Key result
Intracoronary injection of AdvFGF-5 in swine with hibernating myocardium increased wall-thickening to 4.7 mm (P<0.05) and stimulated myocyte hypertrophy and cell cycle reentry.
Why the study?
Does intracoronary AdvFGF-5 improve function and stimulate myocyte hypertrophy in swine with hibernating myocardium?
Does intracoronary AdvFGF-5 improve function and stimulate myocyte hypertrophy in swine with hibernating myocardium?
AdvFGF-5 improves function in hibernating myocardium by stimulating myocyte hypertrophy and cell cycle reentry rather than through angiogenesis.
Answers are grounded in this paper and cite their sources.
Caution against clinical translation; extends preclinical evidence for myocyte regeneration in hibernating myocardium.
Fibroblast growth factors (FGFs) have diverse actions on the myocardium but the importance of stimulating angiogenesis versus direct effects of FGFs on cardiac myocytes is unclear. We used intracoronary injection of a replication-deficient adenoviral construct overexpressing FGF-5 (AdvFGF-5) to improve flow and function in swine with hibernating myocardium. Two-weeks after AdvFGF-5 (n=8), wall-thickening increased from 2.4+/-0.04 to 4.7+/-0.7 mm in hibernating LAD regions (P<0.05) whereas remote wall-thickening was unchanged (6.7+/-0.4 to 5.8+/-0.5 mm). This was associated with small increases in resting flow to dysfunctional myocardium, but flow during adenosine was unchanged (LAD 1.45+/-0.27 versus 1.46+/-0.23 mL/min per g and remote 4.84+/-0.23 versus 4.71+/-0.47 mL/min per g, P=NS). Unexpectedly, animals receiving AdvFGF-5 demonstrated a 29% increase in LV mass over the 2-week period (P<0.05 versus untreated animals with hibernating myocardium and normal shams). Histological analysis confirmed profound myocyte cellular hypertrophy in AdvFGF-5 treated myocardium (19.9+/-0.32 versus 15.2+/-0.92 microm in untreated, P<0.001). Myocytes in the proliferative phase of the cell cycle (Ki-67 staining) increased 7-fold after AdvFGF-5 (2,904+/-405 versus 409+/-233 per 10(6) myocyte nuclei in untreated, P<0.05). Myocyte nuclei in the mitotic phase (phosphorylated histone H3 staining) also increased after AdvFGF-5 (127+/-24 versus 35+/-13 per 10(6) myocyte nuclei in untreated, P<0.05). Thus, rather than angiogenesis, stimulation of hypertrophy and reentry of a small number of myocytes into the mitotic phase of the cell cycle are responsible for the effects of AdvFGF-5 on function. Although additional mechanisms may contribute to the improvement in wall-thickening, overexpression of AdvFGF-5 may afford a way to restore function in hibernating myocardium and ameliorate heart failure in chronic ischemic cardiomyopathy.
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Suzuki et al. (2005) studied hibernating myocardium (n=8). AdvFGF-5 vs. untreated animals and normal shams was evaluated on wall-thickening in hibernating LAD regions (p=<0.05). Intracoronary injection of AdvFGF-5 in swine with hibernating myocardium increased wall-thickening to 4.7 mm (P<0.05) and stimulated myocyte hypertrophy and cell cycle reentry.
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