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

Circulation. 2004 Jul 13;110(2):155-62. doi: 10.1161/01.CIR.0000135591.37759.AF. Epub 2004 Jul 6.


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 O2 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cardiomyopathy, Dilated / diagnostic imaging
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / physiopathology
  • Cardiomyopathy, Dilated / surgery
  • Connectin
  • Diastole
  • Elasticity
  • Electrophoresis, Agar Gel
  • Female
  • Gene Expression Regulation
  • Heart Failure / diagnostic imaging
  • Heart Failure / etiology
  • Heart Failure / metabolism
  • Heart Failure / surgery
  • Heart Transplantation
  • Humans
  • Male
  • Middle Aged
  • Molecular Weight
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • Myocardium / chemistry*
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Oxygen Consumption
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Protein Kinases / biosynthesis
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Signal Transduction
  • Ultrasonography
  • Ventricular Function, Left


  • ANKRD1 protein, human
  • ANKRD2 protein, human
  • ANKRD23 protein, human
  • Connectin
  • Muscle Proteins
  • Nuclear Proteins
  • Protein Isoforms
  • RNA, Messenger
  • Repressor Proteins
  • TTN protein, human
  • Protein Kinases