Myocardial Titin and Collagen in Cardiac Diastolic Dysfunction: Partners in Crime!
High 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)1-3. Cardiomyocyte stiffness relates to elasticity of the giant cytoskeletal protein titin, which spans the sarcomere from Z-disc to M-line and functions as a bidirectional spring responsible for early diastolic recoil and late diastolic distensibility of cardiomyocytes4. In HFPEF patients and in HFPEF animal models5, the observed rise in cardiomyocyte stiffness was always accompanied by increased deposition of collagen and it therefore remained unclear if impaired elasticity of titin could be solely responsible for high myocardial diastolic stiffness and HFPEF. In this issue of Circulation however, Chung et al. provide compelling evidence for titin being the sole perpetrator in the diastolic left ventricular (LV) dysfunction of a HFPEF mouse model6. They generated mice with a deletion of nine immunoglobulin (Ig)-like domains from the proximal tandem Ig segment of titin's 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 of Chung et al. therefore clearly establishes myocardial titin to be able to sufficiently compromise diastolic LV function to induce HFPEF.
- Received May 17, 2013.
- Accepted May 22, 2013.