{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T06:59:33Z","timestamp":1767855573671,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T00:00:00Z","timestamp":1436832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"CVON","award":["CVON-2011-11 ARENA"],"award-info":[{"award-number":["CVON-2011-11 ARENA"]}]},{"name":"NWO - VIDI","award":["91711344"],"award-info":[{"award-number":["91711344"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin\u2010related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca<jats:sup>2+<\/jats:sup>] are present, such as the failing myocardium.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross\u2010bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross\u2010bridge interactions are dependent on cytosolic [Ca<jats:sup>2+<\/jats:sup>] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca<jats:sup>2+<\/jats:sup> handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca<jats:sup>2+<\/jats:sup>] promotes diastolic cross\u2010bridge formation and force generation and thereby increases diastolic stiffness. ADP dose\u2010dependently increased force production in the absence of Ca<jats:sup>2+<\/jats:sup> in membrane\u2010permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca<jats:sup>2+<\/jats:sup> both in human and rat membrane\u2010permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37\u00b0C in the presence of pathological levels of ADP and diastolic [Ca<jats:sup>2+<\/jats:sup>] revealed a 76\u00a0\u00b1\u00a01% contribution of cross\u2010bridge interaction to total diastolic stress in rat membrane\u2010permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme\u2010isolated intact rat cardiomyocytes impaired diastolic re\u2010lengthening associated with diastolic Ca<jats:sup>2+<\/jats:sup> overload. In isolated Langendorff\u2010perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca<jats:sup>2+<\/jats:sup>]. 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\u2010bridges, even at low Ca<jats:sup>2+<\/jats:sup>, and thereby increase myocardial stiffness.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp270354","type":"journal-article","created":{"date-parts":[[2015,6,19]],"date-time":"2015-06-19T23:55:17Z","timestamp":1434758117000},"page":"3899-3916","source":"Crossref","is-referenced-by-count":72,"title":["Synergistic role of ADP and Ca<sup>2+<\/sup> in diastolic myocardial stiffness"],"prefix":"10.1113","volume":"593","author":[{"given":"Vasco","family":"Sequeira","sequence":"first","affiliation":[{"name":"Department of Physiology, Institute for Cardiovascular Research VU University Medical Centre  Amsterdam The Netherlands"}]},{"given":"Aref","family":"Najafi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute for Cardiovascular Research VU University Medical Centre  Amsterdam The Netherlands"}]},{"given":"Mark","family":"McConnell","sequence":"additional","affiliation":[{"name":"Sarver Heart Center University of Arizona  Tucson AZ USA"}]},{"given":"Ewan D.","family":"Fowler","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Garstang Building University of Leeds  Leeds UK"}]},{"given":"Ilse A. 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M.","family":"Stienen","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute for Cardiovascular Research VU University Medical Centre  Amsterdam The Netherlands"},{"name":"Department of Physics and Astronomy VU University  Amsterdam The Netherlands"}]},{"given":"Jil","family":"Tardiff","sequence":"additional","affiliation":[{"name":"Sarver Heart Center University of Arizona  Tucson AZ USA"}]},{"given":"Diederik W. 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