Author + information
- Stefan Koudstaal,
- Maartje Bastings,
- Georgina Ellison,
- Dries Feyen,
- Cheryl Waring,
- Daniele Torella,
- Bert Meijer,
- Joost Sluijter,
- Bernardo Nadal-Ginard,
- Pieter Doevendans,
- Patricia Dankers and
- Steven Chamuleau
The aim of this study was to test the sustained release of insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) using an injectable supramolecular hydrogel based on ureido-pyrimidinone (UPy) moieties in order to recruit and activate endogenous porcine cardiac stem/progenitor cells (epCSCs) towards the infarct borderzone leading to increased myocardial repair in a porcine model of chronic myocardial infarction (MI).
Preclinical data in rodents, dogs and pigs provided proof that IGF-1/HGF treatment could activate c-kitposCD45neg epCSCs thereby giving rise to enhanced myocardial repair, reduction in fibrosis, and cardiomyocyte regeneration in the acute phase of MI.
Acute MI was induced in Dallas Landrace pigs (70 ± 3kg) (n=17) by a 75-min coronary balloon occlusion of the left circumflex artery. After 1 month, all survived animals underwent intramyocardial injections with the NOGA catheter of IGF-1 and HGF (both 0.5µg/ml), dissolved in saline (n=5), incorporated in UPy-hydrogel (n=5), or empty UPy-hydrogel in 4 control (CTRL) pigs. The pigs were sacrificed for immunohistological analysis and functional endpoint analysis by 3D echocardiography 1 month after the injections.
In chronic MI, UPy-IGF-1/HGF reduced infarct scar fibrosis (p = 0.025) and reactive cardiomyocyte hypertrophy (p = 0.017). In the UPy-IGF-1/HGF animals, an almost fourfold increase in c-kitpos CD45neg epCSCs was found in the infarct area compared to CTRLs (p=0.023). This repair/regenerative response ensued in the enhanced formation of small, newly formed cardiomyocytes in UPy-IGF-1/HGF treated hearts (p=0.016). These beneficial histological effects were associated with an improved left ventricular ejection fraction in the UPy-IGF-1/HGF animals (52.9 ± 2.8%) compared to IGF-1/HGF (46.6 ± 1.5%) or CTRLs (43.9 ± 3.6%; p = 0.001).
The sustained delivery of IGF-1/HGF by UPy-hydrogel is an effective and potentially clinically feasible treatment protocol for post-MI heart failure that reduced pathological cardiac remodelling and fostered myocardial regeneration leading to an improved cardiac function in a porcine model of chronic MI.
Poster Sessions, Expo North
Saturday, March 09, 2013, 10:00 a.m.-10:45 a.m.
Session Title: Chronic CAD: Mechanisms of Repair
Abstract Category: 9. Chronic CAD/Stable Ischemic Heart Disease: Basic
Presentation Number: 1109-67
- 2013 American College of Cardiology Foundation