Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness

V. Sequeira Oliveira, A. Najafi, M. McConnell, E.D. Fowler, A.E. Bollen, R.C.I. Wüst, C. dos Remedios, M.H.B. Helmes, E. White, G.J.M. Stienen, J. Tardiff, D.W.D. Kuster, J. van der Velden

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+ handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37 degrees C in the presence of pathological levels of ADP and diastolic [Ca2+] revealed a 76 +/- 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+ overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca2+, and thereby increase myocardial stiffness.
Original languageEnglish
Pages (from-to)3899-3916
JournalJournal of Physiology - London
Volume593
Issue number17
DOIs
Publication statusPublished - 2015

Cite this

Sequeira Oliveira, V., Najafi, A., McConnell, M., Fowler, E. D., Bollen, A. E., Wüst, R. C. I., ... van der Velden, J. (2015). Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness. Journal of Physiology - London, 593(17), 3899-3916. https://doi.org/10.1113/JP270354
Sequeira Oliveira, V. ; Najafi, A. ; McConnell, M. ; Fowler, E.D. ; Bollen, A.E. ; Wüst, R.C.I. ; dos Remedios, C. ; Helmes, M.H.B. ; White, E. ; Stienen, G.J.M. ; Tardiff, J. ; Kuster, D.W.D. ; van der Velden, J. / Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness. In: Journal of Physiology - London. 2015 ; Vol. 593, No. 17. pp. 3899-3916.
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title = "Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness",
abstract = "Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+ handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37 degrees C in the presence of pathological levels of ADP and diastolic [Ca2+] revealed a 76 +/- 1{\%} contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+ overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca2+, and thereby increase myocardial stiffness.",
author = "{Sequeira Oliveira}, V. and A. Najafi and M. McConnell and E.D. Fowler and A.E. Bollen and R.C.I. W{\"u}st and {dos Remedios}, C. and M.H.B. Helmes and E. White and G.J.M. Stienen and J. Tardiff and D.W.D. Kuster and {van der Velden}, J.",
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language = "English",
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Sequeira Oliveira, V, Najafi, A, McConnell, M, Fowler, ED, Bollen, AE, Wüst, RCI, dos Remedios, C, Helmes, MHB, White, E, Stienen, GJM, Tardiff, J, Kuster, DWD & van der Velden, J 2015, 'Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness' Journal of Physiology - London, vol. 593, no. 17, pp. 3899-3916. https://doi.org/10.1113/JP270354

Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness. / Sequeira Oliveira, V.; Najafi, A.; McConnell, M.; Fowler, E.D.; Bollen, A.E.; Wüst, R.C.I.; dos Remedios, C.; Helmes, M.H.B.; White, E.; Stienen, G.J.M.; Tardiff, J.; Kuster, D.W.D.; van der Velden, J.

In: Journal of Physiology - London, Vol. 593, No. 17, 2015, p. 3899-3916.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness

AU - Sequeira Oliveira, V.

AU - Najafi, A.

AU - McConnell, M.

AU - Fowler, E.D.

AU - Bollen, A.E.

AU - Wüst, R.C.I.

AU - dos Remedios, C.

AU - Helmes, M.H.B.

AU - White, E.

AU - Stienen, G.J.M.

AU - Tardiff, J.

AU - Kuster, D.W.D.

AU - van der Velden, J.

PY - 2015

Y1 - 2015

N2 - Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+ handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37 degrees C in the presence of pathological levels of ADP and diastolic [Ca2+] revealed a 76 +/- 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+ overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca2+, and thereby increase myocardial stiffness.

AB - Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+ handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37 degrees C in the presence of pathological levels of ADP and diastolic [Ca2+] revealed a 76 +/- 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+ overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca2+, and thereby increase myocardial stiffness.

U2 - 10.1113/JP270354

DO - 10.1113/JP270354

M3 - Article

VL - 593

SP - 3899

EP - 3916

JO - Journal of Physiology - London

JF - Journal of Physiology - London

SN - 0022-3751

IS - 17

ER -

Sequeira Oliveira V, Najafi A, McConnell M, Fowler ED, Bollen AE, Wüst RCI et al. Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness. Journal of Physiology - London. 2015;593(17):3899-3916. https://doi.org/10.1113/JP270354