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Cited by 33Cardiomyopathy and Myosin StudiesCardiac Fibrosis and RemodelingCardiovascular Function and Risk Factors

Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy: Functional Implications and Mechanistic Insight

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Jaber, Wissam A., Maniu, Calin, Krysiak, Judith, Shapiro, Brian P., Meyer, Donna M., Linke, Wolfgang A., Redfield, Margaret M.·2008·Circulation: Heart Failure
DOI 10.1161/circheartfailure.108.768465PMC PMC2779561
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Abstract

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.

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Crossref · 10.1161/circheartfailure.108.768465

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  • Both compliant N2BA and stiff N2B titin isoforms are expressed in canines (N2BA:N2B ratio ~0.6-1) and humans (ratio ~0.4-1.2).

    “Both compliant N2BA and stiff N2B isoforms are expressed in canines (N2BA:N2B ratio of ~ 0.6–1) and humans (N2BA:N2B ratio of ~0.4–1.2) (Bell, et al., 2000; Cazorla, et al., 2000; Jaber, et al., 2008; Makarenko, et al., 2004; Nagueh, et al., 2004).”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Jaber, et al., 2008

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Authors
Jaber, W. A., Maniu, C., Krysiak, J., Shapiro, B. P., Meyer, D. M., Linke, W. A., & Redfield, M. M.
Affiliations
Mayo Clinic (US)
ORCID
Venue
Circulation: Heart Failure
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2008-09
Volume
1
Issue
3
Pages
192-199
ISSN
  • 1941-3289 (ISSN-L)
  • 1941-3297
DOI
10.1161/circheartfailure.108.768465
PMC
PMC2779561
OpenAlex
W2574577483
Cited by
33
References
40
Citations by year
2025: 2 · 2023: 1 · 2022: 1 · 2020: 1 · 2018: 1 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 6
FWCI
3.15
Type
journal article
Language
en
Open access
Locations
  • Circulation Heart Failure (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (HL63281, R01HL063281)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
titin isoforms, dilated cardiomyopathy, heart failure, extracellular matrix, mechanotransduction, left ventricular diastolic stiffness, left ventricular wall stress
MeSH terms
Animals, Cardiomyopathy, Dilated, Disease Models, Animal, Dogs, Echocardiography, Membrane Proteins, Muscle Proteins, Myocardium, Protein Kinases, Extracellular Matrix Proteins, Protein Isoforms, Ventricular Remodeling, Connectin

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