Published online before print September 2, 2004, doi: 10.1161/01.RES.0000143901.37063.2f
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Submitted on July 30, 2003
Revised on August 17, 2004
Accepted on August 23, 2004
Passive Stiffness Changes Due To Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts
I. Makarenko ;
From the Physiology and Biophysics Laboratory (I.M., W.A.L.), University of Muenster, Muenster, Germany; Institute of Physiology (C.A.O., M.C.L., C.N., M.K., W.A.L.), University of Heidelberg, Heidelberg, Germany; Boston University Medical Center (J.K.G.), Boston, Mass; and the Cardiovascular Research Center (F.d.M., R.J.H.), Massachusetts General Hospital, Boston, Mass.
* To whom correspondence should be addressed. E-mail: wlinke{at}uni-muenster.de.
In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. In this study, we analyzed titin expression in left ventricles of 19 control human donors and 9 severely diseased (nonischemic) dilated cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, and quantitative RT-PCR. Both human-heart groups coexpressed smaller (
3 MDa) N2B-isoform and longer (3.20 to 3.35 MDa) N2BA-isoforms, but the average N2BA:N2B-protein ratio was shifted from 30:70 in controls to 42:58 in DCM hearts, due mainly to increased expression of N2BA-isoforms >3.30 MDa. Titin per unit tissue was decreased in some DCM hearts. The titin-binding protein obscurin also underwent isoform-shifting in DCM. Quantitative RT-PCR revealed a 47% reduction in total-titin mRNA levels in DCM compared with control hearts, but no differences in N2B, all-N2BA, and individual-N2BA transcripts. The reduction in total-titin transcripts followed from a decreased area occupied by myocytes and increased connective tissue in DCM hearts, as detected by histological analysis. Force measurements on isolated cardiomyofibrils showed that titin-based passive tension was reduced on average by 25% to 30% in DCM, a reduction readily predictable with a model of wormlike-chain titin elasticity. Passive-tension measurements on human-heart fiber bundles, before and after titin proteolysis, revealed a much-reduced relative contribution of titin to total passive stiffness in DCM. Results suggested that the titin-isoform shift in DCM depresses the proportion of titin-based stiffness by 10%. We conclude that a lower-than-normal proportion of titin-based stiffness in end-stage failing hearts results partly from loss of titin and increased fibrosis, partly from titin-isoform shift. The titin-isoform shift may be beneficial for myocardial diastolic function, but could impair the contractile performance in systole.
Key words: connectin • heart-failure • diastole/dilated-cardiomyopathy • passive-tension
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