Preclinical Evaluation of Biopolymer-Delivered Circulating Angiogenic Cells in a Swine Model of Hibernating Myocardium

Abstract

M yocardial hibernation is a common clinical condition affecting patients with advanced coronary artery disease, 1 for whom cell-based therapies are targeted. In hibernation, repetitive episodes of ischemia and reperfusion lead to metabolic and functional changes in cardiomyocytes, ultimately impairing left ventricular (LV) function. Current therapies such as coronary artery bypass grafting or percutaneous coronary intervention are well established but not suitable for all patients; in previous clinical research from our group, more than one third of patients referred for revascularization did not undergo intervention because of unsuitable vessel anatomy, comorbidities, or other reasons.1 These patients are at high risk of cardiac events, and novel approaches such as cell-based vasculogenic therapy could provide them with an alternative form of therapy. Clinical Perspective on p 991Circulating angiogenic cells (CACs) constitute a heterogeneous population of peripheral blood-derived fibronectincultured cells. Although what defines their phenotype is still debated, 2 they were shown to uptake acetylated low-density lipoprotein, bind Ulex europaeus agglutinin-1 lectin, and express the pan-leukocyte marker CD45. They can also stain positive for monocyte/macrophage (CD14, CD11b/Mac-1, and CD11c) and endothelial (vascular endothelial growth factor receptor 2, von Willebrand factor, vascular endothelialcadherin, and CD31) markers. [3][4][5] Transplanted cells likely contribute to neovascularization through a paracrine mechanism by secreting and recruiting cardioprotective or proangiogenic growth factors. 6,7 The revascularization potential of Background-Vasculogenic cell-based therapy combined with tissue engineering is a promising revascularization approach targeted at patients with advanced coronary artery disease, many of whom exhibit myocardial hibernation. However, to date, no experimental data have been available in this context; we therefore examined the biopolymer-supported delivery of circulating angiogenic cells using a clinically relevant swine model of hibernating myocardium. Methods and Results-Twenty-five swine underwent placement of an ameroid constrictor on the left circumflex artery.After 2 weeks, animals underwent echocardiography, rest and stress ammonia-positron emission tomography perfusion, and fluorodeoxyglucose positron emission tomography viability scans. The following week, swine were randomized to receive intramyocardial injections of PBS control (n=10), circulating angiogenic cells (n=8), or circulating angiogenic cells+collagen-based matrix (n=7). The imaging protocol was repeated after 7 weeks. Baseline positron emission tomography myocardial blood flow and myocardial flow reserve were reduced in the left circumflex artery territory (both P<0.001), and hibernation (mismatch) was observed. At follow-up, stress myocardial blood flow had increased (P≤0.01) and hibernation decreased (P<0.01) in the cells+matrix group only. Microsphere-measured myocardial blood flow validated the perfusion resu...

Panax Quinquefolium Saponins Attenuate Myocardial Dysfunction Induced by Chronic Ischemia

“…This may explain the greater improvement in WT% and SRS% with PQS. Consistent with previous studies [18,29], myocyte nuclear density was increased by PQS. Treatment with PQS attenuated the cellular hypertrophy, indicating that PQS improve oxygen transport across the sarcolemma in the ischemic myocardium [30].…”

“…Nuclei were counter-stained with DAPI. To determine arteriole density, 6 random fields per slide were captured at 200× magnification using a fluorescent microscope [18]. Blood vessels with a diameter <100 μm were counted by two independent examiners.…”

Targeted Myocardial Restoration with Injectable Hydrogels—In Search of The Holy Grail in Regenerating Damaged Heart Tissue

“…The common modalities used to measure these parameters included: echocardiography, MRI, and immunohistochemistry. Out of the 21 studies, Giordano et al, 2013 [ 19 ], Yamamoto et al, 2001 [ 20 ], Zhou et al, 2012 [ 10 ], Liu et al, 2006 [ 11 ], and Takehara et al, 2008 [ 29 ] did not measure the direct effect of treatment on LV remodeling. The remaining 16 studies that looked into LV remodeling reported either attenuated or equivocal LV remodeling.…”

“…The degree of angiogenesis was mainly quantified using blood vessel density via immunohistochemistry staining. Out of the 21 studies, only 11 [ 10 , 11 , 14 , 19 , 21 , 23 , 25 , 26 , 27 , 28 , 30 ] measured blood vessel density; each of the 11 studies reported an improved effect, implying that hydrogel treatment can have a positive effect on angiogenesis post-MI. Zhou et al [ 10 ] particularly focuses on the density of specific blood vessels—namely arterioles, small vessels, and larger arterioles—all of which show an increase in density.…”

Creation of clinically relevant model of chronic heart failure: Application of multi-modality imaging to define physiology

“…4 This surgical intervention is well established and leads to a classic model of hibernating myocardium. 4,11,12,23 Teramato and colleagues 3 previously reported a swine model of HF induced by permanent ligation on the distal portion of the LAD, followed by proximal placement an ameroid constrictor to occlude the proximal portion. This study was able to demonstrate a high survival rate out to 4-month post-surgery (75%), and characterized LV remodeling in the setting of reduced EF, and increased end-diastolic and end-systolic volumes with initial development of fibrosis in the remote regions.…”