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Basic research in cardiology
10, 2024;119 (5): 795-806.

Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Ming Wu, Peter Pokreisz, Piet Claus, Andrea Casazza, Hilde Gillijns, Ellen Caluwé, Marzia De Petrini, Ann Belmans, Geert Reyns, Desire Collen, Stefan P Janssens
Author Information
  1. Ming Wu: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium. ORCID
  2. Peter Pokreisz: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium.
  3. Piet Claus: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium.
  4. Andrea Casazza: CoBioRes NV, Leuven, Belgium.
  5. Hilde Gillijns: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium.
  6. Ellen Caluwé: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium.
  7. Marzia De Petrini: CoBioRes NV, Leuven, Belgium.
  8. Ann Belmans: Leuven Biostatistics and Statistical Bioinformatics Center, KU Leuven, Leuven, Belgium.
  9. Geert Reyns: CoBioRes NV, Leuven, Belgium.
  10. Desire Collen: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium.
  11. Stefan P Janssens: Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, O&N1, 49 Herestraat, 3000, Leuven, Belgium. stefan.janssens@uzleuven.be.
PMID: 39090343 DOI: 10.1007/s00395-024-01069-7

Abstract

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75 min mid-LAD balloon occlusion followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45 µg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated the treatment effect at 8 w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4 w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14 days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

Keywords

Myocardial ischemia–reperfusion Placental growth factor-2 Post-infarction left ventricular dysfunction Protein therapy Recombinant growth factors

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Grants

  1. PF 10/014/KU Leuven

MeSH Term

Animals
Myocardial Infarction
Placenta Growth Factor
Ventricular Dysfunction, Left
Disease Models, Animal
Swine
Recombinant Proteins
Humans
Pregnancy Proteins
Ventricular Function, Left
Female

Chemicals

Placenta Growth Factor
PGF protein, human
Recombinant Proteins
Pregnancy Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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