Mechanisms by which late coronary reperfusion mitigates postinfarction cardiac remodeling.
Although recanalization of the infarct-related artery late after myocardial infarction (MI) is known to reduce both cardiac remodeling and mortality, the mechanisms responsible are not yet fully understood. We compared infarcted rat hearts in which the infarct-related coronary artery was opened 24 hours after infarction (late reperfusion [LR] group) with those having a permanently occluded artery. Left ventricular dilatation and dysfunction were significantly mitigated in the LR group 1, 2, and 4 weeks post-MI. Attributable, in large part, to the greater number of cells present, the infarcted wall was significantly thicker in the LR group, which likely reduced wall stress and mitigated cardiac dysfunction. Granulation tissue cell proliferation was increased to a greater degree in the LR group 4 days post-MI, whereas the incidence of apoptosis was significantly lower throughout the subacute stage (4 days, 1 week, and 2 weeks post-MI), further suggesting preservation of granulation tissue cells contributes to the thick, cell-rich scar. Functionally, myocardial debris was more rapidly removed from the infarcted areas in the LR group during subacute stages, and stouter collagen was more rapidly synthesized in those areas. Direct acceleration of Fas-mediated apoptosis by hypoxia was confirmed in vitro using infarct tissue-derived myofibroblasts. In salvaged cardiomyocytes, degenerative changes, but not apoptosis, were mitigated in the LR group, accompanied by restoration of GATA-4 and sarcomeric protein expression. Along with various mechanisms proposed earlier, the present findings appear to provide an additional pathophysiological basis for the benefits of late reperfusion.
Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Munehiro
M
Nakagawa
Genzou
G
Takemura
Hiromitsu
H
Kanamori
Kazuko
K
Goto
Rumi
R
Maruyama
Akiko
A
Tsujimoto
Takamasa
T
Ohno
Hideshi
H
Okada
Atsushi
A
Ogino
Masayasu
M
Esaki
Shusaku
S
Miyata
Longhu
L
Li
Hiroaki
H
Ushikoshi
Takuma
T
Aoyama
Masanori
M
Kawasaki
Kenshi
K
Nagashima
Takako
T
Fujiwara
Shinya
S
Minatoguchi
Hisayoshi
H
Fujiwara
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D003598:Cytoskeletal Proteins; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D015425:Myocardial Reperfusion / Q000379:methods; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D020257:Ventricular Remodeling
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; C405542:Klhl41 protein, rat; D003094:Collagen