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

Thavapalachandran, Sujitha and Grieve, Stuart M. and Hume, Robert D. and Le, Thi Yen Loan and Raguram, Kalyan and Hudson, James E. and Pouliopoulos, Jim and Figtree, Gemma A. and Dye, Rafael P. and Barry, Anthony M. and Brown, Paula and Lu, Juntang and Coffey, Sean and Kesteven, Scott H. and Mills, Richard J. and Rashid, Fairooj N. and Taran, Elena and Kovoor, Pramesh and Thomas, Liza and Denniss, Alan Robert and Kizana, Eddy and Asli, Naisana S. and Xaymardan, Munira and Feneley, Michael P. and Graham, Robert M. and Harvey, Richard P. and Chong, James J. H. (2020) Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction. Science Translational Medicine, 12 (524). pp. eaay2140. ISSN 1946-6234

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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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 23 Jan 2020 04:15
Last Modified: 28 Oct 2021 02:03

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