovascular events in patients with advanced heart failure. Clinical trials conducted with beta-blockers have demonstrated that reduction of HR is a fundamental mechanism to explain the reduction of morbidity-mortality in such a disease. Trials conducted with ivabradine, the first selective inhibitor of the I(f) current in cardiac pacemaker cells, have also clearly confirmed that reduction of HR lead to powerful and sustained favourable effects in patients with cardiac failure and post-infarcted myocardial diseases.

The ceiling effect of pharmacological postconditioning with the phytoestrogen genistein is reversed by the GSK3beta inhibitor SB 216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through mitochondrial ATP-dependent potassium channel opening.

In the present study, we investigated the efficacy of pharmacological postconditioning induced by 17beta-estradiol and the phytoestrogen, genistein, against myocardial infarction induced by increasing durations of coronary artery occlusion (CAO). Anesthetized rabbits underwent either 20-min (protocol A) or 30-min (protocol B) CAO, followed by 4 h of coronary artery reperfusion (CAR). Before CAR, they randomly received an intravenous injection of either vehicle (control), 100 or 1000 microg/kg genistein (Geni(100) and Geni(1000), respectively), or 100 microg/kg 17beta-estradiol (17beta-E(100)).

Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction.

Aims: We investigated whether rapid cooling instituted by total liquid ventilation (TLV) improves cardiac and mitochondrial function in rabbits submitted to ischaemia-reperfusion.

Methods And Results: Rabbits were chronically instrumented with a coronary artery occluder and myocardial ultrasonic crystals for assessment of segment length-shortening. Two weeks later they were re-anaesthetized and underwent either a normothermic 30-min coronary artery occlusion (CAO) (Control group, n = 7) or a comparable CAO with cooling initiated by a 10-min hypothermic TLV and maintained by a cold blanket placed on the skin.

Making the heart resistant to infarction: how can we further decrease infarct size?

Acute myocardial infarction (AMI) following coronary artery occlusion is a common cause of mortality and morbidity world-wide. Patients currently receive reperfusion therapy as the only anti-infarct intervention. A number of agents have been evaluated to further improve myocardial salvage, but until recently, none has demonstrated clear efficacy in clinical trials.

Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits.

Postconditioning, i.e., brief intermittent episodes of myocardial ischemia-reperfusion performed at the onset of reperfusion, reduces infarct size after prolonged ischemia.