Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction

Abstract

Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs.

Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair

“…Once advanced heart failure occurs, a heart transplantation is the only option 4 . Regenerative therapies using live cells, proteins, and nuclei acids aims at altering the trajectory of adverse heart remodeling and promoting de novo cardiac repair [5][6][7][8] . However, it is difficult to deliver therapeutics to the heart, with high efficiency and low invasiveness and cost 9 .…”

Effect of captopril on post-infarction remodelling visualized by light sheet microscopy and echocardiography

“…Our data from 3D imaging shows that delayed captopril treatment leads to higher vascular density in the infarcted heart border zone but has neither positive nor negative effect on vascular density in the infarct zone and in the posterior cardiac wall. Still little is known about the dynamic response of microvasculature to MI, although angiogenesis has emerged as a lucrative target in pharmacological research 15 , 16 , 60 . Captopril has been reported to inhibits angiogenesis in tumours 61 and skeletal muscle 62 , 63 , but no significant effect has so far been found on the angiogenesis in the infarcted heart 57 , 64 , 65 .…”

Growth factor therapy for cardiac repair: an overview of recent advances and future directions

“…Recently, our research group has reported the effects of a 7day recombinant human PDGF-AB (rhPDGF-AB) infusion in a clinically relevant porcine myocardial ischemia-reperfusion model. Compared with controls, rhPDGF-AB-treated animals exhibited increased infarct collagen anisotropy, maturation of collagen and increased vascular density (Thavapalachandran et al 2020). Functionally, this was associated with a 12% improvement in LVEF in the rhPDGF-AB group 28 days post-injury, decreased inducible ventricular tachycardia and a 40% reduction in arrhythmic mortality compared to the control group, which was mostly attributed to reduced infarct heterogeneity (Thavapalachandran et al 2020).…”