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Cited by 486Cardiomyopathy and Myosin StudiesCardiovascular Function and Risk FactorsCardiac Fibrosis and Remodeling

Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy

Nagueh, Sherif F., Shah, Gopi, Wu, Yiming, Torre-Amione, Guillermo, King, Nicholas M.P., Lahmers, Sunshine, Witt, Christian C., Becker, Katy +2 more·2004·Circulation
DOI 10.1161/01.cir.0000135591.37759.af
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Abstract

Background— The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function. Methods and Results— SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly ( P <0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (n=7), intermediate in those with pseudonormal filling (n=6), and lowest in the group with restrictive filling (n=7). Mechanical measurements on LV muscle strips dissected from these hearts (n=8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O 2 consumption (n=10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients). Conclusions— Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression.

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Crossref · 10.1161/01.cir.0000135591.37759.af

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  • Human ventricles express both compliant N2BA and stiff N2B titin isoforms with a relative N2BA:N2B ratio of ~0.4-1.2.

    “Human ventricles express both compliant N2BA and stiff N2B titin isoforms with a relative N2BA:N2B ratio of ~0.4–1.2”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Nagueh, et al., 2004

  • One report concluded that swine not only expressed more N2BA than humans, but the N2BA:N2B ratio was more similar to dilated human cardiomyopathy, a condition where N2BA expression is upregulated.

    “one of these reports (Chung, et al., 2011) concluded that not only swine expressed more N2BA than humans, but additionally the N2BA:N2B ratio of this animal model was more similar to dilated human cardiomyopathy, a condition were N2BA expression is upregulated (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 Nagueh, et al., 2004

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Authors
Nagueh, S. F., Shah, G., Wu, Y., Torre-Amione, G., King, N. M. P., Lahmers, S., Witt, C. C., Becker, K., Labeit, S., & Granzier, H. L.
Affiliations
  • Baylor College of Medicine (US)
  • From the Section of Cardiology (S.F.N., G.S., G.T.-A., K.B.), Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Veterinary and Comparative Anatomy (Y.W., N.M.P.K., S. Lahmers, C.C.W., S. Labeit, H.L.G.), Pharmacology and Physiology, Washington State University, Pullman, Wash; and Institut für Anästhesiologie und Operative Intensivmedizin (C.C.W., S. Labeit), Universitätsklinikum Mannheim, Mannheim, Germany.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2004-07-13
Volume
110
Issue
2
Pages
155-162
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/01.cir.0000135591.37759.af
OpenAlex
W2168324813
Cited by
486
References
27
Citations by year
2026: 12 · 2025: 19 · 2024: 17 · 2023: 23 · 2022: 27 · 2021: 25 · 2020: 21 · 2019: 17 · 2018: 36 · 2017: 33 · 2016: 29 · 2015: 25 · 2014: 23 · 2013: 25 · 2012: 26
FWCI
9.17
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL061497, HL-62881, R01HL062881, HL 61497)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
titin, dilated cardiomyopathy, heart failure, myocardial stiffness, left ventricular function, titin isoforms, diastolic filling, ankyrin repeat proteins, myocardial relaxation, exercise tolerance
MeSH terms
Adult, Aged, Cardiomyopathy, Dilated, Diastole, Elasticity, Electrophoresis, Agar Gel, Female, Gene Expression Regulation, Heart Failure, Humans, Male, Middle Aged, Molecular Weight, Muscle Proteins, Myocardium, Nuclear Proteins, Oxygen Consumption, Protein Kinases, Repressor Proteins, RNA, Messenger, Ultrasonography, Signal Transduction, Heart Transplantation, Ventricular Function, Left, Protein Isoforms, Connectin

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