Research ArticleCardiology

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

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaay2140
DOI: 10.1126/scitranslmed.aay2140

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Straightening up scars

As a result of myocardial infarction (MI; heart attack), scar tissue forms that negatively affects cardiac function. Thavapalachandran et al. investigated the potential therapeutic effects of intravenous delivery of recombinant human platelet-derived growth factor-AB (rhPDGF-AB) after MI in a randomized, double-blinded study in pigs. Cardiac function was improved 28 days after treatment was initiated and rhPDGF-AB enhanced angiogenesis; however, there was no difference in the size of scars between rhPDGF-AB–treated and vehicle-treated pigs. Scars in rhPDGF-AB–treated pigs showed less heterogeneity and greater fiber alignment, and rhPDGF-AB–treated pigs were less susceptible to arrhythmia after MI. Results support the translational potential of rhPDGF-AB to modulate scars and augment cardiac repair.

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.

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