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Wiley Open Access, Journal of the American Heart Association, 3(5), 2016

DOI: 10.1161/jaha.115.002836

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Alterations in Multi‐Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein‐C

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

Abstract

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.