Contractile function assessment by intraventricular balloon alters the ability of regional ischaemia to evoke ventricular fibrillation

Abstract

BACKGROUND AND PURPOSEIn drug research using the rat Langendorff heart preparation, it is possible to study left ventricular (LV) contractility using an intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently would halve animal requirements. We aimed to test the validity of this approach. EXPERIMENTAL APPROACHThe electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents in a randomized and blinded study. KEY RESULTSIVB-induced proarrhythmia was anticipated, but in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB reduced ischaemia-induced ventricular fibrillation (VF) incidence as a trend. Repeating studies in hearts with large IZs revealed the effect to be significant. There were no changes in QT interval or other variables that might explain the effect. Insertion of an IVB that was minimally inflated had no effect on any variable compared with 'no IVB' controls. The antiarrhythmic effect of verapamil (a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by intracellular 31 phosphorus ( 31 P) nuclear magnetic resonance (NMR) spectroscopy. CONCLUSIONS AND IMPLICATIONSIVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely to be due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach, with implications for drug discovery and safety assessment.

Facilitation of ischaemia‐induced ventricular fibrillation by catecholamines is mediated by β1 and β2 agonism in the rat heart in vitro

“…Male Wistar rats (Harlan UK; 220–410 g) were anaesthetized by i.p. injection of a lethal dose of sodium pentobarbitone (170 mg·kg −1 ) and co‐administered sodium heparin (160 IU·kg −1 ) (Wilder et al, ). A surgical level of anaesthesia was determined by the absence of pedal and corneal reflexes, prior to cardiac excision and exsanguination.…”

“…An arrhythmia score was assigned to each heart for ischaemia and (separately) for reperfusion in order to permit parametric statistical analysis. All these assessments were as described previously (Wilder et al, ).…”

Mode of perfusion influences infarct size, coronary flow and stress kinases in the isolated mouse heart

“…The difference in infarct size between these two groups was found in the endocard and may represent a balloon-induced injury. In a recent study in rats, no difference was found in infarct size between a balloon group and a non-balloon group, but interestingly, they found an increase in lactate release after removal of the balloon compared to no balloon, indicating a subendocardial hypoxia with the balloon present (Wilder et al 2016). Another interesting finding was a balloon-induced alteration in post-ischaemic ability for ventricular fibrillation (Wilder et al 2016).…”

“…In some groups (see below) a fluid-filled balloon-tipped pressure catheter was inserted into the left ventricle via the left atrium to measure heart rate (HR) and ventricular pressures using the Powerlab system (ADInstruments, NSW, Australia). Intraventricular balloon for mice are not commercially available and was made in the lab using non-compressive ultrathin plastic (Wilder et al, 2016).…”

“…In some groups, a fluidfilled balloon-tipped pressure catheter was inserted into the left ventricle via the left atrium to measure heart rate (HR) and ventricular pressures using the Powerlab system (AD Instruments). Intraventricular balloon for mice is not commercially available and was made in the laboratory using non-compressive ultrathin plastic (Wilder et al 2016). The balloon should have the following characteristics (Liao et al 2012): right size, highly flexible, high compliance and high linear frequency response.…”