Myocardial length-force relationship in end stage dilated cardiomyopathy and normal human myocardium: analysis of intact and skinned left ventricular trabeculae obtained during 11 heart transplantations

Vahl, CF; Timek, Tomasz A.; Bonz, Andreas; N, Kochsiek; Fuchs, Herbert E.; Schäffer, Leo; Rosenberg, Mark; Dillmann, Roland; Hagl, S.

doi:10.1007/bf00788521

Cited by 33 publications

(32 citation statements)

References 25 publications

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“…2 Human DCM hearts were also found to have higher-than-normal passive stiffness. 31 In the present work, the relationship between titin-derived passive stiffness and non-titin-based stiffness (ECM, intermediate filaments) was found to be altered in nonischemic DCM HHs: the relative contribution of titin to total passive stiffness was greatly reduced compared with that in control-donor HHs. Two recent studies suggested that failing human 19 and dog 21 hearts adjust their passive stiffness by titin-isoform switching.…”

mentioning

confidence: 83%

Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts

Makarenko

Opitz²,

Leake³

et al. 2004

Circulation Research

296

251

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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 (approximately 3 MDa) N2B-isoform and longer (3.20 to 3.35 MDa) N2BA-isoforms, but the average N2BA:N2B-protein ratio was shifted from approximately 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 sarcomeric 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 approximately 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.

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confidence: 83%

Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts

Makarenko

Opitz²,

Leake³

et al. 2004

Circulation Research

296

251

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“…In human heart failure, the Frank-Starling mechanism and LDA have been reported to be normal [56], reduced [94,96,13], or lost based on the weak increase in Ca 2+ sensitivity of myofibrils after stretch [80]. Alterations of cardiac contractility, as a consequence of remodeling of the whole heart, have been described also in a rat model after myocardial infarction (MI) [6].…”

Section: Consequences Of Alterations In Lda Heterogeneity On Cardiac mentioning

confidence: 99%

Regional variation in myofilament length-dependent activation

Cazorla

Lacampagne

2011

Pflugers Arch - Eur J Physiol

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The Frank-Starling law is an important regulatory mechanism of the heart that links the end-diastolic volume with the systolic ejection fraction. This beat-to-beat regulation of the heart, underlined at the cellular level by higher myofilament calcium sensitivity at longer sarcomere length, is known as length-dependent activation or stretch sensitization of activation. However, the heart is structurally and functionally heterogeneous and asymmetrical. Specifically, contractile properties are not uniform within the left ventricle partly due to transmural differences in action potential waveforms and calcium homeostasis. The present review will focus on the role of the contractile machinery in the transmural contractile heterogeneity and its adaptation to changes in muscle strain. The expression of different myosin isoforms, the level of titin-based passive tension, and thin and thick sarcomeric regulatory proteins are considered to explain the regional cellular contractile properties. Finally, the importance of transmural heterogeneity of length-dependent activation and the consequences of its modification on the heart mechanics are discussed. Despite extensive research since the characterization of the Frank-Starling law, the molecular mechanisms by which strain information is transduced to the contractile machinery have not been fully determined yet.

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“…As we mentioned in the Introduction, experimental data on the mechanical activity in cellular or multicellular human myocardial preparations are very limited. In few experimental works performed in the nineties of the 20th century, contraction of papillary muscle and trabeculae from the ventricles of the human hearts were studied in isometric mode [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] and only two papers report on contractions under mechanical loads [47,55]. Below, in our simulations we compare, wherever possible, the data of numerical experiments with the results from the listed works.…”

Section: Figmentioning

confidence: 99%

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

Balakina-Vikulova

Panfilov

Solovyova

et al. 2019

Preprint

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Experiments on animal hearts (rat, rabbit, guinea pig, etc.) have demonstrated that mechano-calcium feedback (MCF) and mechano-electric feedback (MEF) are very important for myocardial self-regulation because they adjust the cardiomyocyte contractile function to various mechanical loads and to mechanical interactions between heterogeneous myocardial segments in the ventricle walls. In in vitro experiments on these animals, MCF and MEF manifested themselves in several basic classical phenomena (e.g. load dependence, length dependence of isometric twitches, etc.), and in the respective responses of calcium transients and action potentials. However, it is extremely difficult to study simultaneously the electrical, calcium, and mechanical activities of the human heart muscle in vitro. Mathematical modeling is a useful tool for exploring these phenomena. We have developed a novel model to describe electromechanical coupling and mechano-electric feedbacks in the human cardiomyocyte. It combines the ‘ten Tusscher – Panfilov’ electrophysiological model of the human cardiomyocyte with our module of myocardium mechanical activity taken from the ‘Ekaterinburg – Oxford’ model and adjusted to human data. Using it, we simulated isometric and afterloaded twitches and effects of MCF and MEF on excitation-contraction coupling. MCF and MEF were found to affect significantly the duration of the calcium transient and action potential in the human cardiomyocyte model in response to both smaller afterloads as compared to bigger ones and various mechanical interventions applied during isometric and afterloaded twitches.

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Myocardial length-force relationship in end stage dilated cardiomyopathy and normal human myocardium: analysis of intact and skinned left ventricular trabeculae obtained during 11 heart transplantations

Cited by 33 publications

References 25 publications

Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts

Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts

Regional variation in myofilament length-dependent activation

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

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