A novel porcine model of early left ventricular dysfunction for translational research

Abstract

Nadim Malik, Kelly A Farrell, Sarah B Withers, Elizabeth J Wright, Cathy M HoltInstitute for Cardiovascular Science, University of Manchester, Manchester, United KingdomBackground: The early stages of left ventricular (LV) dysfunction account for a much larger proportion of the population with heart disease than that with clinical heart failure. However, LV dysfunction is more difficult to diagnose than established heart failure, and because of this it is not usually treated. Research on LV dysfunction is commonly conducted in small animal models in which the cardiac pathophysiology is dissimilar to that in humans, thereby restricting translation. This study aimed to use a novel pig model of mild to moderate early ischemic LV dysfunction to assess the effects of such dysfunction in the myocardium.Methods: Multiple areas of controlled microinfarcts were created via microembolization using embolization beads, with invasive hemodynamic and transthoracic echocardiographic assessment of LV function. Four weeks after intervention, the hearts were explanted for determination of the infarcted surface area and analysis of calcium regulatory proteins.Results: In vivo hemodynamic measurements confirmed a >25% decrease in LV dP/dt (maximum and minimum) with creation of microinfarcts compared with baseline, whilst echocardiography showed mild to moderate LV dysfunction. Perioperative mortality was 10%–15%. In surviving pigs, morphometry at 4 weeks confirmed that up to 20% of the total LV surface area contained microinfarcts. Western blot analysis showed alterations in levels of the calcium regulatory proteins, sarcoplasmic reticulum Ca2+ ATPase and sodium-calcium exchange, in infarcted areas, compared with normal LV tissue from the same animals.Conclusion: These results demonstrate the usefulness of this model for investigation of the precise molecular and cellular changes associated with early mild to moderate LV dysfunction from ischemic injury, and its potential use for modulating these changes with the aim of achieving functional reversibility or regeneration of the myocardium.Keywords: left ventricular dysfunction, heart failure, porcine model