Wiley Open Access, Journal of the American Heart Association, 3(5), 2016
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Background The geometric organization of myocytes in the ventricular wall comprises the structural underpinnings of cardiac mechanical function. Cardiac myosin binding protein‐C ( MYBPC 3) is a sarcomeric protein, for which phosphorylation modulates myofilament binding, sarcomere morphology, and myocyte alignment in the ventricular wall. To elucidate the mechanisms by which MYBPC 3 phospho‐regulation affects cardiac tissue organization, we studied ventricular myoarchitecture using generalized Q‐space imaging ( GQI ). GQI assessed geometric phenotype in excised hearts that had undergone transgenic ( TG ) modification of phospho‐regulatory serine sites to nonphosphorylatable alanines ( MYBPC 3 AllP−/(t/t) ) or phospho‐mimetic aspartic acids ( MYBPC 3 AllP+/(t/t) ). Methods and Results Myoarchitecture in the wild‐type ( MYBPC 3 WT ) left‐ventricle ( LV ) varied with transmural position, with helix angles ranging from −90/+90 degrees and contiguous circular orientation from the LV mid‐myocardium to the right ventricle ( RV ). Whereas MYBPC 3 AllP+/(t/t) hearts were not architecturally distinct from MYBPC 3 WT , MYBPC 3 AllP−/(t/t) hearts demonstrated a significant reduction in LV transmural helicity. Null MYBPC 3 (t/t) hearts, as constituted by a truncated MYBPC 3 protein, demonstrated global architectural disarray and loss in helicity. Electron microscopy was performed to correlate the observed macroscopic architectural changes with sarcomere ultrastructure and demonstrated that impaired phosphorylation of MYBPC 3 resulted in modifications of the sarcomere aspect ratio and shear angle. The mechanical effect of helicity loss was assessed through a geometric model relating cardiac work to ejection fraction, confirming the mechanical impairments observed with echocardiography. Conclusions We conclude that phosphorylation of MYBPC 3 contributes to the genesis of ventricular wall geometry, linking myofilament biology with multiscale cardiac mechanics and myoarchitecture.