Establishment of MEA Measurements to Study Ventricular Arrhythmias in a Mouse Model of Cardiac Mechanical Unloading by Heterotopic Heart Transplantation

Objectives: Unloading of failing hearts by assist devices can lead to negative alterations in cardiomyocyte physiology, causing, e.g., ventricular arrhythmias, associated with increased mortality and morbidity. Observations in patients and translational animal models indicate that reduction in workload itself induces impaired calcium handling and cellular electrophysiology. Pathophysiological relevance of these alterations is unclear. Multielectrode arrays (MEA) are used to measure extracellular field potentials, up to now mainly in brain slices to obtain information on spike activities. We established MEA investigation of heterotopically transplanted mouse hearts to study electrophysiology and -pathophysiology of unloaded cardiac tissue to allow a better understanding of the origin and propagation of the arrhythmic potentials.

Methods: The transplantation-technique is based on internationally accepted hHTX models in rodents, leading to complete mechanical unloading. Slices of orthotopic and unloaded mouse hearts (300µm) were cut with a microtome in a Tyrode's solution containing 0.9 mM Ca²⁺ and BDM (2,3-Butanedione Monoxime), a contraction blocker. They were then transferred into a warm buffer solution without BDM and began to beat spontaneously. A MEA with 64 electrodes was used to measure electrical activity. Conduction velocity, propagation direction and the QT interval were analyzed.

Results: Compared with orthotopic hearts of recipient animals, 14 days of LV unloading induced weight reduction of the graft by ~25%. Slices of orthotopic and unloaded hearts allowed stable measurements of field potential duration and propagation maps up to two hours. Field potential durations of orthotopic, range 65 ms–105 ms, and unloaded mouse hearts, range 92 ms–144 ms, were measured and showed no rate dependency in a defined frequency span.

Conclusion: We present our first results establishing MEA measurements and the first data of field potentials in slices of adult mouse hearts. MEA analysis of severely atrophied heterotopically transplanted mouse hearts is feasible, allowing studies of electrophysiological alterations in unloaded hearts.