Cytoskeletal remodeling of desmin is a more accurate measure of cardiac dysfunction than fibrosis or myocyte hypertrophy

• Published in: Life sciences (1973) 2008-12, Vol.83 (23), p.786-794
• Main Authors: Monreal, Gretel, Nicholson, Lisa M., Han, Bing, Joshi, Mandar S., Phillips, Alistair B., Wold, Loren E., Bauer, John Anthony, Gerhardt, Mark A.
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - chemistry; Biomarkers - metabolism; Blotting, Western; Cell Size; Cytoskeleton; Cytoskeleton - metabolism; Desmin; Desmin - biosynthesis; Desmin - chemistry; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Fibrosis; Heart failure; Heart Failure - diagnosis; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Heart Function Tests; Immunohistochemistry; Myocytes; Myocytes, Cardiac - pathology; Protein Conformation; Remodeling; Sheep; Structure/function; Ventricular Dysfunction, Left - physiopathology; Ventricular Remodeling
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2008.09.026

Fibrosis and myocyte hypertrophy are classical remodeling parameters in heart failure (HF); however, an intriguing possibility is that myocytes undergo intracellular remodeling which decrease compliance, contributing to diastolic dysfunction. The most obvious candidates are cytoskeletal proteins. The cytoskeletal protein desmin reinforces the sarcomeres, enabling force generation. As a contributor to sarcomere performance, desmin may represent a better appraisal of dysfunction than fibrosis or myocyte hypertrophy. HF was induced in sheep via coronary microembolization. Echocardiography was performed at baseline, 4-, and 12-months in HF. Desmin, fibrosis, and myocyte hypertrophy from infarcted LV posterior and noninfarcted LV anterior walls were measured using Western blot, immunohistochemistry, and digital image analysis. Multivariate regression analysis was performed, providing structure/function mechanisms. ⁎ p < 0.05. EF decreased from 55% to 24%⁎. LV end-diastolic area (LVEDA) increased 123%⁎ at month-12. Fibrosis increased only in posterior LV whereas myocyte hypertrophy increased in both LV posterior and LV anterior regions but only at month-12. Desmin content progressively increased 121%⁎ at month-4 and 182%⁎ at month-12 in both LV posterior and anterior walls. Multivariate linear regression (beta coefficient standardization) demonstrated that desmin was a much better predictor of EF ( β = − 0.38⁎) and LVEDA ( β = 0.58⁎) than fibrosis or myocyte hypertrophy. Desmin, fibrosis, and myocyte hypertrophy are temporally and spatially heterogeneous in HF. Desmin content more accurately correlated with remodeling than fibrosis or myocyte hypertrophy, suggesting that intra-myocyte responses, likely related to mechanical stretch, are better predictors of LV function and may represent novel targets for therapeutic intervention.