Search

Introduction Ventricular arrhythmias (VA) and heart failure (HF) are the major complications following myocardial infarction (MI). In both conditions, there is a key role for perturbed calcium homeostasis of which the underlying mechanisms remain unclear. A preclinical model that faithfully presents most of the features of MI-induced HF has been lacking. The complexity of this syndrome means that animal modelling is difficult. As the hearts of large animals share many electrophysiological similarities to humans, ovine modelling of cardiac diseases could better reflect human pathologies than in small mammals. Question Is it possible to develop a clinically relevant ovine model with moderate cardiac dysfunction following myocardial infarction? Methods MI was induced in sheep by inflating an angioplasty balloon distal to the second diagonal branch of the left anterior descending artery for 90 min. Cardiac function was monitored for 20 weeks using electrocardiography (ECG), echocardiography, blood biochemical analysis, and subjective signs of cardiac deterioration (lethargy, dyspnoea, and cough). 20 weeks post-MI, the animals were humanely killed and single left ventricular myocytes were isolated from the infarct border zone. Changes in cellular electrophysiology and intracellular calcium concentration were monitored using whole-cell patch technique in voltage-clamp mode and the calcium sensitive fluorescent indicator Fura-2 (K5 salt). Results By using minimally invasive procedures, we obtained a survival rate of 80% (n=15). During surgery, our data show clinical features of ischaemia, including changes in the ECG features (elevation of the ST and T segment, left bundle branch block and/or pathological Q waves) and elevation of the cardiac biomarker such as troponin I. Following MI, we observed a decline in ejection fraction (−25±3%, p Conclusion We successfully established an ovine MI model using minimally invasive procedure which displays a moderately impaired cardiac function, reduced contractility, and pro-arrhythmic electrophysiological remodelling. Future analysis will examine the role of the L-type calcium channel with respect to the excitation-contraction coupling process and myocyte contractility and how we can improve therapeutic strategies towards VA and HF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Funding Acknowledgements British Heart Foundation Introduction Myocardial infarction (MI) is a leading cause of mortality with complications such as left ventricular dysfunction and arrhythmias. Despite the well characterized clinical characteristics of MI, little is known about the cellular remodeling that occurs. Altered calcium (Ca2+) handling in disease can give rise to Ca2+ waves resulting in a transient inward current via the Na+- Ca2+ exchanger. Under certain conditions this causes membrane depolarization and potentially triggered arrhythmias. Since abnormal intracellular Ca2+ handling leads to both dysfunction and arrhythmias, an ovine MI model was established to simultaneously investigate cellular and in vivo alterations that occur post-MI. Methods: Young female sheep (∼18 months) were randomly allocated as control or for MI induction surgery. A minimally invasive technique was used to create the infarct by occluding the left anterior descending coronary artery. Electrocardiograms (ECG) were recorded at intervals. At 8 weeks, ventricular cells were isolated from the infarct border zone (BZ) and loaded with a Ca2+ indicator to study the systolic calcium transient, calcium sparks and occurrence of calcium waves. Statistical significance was taken as p