| Abstrakt: |
Rationale:The mechanical consequences of ischemia-reperfusion (I-R) injury to the myocardium are associated with altered myofiber helicity possibly attributable to proteolytic degradation of sarcomere scaffold proteins, such as MYBPC3. Therefore, changes in myofiber helicity might also provide a biomarker for regional protection from injury.Hypothesis:Constitutive ablation of the calpain targeting site (CTS) in cardiac MYBPC3 confers resistance to calpain-mediated proteolysis and decreases infarct size.Methods:Following sequential left LAD ligation (30 min) and reperfusion (24 hours) in non-transgenic (NTG) (n=3) and transgenic (TG) mice expressing MYBPC3?CTS(n=3), high angular resolution diffusion-weighted ?Q-Space? MRI was performed using a Bruker 7T magnet with cryoprobe (512 directions, b=750 s/mm2). Patterns of inter-voxel coherence (tractography) were reconstructed, and helix angles (HA) assessed at 6 ROIs aligned across the thickness of the myocardium in each of 8 LV regions, normalized to a common vector.Results:The linearized HA slope of non-ischemic NTG hearts was well conserved across the LV (mean = -9.5, SD = 0.41), while the ischemic zone of NTG mice demonstrated reduced directional coherence and HA slope (mean = -7.9, SD = 0.76, p=0.002). Mice expressing cardiac-specific MYBPC3?CTSdisplayed variable HA slope (mean = -6.5, SD = 5.9) within the infarct core, also reduced relative to non-ischemic tissue (p=0.159). However, MYBPC3?CTShearts exhibited slope normalization in the infarct periphery similar to that of non-ischemic NTG tissue (mean = -9.4, SD = 0.49, p=0.942), while the analogous peripheral ischemic region in NTG mice was significantly different from non-ischemic tissue (mean slope = -12.0, SD = 0.56, p<0.001).Conclusions:Myoarchitectural injury following I-R may be partly mediated by calpain-induced cleavage of MYBPC3, while CTS ablation affords architectural protection, most notably in the infarct periphery. |
