title: Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone.
abstract: After myocardial infarction, a poorly contracting nonischemic border zone forms adjacent to the infarct. The cause of border zone dysfunction is unclear. The goal of this study was to determine the myofilament mechanisms involved in postinfarction border zone dysfunction. Two weeks after anteroapical infarction of sheep hearts, we studied in vitro isometric and isotonic contractions of demembranated myocardium from the infarct border zone and a zone remote from the infarct. Maximal force development (Fmax) of the border zone myocardium was reduced by 31 ± 2% versus the remote zone myocardium (n = 6/group, P < 0.0001). Decreased border zone Fmax was not due to a reduced content of contractile material, as assessed histologically, and from myosin content. Furthermore, decreased border zone Fmax did not involve altered cross-bridge kinetics, as assessed by muscle shortening velocity and force development kinetics. Decreased border zone Fmax was associated with decreased cross-bridge formation, as assessed from muscle stiffness in the absence of ATP where cross-bridge formation should be maximized (rigor stiffness was reduced 34 ± 6%, n = 5, P = 0.011 vs. the remote zone). Furthermore, the border zone myocardium had significantly reduced phosphorylation of myosin essential light chain (ELC; 41 ± 10%, n = 4, P < 0.05). However, for animals treated with doxycycline, an inhibitor of matrix metalloproteinases, rigor stiffness and ELC phosphorylation were not reduced in the border zone myocardium, suggesting that doxycycline had a protective effect. In conclusion, myofilament dysfunction contributes to postinfarction border zone dysfunction, myofilament dysfunction involves impaired cross-bridge formation and decreased ELC phosphorylation, and matrix metalloproteinase inhibition may be beneficial for limiting postinfarct border zone dysfunction.
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Rafael
authors.initials: R
authors.lastname: Shimkunas
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Om
authors.initials: O
authors.lastname: Makwana
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Spaulding
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Mona
authors.initials: M
authors.lastname: Bazargan
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Khazalpour
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Takaba
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Bat-Erdene
authors.initials: BE
authors.lastname: Myagmar
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Simpson
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ratcliffe
authors.affiliation: Veterans Affairs Medical Center, San Francisco, California; and Departments of Medicine and Surgery, University of California-San Francisco (UCSF), Joint University of California-Berkeley/UCSF Bioengineering Group, San Francisco, California Anthony.Baker@ucsf.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D012756:Sheep
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D018994:Myosin Light Chains; D000255:Adenosine Triphosphate; D004318:Doxycycline
keywords: contraction; essential light chain; infarct; matrix metalloproteinase; myofilament