Published Online
on June 25, 2008

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Original Article

Titin isoforms, extracellular matrix, and global chamber remodeling in experimental dilated cardiomyopathy: functional implications and mechanistic insights

Wissam A. Jaber¹; Calin Maniu¹; Judith Krysiak²; Brian P. Shapiro¹; Donna M. Meyer¹; Wolfgang A. Linke² and Margaret M. Redfield^1,3

¹ Mayo Clinic and Foundation, Rochester, MN;
² Physiology and Biophysics Unit, University of Muenster, Muenster, Germany

³ E-mail: redfield.margaret{at}mayo.edu

Background—Altered titin isoforms may modify cardiac function in heart failure (HF) but the nature of isoform switches and associated functional implications are not well defined. Limited studies have reported increased compliant isoform (N2BA) expression in human systolic HF. Titin may also modulate stretch-regulated responses such as myocardial natriuretic peptide (NP) production.

Methods and Results—We characterized titin isoform expression and extracellular matrix (ECM) in all four cardiac chambers and the LV epi- and endocardium in normal dogs (n=6) and those with HF (n=6) due to tachypacing and characterized functional implications at the LV myofiber and chamber level. Recognizing the potential for uncoupling of the ECM and cardiomyocyte in tachypacing, we also assessed myocardial NP production, a molecular marker of stretchregulated responses. All chambers were dilated in HF but the ECM was not increased. HF dogs had markedly lower N2BA in atria and right ventricle (RV). In failing LV, N2BA was decreased only in the epicardium where myofiber passive stiffness was increased. However, LV chamber mechanics were driven by the marked LV dilatation with no increase in LV diastolic stiffness. NP levels increased dramatically in the endocardium in relation to increases in LV wall stress.

Conclusion—Tachypacing HF is characterized by decreases in compliant titin isoform expression in the atria, RV and LV epicardium. However, LV chamber mechanics are principally determined by geometric and ECM changes rather than titin-based myofiber stiffness in this model. Stretch-regulated myocardial responses (NP production) appeared intact suggesting that the mechanotransduction role of titin was not impaired in HF.

Key Words: diastole • heart failure • mechanics • remodeling