Cardiac Expression of Placental Growth Factor Predicts the Improvement of Chronic Phase Left Ventricular Function in Patients With Acute Myocardial Infarction
Hajime Iwama, MD,
Shiro Uemura, MD*,
Noriyuki Naya, BS,
Kei-ichi Imagawa, PhD,
Yasuhiro Takemoto, MD,
Osamu Asai, MD,
Kenji Onoue, MD,
Satoshi Okayama, MD,
Satoshi Somekawa, MD,
Yoshitomi Kida, MD,
Yukiji Takeda, MD,
Kimihiko Nakatani, MD,
Minoru Takaoka, MD,
Hiroyuki Kawata, MD,
Manabu Horii, MD,
Tamio Nakajima, MD,
Naofumi Doi, MD and
Yoshihiko Saito, MD
First Department of Medicine, Nara Medical University, Kashihara, Nara, Japan
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Figure 1 (A) Peripheral blood plasma cytokine levels in patients with acute myocardial infarction (AMI). Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) were significantly higher than control in blood samples from AMI patients. Bars represent means ± SE. (B) Placental growth factor levels in plasma samples taken from the coronary artery ostium (CAos) and coronary sinus (CS) before and just after percutaneous coronary intervention. Before recanalization (RC) of an infarct-related artery, plasma PlGF levels were similarly low in the CAos and CS. After RC, PlGF levels were significantly increased in both the CAos and CS, as compared to before RC, and levels in the CS were significantly higher than in the CAos. Closed circles and bars represent means ± SE.
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Figure 2 Relationship between plasma placental growth factor (PlGF) levels on day 3 post-myocardial infarction and peripheral white blood cell (WBC) counts. Neither PlGF (A) nor vascular endothelial growth factor (VEGF) (B) correlated with total peripheral WBC counts. Placental growth factor levels positively correlated with peak monocyte counts (C), though VEGF levels did not (D). PBMC = peripheral blood.
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Figure 3 Relationship between plasma placental growth factor (PlGF) levels on day 3 post-myocardial infarction and left ventricular ejection fraction (EF) during the acute phase. Whereas plasma PlGF levels negatively correlated with left ventricular EF at the onset of acute myocardial infarction (A), plasma vascular endothelial growth factor (VEGF) levels did not (B). Plasma PlGF levels on day 3 post-myocardial infarction were positively correlated with the changes of left ventricular EF ( EF) that occurred between the acute and chronic phases (C); VEGF levels were not (D).
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Figure 4 Expression of placental growth factor (PlGF) mRNA in the hearts of mice subjected to myocardial infarction induced by coronary artery ligation. Quantitative real-time polymerase chain reaction revealed that expression of PlGF mRNA was significantly up-regulated in infarct hearts, as compared to sham-operated hearts on days 1 and 3 post-myocardial infarction, but had returned to levels that did not differ from control by days 7 and 28. AMI = acute myocardial infarction.
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Figure 5 Photomicrographs showing immunohistochemical staining of placental growth factor in mouse heart on day 3 post-myocardial infarction. (A) Infarct myocardium (original magnification, 60x). (B and C) Higher magnification (240x) of the corresponding box (A). The staining shows strong expression of placental growth factor protein in the endothelium within the infarct region (B), as well as in interstitial cells (C). The staining shows an absence of placental growth factor protein in the non-infarct area (D). Arrows indicate vascular tissue, arrowheads interstitial cells.
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Figure 6 Photomicrographs showing immunofluorescent staining of a small artery and infiltrating cell within the infarct myocardium. (A) Combination staining of the target vessel with anti-placental growth factor (red) and anti-von Willebrand factor (green) antibodies. Yellow coloration indicates placental growth factor expression within vascular endothelial cells. (B) Combination staining with anti-placental growth factor (red) and anti-alpha-smooth muscle actin (green) antibodies. Note that placental growth factor expression is restricted to the intima of the target vessel. (C) Combination staining with anti-placental growth factor (red) and anti-CD11b (green) antibodies. Placental-growth-factor-expressing cell in the interstitium did not cross-react with CD11b-positive cell (macrophage). Original magnification, 800x. DAPI was used for nuclear staining (blue).
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Figure 7 Placental growth factor (PlGF) gene expression and angiogenesis in ischemic myocardium. (A) Relation between the duration of ischemia and the PlGF gene expression three days after surgery in mouse models of myocardial infarction (MI, as permanent occlusion) and ischemia-reperfusion (IR). Bars represent PlGF mRNA levels of infarct heart tissue. Placental growth factor mRNA expression levels were significantly increased in both in 60 min. Ischemia-reperfusion and MI models compared with sham operated mice. (B) Relation between the duration of ischemia and the blood vessel density in the marginal area of infarct myocardium in mouse models of MI and IR. Heart tissue was sampled seven days after surgery. Bars represent alpha-smooth muscle actin-positive blood vessel counts in infarct lesion per field under x400 microscopy. Blood vessel densities in both MI and IR are significantly increased compared with sham, and blood vessel density in MI is significantly higher (2.5x) compared with IR. *p < 0.001 for MI and IR vs. sham; **p < 0.001 for MI vs. IR; ***p < 0.01 for IR 60 min vs. sham.
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