Schematic illustrating the postulated mechanism of intramyofibril sarcomeric asynchrony in the in vivo beating heart. (A) Changes in the lengths of five sequentially connected sarcomeres along a myofibril during a cardiac cycle under normal physiological conditions (e.g., ΔLVP 96.4 mm Hg in the present study). Average SL during diastole is ∼2.05 µm (compare Fig. S16 and Kobirumaki-Shimozawa et al., 2016). Upon systole, sarcomeres at nos. 2 and 5 exhibit greater shortening than those at nos. 1 and 3 due to their longer SL (via length-dependent activation, see text; active force shown by pink closed arrows). Concomitantly, the no. 4 sarcomere, which is short during diastole, is lengthened by its neighbors, producing inward-oriented, titin-based passive force (blue closed arrows). Upon diastole, shortened sarcomeres (nos. 1, 2, 3, and 5) lengthen due, at least in part, to outward-oriented, titin-based restoring force (blue open arrows in sarcomeres at nos. 2 and 5), but the one at no. 4 shortens due to inward-oriented, titin-based passive force (produced in systole), causing asynchrony. (B) Sarcomere interactions during conditions of depressed contractility (ΔLVP <10 mm Hg; i.e., ΔLVP 7.2 or 4.7 mm Hg in the present study). Average SL is greater than ∼2.25–2.30 µm during diastole (compare Fig. S16). Sarcomeres with longer diastolic lengths (nos. 2 and 4) exhibit greater length-dependent activation (active force shown by pink closed arrows) and shorten upon systole at the expense of shorter sarcomeres, which are lengthened (nos. 1, 3, and 5). Thus, titin-based passive force (blue closed arrows) markedly increases in sarcomeres at nos. 1, 3, and 5, causing them to abruptly shorten upon diastole, stretching their neighbors (nos. 2 and 4). Consequently, sarcomeres move in marked asynchrony under depressed conditions.