Ahmad T, Miller PE, McCullough M, Desai NR, Riello R, Psotka M, Böhm M, Allen LA, Teerlink JR, Rosano GMC, Lindenfeld J (2019) Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials. Eur J Heart Fail 21(9):1064–1078. https://doi.org/10.1002/ejhf.1557

Article  PubMed  Google Scholar 

Awinda PO, Bishaw Y, Watanabe M, Guglin MA, Campbell KS, Tanner BCW (2020) Effects of mavacamten on Ca2+ sensitivity of contraction as sarcomere length varied in human myocardium. Br J Pharmacol 177(24):5609–5621. https://doi.org/10.1111/bph.15271

Article  CAS  PubMed  PubMed Central  Google Scholar 

Awinda PO, Watanabe M, Bishaw Y, Huckabee AM, Agonias KB, Kazmierczak K, Szczesna-Cordary D, Tanner BCW (2021) Mavacamten decreases maximal force and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 320(2):H881–H890. https://doi.org/10.1152/ajpheart.00345.2020

Article  CAS  PubMed  Google Scholar 

Bellumkonda L (2021) Omecamtiv mecarbil in systolic heart failure. N Engl J Med 384(20):1967. https://doi.org/10.1056/NEJMc2102893

Article  PubMed  Google Scholar 

Bonapace S, Molon G (2021) Omecamtiv mecarbil in systolic heart failure. N Engl J Med 384(20):1967. https://doi.org/10.1056/NEJMc2102893

Article  PubMed  Google Scholar 

Boknik P, Drzewiecki K, Eskandar J, Gergs U, Grote-Wessels S, Fabritz L, Kirchhof P, Müller FU, Stümpel F, Schmitz W, Zimmermann N, Kirchhefer U, Neumann J (2018) Phenotyping of mice with heart specific overexpression of A2A-adenosine receptors: evidence for cardioprotective effects of A2A-adenosine receptors. Front Pharmacol 22(9):13. https://doi.org/10.3389/fphar.2018.00013

Article  CAS  Google Scholar 

Butler L, Cros C, Oldman KL, Harmer AR, Pointon A, Pollard CE, Abi-Gerges N (2015) Enhanced characterization of contractility in cardiomyocytes during early drug safety assessment. Toxicol Sci 145(2):396–406. https://doi.org/10.1093/toxsci/kfv062 (Epub 2015 Mar 29)

Article  CAS  PubMed  Google Scholar 

Dashwood A, Cheesman E, Wong YW, Haqqani H, Beard N, Hay K, Spratt M, Chan W, Molenaar P (2021) Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (-)-noradrenaline. Pharmacol Res Perspect 9(3):e00760. https://doi.org/10.1002/prp2.760

Article  CAS  PubMed  PubMed Central  Google Scholar 

Endoh M. Does levosimendan act as a Ca2+ sensitizer or PDE3 inhibitor?: Commentary on Orstavik et al., Br J Pharmacol 171: 5169–5181. Br J Pharmacol. 2015 Sep;172(18):4594–4596. https://doi.org/10.1111/bph.12649.

Fülöp GÁ, Oláh A, Csipo T, Kovács Á, Pórszász R, Veress R, Horváth B, Nagy L, Bódi B, Fagyas M, Helgadottir SL, Bánhegyi V, Juhász B, Bombicz M, Priksz D, Nanasi P Jr, Merkely B, Édes I, Csanádi Z, Papp Z, Radovits T, Tóth A (2021) Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans. Basic Res Cardiol 116(1):24. https://doi.org/10.1007/s00395-021-00866-8

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gao BX, Sutherland W, Vargas HM, Qu Y (2020) Effects of omecamtiv mecarbil on calcium-transients and contractility in a translational canine myocyte model. Pharmacol Res Perspect 8(5):e00656. https://doi.org/10.1002/prp2.656

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gergs U, Bernhardt G, Buchwalow IB, Edler H, Fröba J, Keller M, Kirchhefer U, Köhler F, Mißlinger N, Wache H, Neumann J. Initial characterization of transgenic mice overexpressing human histamine H2 receptors. J Pharmacol Exp Ther. 2019a Apr;369(1):129-141. https://doi.org/10.1124/jpet.118.255711.

Gergs U, Böckler A, Ebelt H, Hauptmann S, Keller N, Otto V, Pönicke K, Schmitz W, Neumann J. Human 5-HT4receptor stimulation in atria of transgenic mice. Naunyn Schmiedebergs Arch Pharmacol. 2013 May;386(5):357-67. https://doi.org/10.1007/s00210-013-0831-x

Gergs U, Fahrion CM, Bock P, Fischer M, Wache H, Hauptmann S, Schmitz W, Neumann J (2017) Evidence for a functional role of calsequestrin 2 in mouse atrium. Acta Physiol (oxf) 219(3):669–682. https://doi.org/10.1111/apha.12766

Article  CAS  Google Scholar 

Gergs U, Neumann J, Simm A, Silber RE, Remmers FO, Läer S (2009) Phosphorylation of phospholamban and troponin I through 5-HT4 receptors in the isolated human atrium. Naunyn Schmiedebergs Arch Pharmacol 379(4):349–359. https://doi.org/10.1007/s00210-008-0371-y

Article  CAS  PubMed  Google Scholar 

Gergs U, Trapp T, Bushnaq H, Simm A, Silber RE, Neumann J. Age-dependent protein expression of serine/threonine phosphatases and their inhibitors in the human cardiac atrium. Adv Med. 2019b Jan 2;2019b:2675972. https://doi.org/10.1155/2019/2675972.

Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, Henze M, Kawas R, Oslob JD, Rodriguez HM, Song Y, Wan W, Leinwand LA, Spudich JA, McDowell RS, Seidman JG, Seidman CE (2016) A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351(6273):617–621. https://doi.org/10.1126/science.aad3456

Article  CAS  PubMed  PubMed Central  Google Scholar 

Komamura K (2021) Omecamtiv mecarbil in systolic heart failure. N Engl J Med 384(20):1966–1967. https://doi.org/10.1056/NEJMc2102893

Article  PubMed  Google Scholar 

Lookin O, Kuznetsov D, Protsenko Y (2022) Omecamtiv mecarbil attenuates length-tension relationship in healthy rat myocardium and preserves it in monocrotaline-induced pulmonary heart failure. Clin Exp Pharmacol Physiol 49(1):84–93. https://doi.org/10.1111/1440-1681.13584

Article  CAS  PubMed  Google Scholar 

Maack C, Eschenhagen T, Hamdani N, Heinzel FR, Lyon AR, Manstein DJ, Metzger J, Papp Z, Tocchetti CG, Yilmaz MB, Anker SD, Balligand JL, Bauersachs J, Brutsaert D, Carrier L, Chlopicki S, Cleland JG, de Boer RA, Dietl A, Fischmeister R, Harjola VP, Heymans S, Hilfiker-Kleiner D, Holzmeister J, de Keulenaer G, Limongelli G, Linke WA, Lund LH, Masip J, Metra M, Mueller C, Pieske B, Ponikowski P, Ristić A, Ruschitzka F, Seferović PM, Skouri H, Zimmermann WH, Mebazaa A (2019) Treatments targeting inotropy. Eur Heart J 40(44):3626–3644. https://doi.org/10.1093/eurheartj/ehy600

Article  CAS  PubMed  Google Scholar 

Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W, Katori T, Kass DA, Shen YT, Vatner SF, Morgans DJ (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331(6023):1439–1443. https://doi.org/10.1126/science.1200113

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mamidi R, Gresham KS, Li A, dos Remedios CG, Stelzer JE (2015) Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C. J Mol Cell Cardiol 85:262–272. https://doi.org/10.1016/j.yjmcc.2015.06.011

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mamidi R, Holmes JB, Doh CY, Dominic KL, Madugula N, Stelzer JE (2021) cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation. J Gen Physiol 153(7):e202012816. https://doi.org/10.1085/jgp.202012816

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mamidi R, Li J, Gresham KS, Verma S, Doh CY, Li A, Lal S, Dos Remedios CG, Stelzer JE (2017) Dose-dependent effects of the myosin activator omecamtiv mecarbil on cross-bridge behavior and force generation in failing human myocardium. Circ Heart Fail 10(10):e004257. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004257

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nagy L, Kovács Á, Bódi B, Pásztor ET, Fülöp GÁ, Tóth A, Édes I, Papp Z (2015) The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat. Br J Pharmacol 172(18):4506–4518. https://doi.org/10.1111/bph.13235

Article  CAS  PubMed  PubMed Central  Google Scholar 

Neumann J, Boknik P, Kirchhefer U, Gergs U (2021a) The role of PP5 and PP2C in cardiac health and disease. Cell Signal 85:110035. https://doi.org/10.1016/j.cellsig.2021.110035

Article  CAS  PubMed  Google Scholar 

Neumann J, Boknik P, Matherne GP, Lankford A, Schmitz W (2003) Pertussis toxin sensitive and insensitive effects of adenosine and carbachol in murine atria overexpressing A(1)-adenosine receptors. Br J Pharmacol 138(1):209–217. https://doi.org/10.1038/sj.bjp.0705012

Article  CAS  PubMed  PubMed Central  Google Scholar 

Neumann J, Eschenhagen T, Grupp IL, Haverich A, Herzig JW, Hirt S, Kalmár P, Schmitz W, Scholz H, Stein B, Wenzlaff H, Zimmermann N (1996) Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium. J Pharmacol Exp Ther 277(3):1579–1585

CAS  PubMed  Google Scholar 

Neumann J, Grobe JM, Weisgut J, Schwelberger HG, Fogel WA, Marušáková M, Wache H, Bähre H, Buchwalow IB, Dhein S, Hofmann B, Kirchhefer U, Gergs U (2021b) Histamine can be formed and degraded in the human and mouse heart. Front Pharmacol 11(12):582916. https://doi.org/10.3389/fphar.2021.582916

Article  CAS  Google Scholar 

Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759–769. https://doi.org/10.1016/S0140-6736(20)31792-X.

Orstavik O, Ata SH, Riise J, Dahl CP, Andersen GØ, Levy FO, Skomedal T, Osnes JB, Qvigstad E (2014) Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart. Br J Pharmacol 171(23):5169–5181. https://doi.org/10.1111/bph.12647

Article  CAS  PubMed  PubMed Central  Google Scholar 

Solaro RJ, Rüegg JC (1982) Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent. Circ Res 51(3):290–294. https://doi.org/10.1161/01.res.51.3.290

Article  CAS  PubMed  Google Scholar 

Shen YT, Malik FI, Zhao X, Depre C, Dhar SK, Abarzúa P, Morgans DJ, Vatner SF (2010) Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure. Circ Heart Fail 3(4):522–527. https://doi.org/10.1161/CIRCHEARTFAILURE.109.930321

Article  PubMed  Google Scholar 

Stern JA, Markova S, Ueda Y, Kim JB, Pascoe PJ, Evanchik MJ, Green EM, Harris SP (2016) A small molecule inhibitor of sarcomere contractility acutely relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy. PLoS ONE 11(12):e0168407. https://doi.org/10.1371/journal.pone.0168407

Article  CAS  PubMed  PubMed Central  Google Scholar 

Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Adams KF, Anand I, Arias-Mendoza A, Biering-Sørensen T, Böhm M, Bonderman D, Cleland JGF, Corbalan R, Crespo-Leiro MG, Dahlström U, Echeverria Correa LE, Fang JC, Filippatos G, Fonseca C, Goncalvesova E, Goudev AR, Howlett JG, Lanfear DE, Lund M, Macdonald P, Mareev V, Momomura SI, O'Meara E, Parkhomenko A, Ponikowski P, Ramires FJA, Serpytis P, Sliwa K, Spinar J, Suter TM, Tomcsanyi J, Vandekerckhove H, Vinereanu D, Voors AA, Yilmaz MB, Zannad F, Sharpsten L, Legg JC, Abbasi SA, Varin C, Malik FI, Kurtz CE; GALACTIC-HF Investigators. Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials. Eur J Heart Fail. 2020 Nov;22(11):2160–2171. https://doi.org/10.1002/ejhf.2015. Epub 2020 Oct 27. Erratum in: Eur J Heart Fail. 2021 Dec 20