Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity.
BACKGROUND
Local delivery methods can target therapies to specific tissues and potentially avoid toxicity to other organs. Platelet-derived growth factor can protect the myocardium, but it also plays an important role in promoting pulmonary hypertension. It is not known whether local myocardial delivery of platelet-derived growth factor during myocardial infarction (MI) can lead to sustained cardiac benefit without causing pulmonary hypertension.


RESULTS
We performed a randomized and blinded experiment of 127 rats that survived experimental MI or sham surgery. We delivered platelet-derived growth factor (PDGF)-BB with self-assembling peptide nanofibers (NFs) to provide controlled release within the myocardium. There were 6 groups with n > or = 20 in each group: sham, sham+NF, sham+NF/PDGF, MI, MI+NF, and MI+NF/PDGF. Serial echocardiography from 1 day to 3 months showed significant improvement of ventricular fractional shortening, end-systolic dimension, and end-diastolic dimension with local PDGF delivery (P < 0.05 for MI+NF/PDGF versus MI or MI+NF). Catheterization at 4 months revealed improved ventricular function in the controlled delivery group (left ventricular end-diastolic pressure, cardiac index, +dP/dt, -dP/dt, and time constant of exponential decay all P < 0.05 for MI+NF/P versus MI or MI+NF). Infarcted myocardial volume was reduced by NF/PDGF therapy (34.0 +/- 13.3% in MI, 28.9 +/- 12.9% in MI+NF, and 12.0 +/- 5.8% in MI+NF/PDGF; P < 0.001). There was no evidence of pulmonary toxicity from the therapy, with no differences in right ventricular end-systolic pressure, right ventricular dP/dt, bromodeoxyuridine staining, or pulmonary artery medial wall thickness.


CONCLUSIONS
Intramyocardial delivery of PDGF by self-assembling peptide NFs leads to long-term improvement in cardiac performance after experimental infarction without apparent pulmonary toxicity. Local myocardial protection may allow prevention of heart failure without systemic toxicity.
Hsieh
Patrick C H
PC
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Mass., USA.
MacGillivray
Catherine
C
Gannon
Joseph
J
Cruz
Francisco U
FU
Lee
Richard T
RT
D000818:Animals; D016503:Drug Delivery Systems; D004452:Echocardiography; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D007267:Injections / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology*; D036103:Nanotechnology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D016276:Ventricular Function / Q000187:drug effects* / Q000502:physiology
D010982:Platelet-Derived Growth Factor