Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

Abstract

21Background: In the field of cell therapy for heart disease, a new paradigm of repeated 22 dosing of cells has recently emerged. However, the lack of a repeatable cell delivery 23 method in preclinical studies in rodents is a major obstacle to investigating this 24 paradigm. 25 Methods and Results:We have established and standardized a method of 26 echocardiography-guided percutaneous left ventricular intracavitary injection (echo-27 guided LV injection) as a cell delivery approach in infarcted mice. Here, we describe the 28 method in detail and address several important issues regarding it. First, by integrating 29 anatomical and echocardiographic considerations, we have established strategies to 30 determine a safe anatomical window for injection in infarcted mice. Second, we 31 summarize our experience with this method (734 injections). The overall survival rate 32 was 91.4%. Previous studies results suggest that 1×10 6 cells delivered via this method 33 yielded similar retention in the heart at 24 h as 1×10 5 cells delivered via intracoronary or 34 intramyocardial injection. Lastly, we examined the efficacy of this cell delivery approach. 35Compared with vehicle treatment, cardiac mesenchymal cells (CMCs) delivered via this 36 method improved cardiac function assessed both echocardiographically and 37 hemodynamically. Furthermore, repeated injections of CMCs via this method yielded 38 greater cardiac function improvement than single dose administration. 39 Conclusion: Echo-guided LV injection is a feasible, reproducible, relatively less 40 invasive and effective delivery method for cell therapy in heart disease. It is an 41 important approach that could move the field of cell therapy forward, especially with 42 regard to repeated cell administrations. 43 44 Introduction 45 Despite two decades of intensive research in cell therapy for heart disease, the optimal 46 cell type, dosage, delivery method and frequency are still elusive, as is the mechanism 47 behind the observed cardiac benefits of cell therapy[1, 2]. The available evidence 48 supports two fundamental concepts: i) the majority of cell-related effects do not result 49 from direct cardiomyocyte differentiation but rather from paracrine mechanisms[3], ii) all 50 cells, regardless of cell type or delivery approach, fail to engraft in the heart to a 51 significant extent[4]. Therefore, expecting a single administration of short-lasting cells to 52 produce long-term benefits may be unrealistic. A paradigm shift from single 53 administration to repeated administrations of cells is underway[1, 3-5]. 54 Typical cell delivery approaches in clinical studies include intracoronary infusion, 55 transendocardial injection, and direct epicardial injection[1, 2]. The first two are catheter-56 based, and can be repeated without opening the chest although it would be practically 57 difficult to perform repeated catheter-based deliveries in humans. However, in 58 preclinical studies in rodents, repeated cell administrations can be difficult to perform. 59 Most cell...