Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction

Figures

• 

  Fig. 1. Variations of states of regulatory units (RUs) in the C-zone of atrial sarcomeres. A, Atrial sarcomere showing cardiac myosin binding protein C (cMyBP-C) containing C-zones, which also contain (MyBP-HL) myosin binding protein-HL. Z-disks connect thin filaments and link titin to the M-band. B. C-zone regulatory RUs in a relaxed state with a SRX (grey) motor, with a DRX motor (orange), and with a force generating motor (red), inducing thick filament strain. In the thin filament OFF sate, tropomyosin (Tm), which blocks acto-myosin interactions, is immobilized by strong binding of the cardiac troponin I (cTnI) inhibitory peptide and weak binding of cTnI switch peptide to the cTnC regulatory Ca-binding site, strong binding of the cTnI mobile C-terminal domain and cTnT N-terminus to actin-Tm, and cTnT-C-terminal interactions with cTnC. In early systolic tension, strain modifies the states of N-terminal, middle, and C-terminal domains of cMyBP-C that influence the state of actin-Tn-Tm as well as the movement of DRX motors toward the thin filaments that may bind to TnT. The myosin light chain 2 phosphorylation (MLC2a-P) promotes the strain dependent movement of DRX motors toward the thin…

• 

  Fig. 2. Left panel. Left atrial pressure-volume (P-V) loop. Colored lines denoting reservoir (filling of the atrial chamber), conduit (transfer of volume to left ventricle), and ejection phases, in which atrial contractions add a “booster” volume of blood (~15–30%) to the ventricles within ~100 msec. The slope of the dashed line indicates elastance during filling (Adapted from Wright et al. [118]). See Fig. 3 and text for the state of sarcomere RUs in each of the phases. Right panel. Different elements of LA strain measurement by speckle tracking echocardiography shown with time dependent changes in LA volume, pressure, and the EKG. LASr (LA reservoir strain); LASc (LA conduit strain) and LASb (LA booster strain). Note that LV strain is most prominent during the reservoir phase.

• 

  Fig. 3. Atrial regulatory units (RUs) in the C-zone of atrial sarcomeres in the transition of phases of the pressure-volume loop. Reservoir relaxed RUs are shown with Off, SRX motors which continues in the conduit phase transitioning to early systole with some motors in the partially on DRX state and On states. More motors enter into the On state promoting ejection. As sarcomere activation wanes there is a transition to the relaxed state/reservoir phase completing the cycle.

• 

  Fig. 4. Phases of the left atrial pressure-volume (P-V) in a basal state (colored lines) and in exercise (solid black line). The slope of the dashed lines indicates the elastance, which is increased in exercise, indicating its reciprocal, compliance, declines in exercise together with enhanced kinetics of the phases. See text and Fig. 2 legend for further description. Depiction of the P-V loops is based on human data reported by Wright et al. [118]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

• 

  Fig. 5. Scheme illustrating shared downstream effects of adverse sarcomere function in genetic and acquired atrial cardiomyopathy (ACM). Genetic ACM directly causes ACM by inducing a transition from homeostatic sarcomere functional flexibility. to persistent mechanical and mechano-signaling dysfunction leading to adverse mechano-transduction/remodeling. The result is induction of altered atrial stretch/contractility that generate mechanical cues leading to alterations in mechano-electrical coupling and mechano-transduction/transcriptional regulation/remodeling. See Fig. 6 and the text for further discussion.

• 

  Fig. 6. Scheme summarizing roles of adverse sarcomere function inducing altered atrial stretch/contractility that generate mechanical cues leading to alterations in the elements of mechano-electrical coupling and mechano-transduction/transcriptional regulation/remodeling. The response to this pathological process is shown at the bottom of the figure by data redrawn from O'Neill et al. comparing LA strain in control individual and in a patient with ACM [119]. See text for further discussion.