Heart Failure Extensible Behavior of Titin in the Miniswine Left Ventricle

Background—The sarcomeric protein titin is a molecular spring responsible for passive tension and restoring forces of cardiomyocytes. Extension of titin as a function of sarcomere length (SL) has been studied in rodents, which predominantly express the smaller, stiffer N2B titin isoform. Large mammals coexpress roughly equal proportions of N2B and N2BA titin, the larger, more compliant isoform. We hypothesized that extension of titin in relation to SL differs in large mammals and that this difference is functionally important. Methods and Results—We characterized the filling pressure–SL relation in diastolic-arrested miniswine left ventricles. SL was 2.15 to 2.25 m at a filling pressure of 0 mm Hg and reached a maximum of 2.50 m with overfilling. In the normal filling pressure range, SL ranged from 2.32 to 2.40 m. We assessed titin extension as a function of SL using immunoelectron microscopy, which allowed delineation of the behavior of specific spring segments. The major isoform difference was that the N2B-Us segment extended 4-fold more as a function of SL in N2B compared with N2BA titin. Using this segment, we estimated sarcomeric force development with a worm-like chain model and found that N2B develops markedly greater force than N2BA titin. The resulting force with coexpression of N2B and N2BA titin is intermediate. Conclusions—In light of murine studies showing that operating SLs are shorter than in miniswine, our results indicate that coexpression of the 2 titin isoforms in large mammals allows longer SLs without the development of excessive diastolic tension. (Circulation. 2010;121:768-774.)