Abstract
Introduction: Nanomedicine offers great potential for treatment of cardiovascular disease. We tested whether intramyocardial (IM) injection of pro-angiogenic hepatocyte growth factor (HGF) and anti-apoptotic-myogenic insulin-like growth factor (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) improves targeted drug delivery and left ventricular (LV) function recovery in a porcine ischemia-reperfusion (I/R) model.
Methods: Myocardial infarction (MI) was induced by 75min balloon occlusion of the mid-LAD followed by reperfusion. After 1w, pigs (n=6) with marked LV dysfunction (EF<45%) were randomized to fusion imaging-guided IM injections of 8 mg Cy5-labelled AlgS-NP loaded with 200μg HGF and IGF-1 (GF) or with phosphate-buffered saline (CON) using the MYOSTAR injection catheter. AlgS-NP retention in the heart was determined by measuring Cy5 levels in peripheral blood. At 8w, treatment effect was evaluated using myocardial magnetic resonance imaging and coronary flow reserve (CFR) measurements.
Results: At 1w after MI, EF was 35±4% (range 32-40%) and infarct size (IS)/LVmass 22±3% (range 19-25%). Myocardial retention of AlgS-NP was ~85% at 5 min after IM injection and thereafter systemic leakage was markedly reduced compared to intracoronary injection (IC) of the same dose AlgS-NP (Fig A). After 8 w, IS decreased by half in GF-treated pigs, but was unchanged in CON (P=0.02, Fig. B). LVEF significantly improved in the GF-treated group (43±4% vs. 32±2%, P=0.01, Fig. C), which was attributable to a greater reduction in end-systolic volume. The reduction in IS was also associated with a trend towards improvement in CFR (P=0.077, Fig. D).
Conclusions: Targeting of AlgS-nanoparticle-encapsulated HGF and IGF-1 to the ischemic myocardium significantly increases the effective concentration at the site of action, improves LV repair, and offers the prospect of innovative treatment for patients with refractory ischemic heart disease.
Methods: Myocardial infarction (MI) was induced by 75min balloon occlusion of the mid-LAD followed by reperfusion. After 1w, pigs (n=6) with marked LV dysfunction (EF<45%) were randomized to fusion imaging-guided IM injections of 8 mg Cy5-labelled AlgS-NP loaded with 200μg HGF and IGF-1 (GF) or with phosphate-buffered saline (CON) using the MYOSTAR injection catheter. AlgS-NP retention in the heart was determined by measuring Cy5 levels in peripheral blood. At 8w, treatment effect was evaluated using myocardial magnetic resonance imaging and coronary flow reserve (CFR) measurements.
Results: At 1w after MI, EF was 35±4% (range 32-40%) and infarct size (IS)/LVmass 22±3% (range 19-25%). Myocardial retention of AlgS-NP was ~85% at 5 min after IM injection and thereafter systemic leakage was markedly reduced compared to intracoronary injection (IC) of the same dose AlgS-NP (Fig A). After 8 w, IS decreased by half in GF-treated pigs, but was unchanged in CON (P=0.02, Fig. B). LVEF significantly improved in the GF-treated group (43±4% vs. 32±2%, P=0.01, Fig. C), which was attributable to a greater reduction in end-systolic volume. The reduction in IS was also associated with a trend towards improvement in CFR (P=0.077, Fig. D).
Conclusions: Targeting of AlgS-nanoparticle-encapsulated HGF and IGF-1 to the ischemic myocardium significantly increases the effective concentration at the site of action, improves LV repair, and offers the prospect of innovative treatment for patients with refractory ischemic heart disease.
| Original language | English GB |
|---|---|
| Article number | A12785 |
| Journal | Circulation |
| Volume | 140 |
| Issue number | 1 Supplement |
| State | Published - 2019 |