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Original Articles

Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy

Functional Implications and Mechanistic Insight

Wissam A. Jaber, MD; Calin Maniu, MD; Judith Krysiak, MSc; Brian P. Shapiro, MD; Donna M. Meyer; Wolfgang A. Linke, PhD and Margaret M. Redfield, MD

From the Mayo Clinic and Foundation, Rochester, Minn (W.A.J., C.M., B.P.S., D.M.M., M.M.R.); and Physiology and Biophysics Unit, University of Muenster, Muenster, Germany (J.K., W.A.L.).

Correspondence to Margaret M. Redfield, MD, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905. E-mail redfield.margaret{at}mayo.edu

Received January 23, 2008; accepted June 19, 2008.

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 an increased compliant isoform (N2BA) expression in human systolic HF. Titin may also modulate stretch-regulated responses such as myocardial natriuretic peptide production.

Methods and Results— We characterized titin isoform expression and extracellular matrix in all 4 cardiac chambers and the left ventricular (LV) epicardium 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 extracellular matrix and cardiomyocyte in tachypacing, myocardial natriuretic peptide production, a molecular marker of stretch-regulated responses, was also assessed. All chambers were dilated in HF, but the extracellular matrix was not increased. HF dogs had markedly lower N2BA in the atria and right ventricle. In failing LVs, 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. Natriuretic peptide concentrations increased markedly in the endocardium in relation to increases in LV wall stress.

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

Key Words: diastole • heart failure • mechanics • remodeling

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CLINICAL PERSPECTIVE

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