Abstract 12139: Calpain Inhibition Attenuates Contractile Dysfunction Induced by Cardiac Dyssynchrony
Introduction: Cardiac dyssynchrony confers poor prognosis in heart failure, but whether dyssynchrony is merely a marker for contractile dysfunction, or actively contributes to it, is uncertain. In vivo, dyssynchrony causes local muscle lengthening during electrical activation. In skeletal muscle, forced lengthening during contraction (LEN-CON) activates the calcium sensitive protease calpain and causes contractile dysfunction and sarcomere disorganization.
Hypothesis: Calpain inhibition attenuates contractile dysfunction and sarcomere disorganization in cardiac muscle subjected to LEN-CON.
Methods: Rat right ventricular trabeculae (cross sectional area 0.06±.04 mm2) at fixed diastolic length L0 were paced at 1 Hz for 1 hr and allowed to shorten against normal load (50% initial isometric force F0,CONTROL n=4), or forced to lengthen to 110% L0 during each contraction without (UNTREATED n=12) or with (TREATED n=14) calpain inhibitor (calpeptin 1 μM). After 1 hr, isometric force was remeasured (F1Hr), and sarcomere length, length dispersion and organization in trabeculae fixed in diastole at L0 and stained for α-actinin were quantified by Fourier power spectrum analysis of digitally deconvolved photomicrographs.
Results: In CONTROL, isometric force was unchanged after 1 hr (F1Hr/F094±18%, mean±SD). In UNTREATED, 1 hr LEN-CON caused dysfunction (F1Hr/F050±9%, p<.001 vs CONTROL). In TREATED, dysfunction from LEN-CON was attenuated (F1Hr/F063±16%, p=.02 vs UNTREATED). Sarcomere length after LEN-CON was similar in UNTREATED and TREATED (2.21±.20 vs 2.12±.09 μm, p=NS), but TREATED showed less length dispersion and better preserved sarcomere organization (FIG) by Fourier analysis (p<.05).
Conclusions: Lengthening contraction causes dysfunction and sarcomere disorganization in cardiac muscle, at least in part through calpain activation. Calpain inhibition may have potential to ameliorate contractile dysfunction due to dyssynchrony in vivo.
Author Disclosures: C.R. Greyson: None. S. Ye: None. L. Lu: None. G.G. Schwartz: None. J.S. Walker: None.
- © 2015 by American Heart Association, Inc.