Dual filament regulation of cardiac contraction

This thesis aims at investigating the molecular mechanisms that regulate cardiac muscle contraction, focusing on how the heart responds to changes in load. Combined mechanical and X-ray diffraction experiments were performed on intact trabeculae and papillary muscles from rat ventricle during afterload contractions, to reproduce the conditions similar to those of the working heart. These experiments made it possible to monitor the progressive recruitment of myosin motors from their OFF state along the thick filament and their attachment to the thin filament at different afterloads. A structural model simulation of the intensity and interference–fine structure of the M3 reflection demonstrates that: (i) as the afterload increase from 0.25 to 0.75 Tp, motor attachments spread progressively toward the periphery of the half thick filament, consistent with the near–neighbour cooperative activation of the thin filament by attached motors; (ii) the force–dependence spread of motor attachments throughout the thick filament is larger in afterload contraction than that in the isometric contraction at the same force. This is consistent with the higher power output and rate of energy consumption required during shortening. Under the condition that the progression of attachments is biassed by cooperative thin filament activation, the lead can be explained by the higher rate of motor attachment/detachment during shortening.