Myocardial titin and collagen in cardiac diastolic dysfunction: partners in crime.

H igh myocardial diastolic stiffness has usually been attributed to excessive myocardial collagen deposition. Over the last decennium, stiff cardiomyocytes were also identified as important contributors to high myocardial diastolic stiffness , especially in heart failure (HF) with preserved ejection fraction (HFPEF). Cardiomyocyte stiffness relates to elasticity of the giant cytoskeletal protein titin, which spans the sarcomere from the Z disk to the M line and functions as a bidi-rectional spring responsible for early diastolic recoil and late diastolic distensibility of cardiomyocytes. 4 In HFPEF patients and in HFPEF animal models, 5 the observed increase in car-diomyocyte stiffness was always accompanied by increased deposition of collagen; therefore, it remained unclear whether impaired elasticity of titin could be solely responsible for high myocardial diastolic stiffness and HFPEF. In this issue of Circulation, however, Chung et al 6 provide compelling evidence for titin being the sole perpetrator in the diastolic left ventricular (LV) dysfunction of an HFPEF mouse model. They generated mice with a deletion of nine immunoglobu-lin (Ig)-like domains from the proximal tandem Ig segment of the titin spring region (IG KO). This deletion extended the remaining titin spring segments and increased overall titin stiffness. Despite unaltered myocardial collagen content or composition, the IG KO mice developed HFPEF, evident from a reduced exercise tolerance, an enlarged left atrium, and a steeper LV end-diastolic pressure-volume relationship. The elegant study by Chung et al therefore clearly establishes myocardial titin to be able to sufficiently compromise dia-stolic LV function to induce HFPEF. Titin, with a molecular mass of up to 3800 kDa, spans half-sarcomeres from the Z disk to the M band and contains a molecular spring segment, the I-band region, that supports early diastolic recoil and late diastolic resistance to stretch (Figure 1A). The I-band region has a complex structure comprising 3 extensible segments: tandem Ig-like domain regions with a proximal and a distal segment, a proline-glutamate-valine-lysine segment, and a unique sequence that is part of the N2B element (N2-Bus) and expressed only in cardiac titin. In the study by Chung et al, 6 9 Ig-like domains from the proximal tandem Ig segment were deleted. This shortened the overall length of titin and increased titin stiffness. Changes in titin stiffness have also been reported after isoform shifts or posttranslational modifications like phosphorylation or oxidation. The 2 main titin isoforms expressed in human (and other mammalian) hearts are N2B, which is the shorter and …