{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:10:17Z","timestamp":1781669417256,"version":"3.54.5"},"reference-count":98,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["MOHW104-TDU-B-211-113-003, MOHW106-TDU-B-211-113001"],"award-info":[{"award-number":["MOHW104-TDU-B-211-113-003, MOHW106-TDU-B-211-113001"]}],"id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Yang-Ming University","award":["E107F-M01-0501"],"award-info":[{"award-number":["E107F-M01-0501"]}]},{"DOI":"10.13039\/501100003711","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 106-2314-B-075 -051 -MY3, MOST 109-2314-B-010-061 -"],"award-info":[{"award-number":["MOST 106-2314-B-075 -051 -MY3, MOST 109-2314-B-010-061 -"]}],"id":[{"id":"10.13039\/501100003711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved or mildly reduced left ventricular ejection fraction. In this regard, understanding the molecular basis for cardiomyopathies is expected to fill in the knowledge gap and generate new therapies to improve prognosis for HF. This review discusses an evolutionary mechanism designed to regulate cardiac contraction and relaxation through the most often genetically determined cardiomyopathies associated with HF. In addition, both the myosin inhibitor and myosin activator are promising new treatments for cardiomyopathies. A comprehensive review from genetic mutations to the molecular basis of direct sarcomere modulators will help shed light on future studies for a better characterization of HF etiologies and potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms22126617","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T13:29:58Z","timestamp":1624282198000},"page":"6617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-4631","authenticated-orcid":false,"given":"Yu-Jen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116081, Taiwan"},{"name":"Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"Institute of Public Health, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9666-1273","authenticated-orcid":false,"given":"Chian-Shiu","family":"Chien","sequence":"additional","affiliation":[{"name":"Innovative Cellular Therapy Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chern-En","family":"Chiang","sequence":"additional","affiliation":[{"name":"General Clinical Research Center, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Department of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Huan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Education, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3885-6600","authenticated-orcid":false,"given":"Hao-Min","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Public Health, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Department of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei 112304, Taiwan"},{"name":"Center for Evidence-Based Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1002\/ejhf.1858","article-title":"Epidemiology of heart failure","volume":"22","author":"Groenewegen","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/ehf2.12005","article-title":"Heart failure: Preventing disease and death worldwide","volume":"1","author":"Ponikowski","year":"2014","journal-title":"ESC Heart Fail."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1093\/eurheartj\/ehaa158","article-title":"Time to rename the middle child of heart failure: Heart failure with mildly reduced ejection fraction","volume":"41","author":"Lam","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa1908655","article-title":"Angiotensin\u2013Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction","volume":"381","author":"Solomon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1136\/bmj.320.7228.167","article-title":"ABC of heart failure. Pathophysiology","volume":"320","author":"Jackson","year":"2000","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2016.163","article-title":"Neurohormonal activation in heart failure with reduced ejection fraction","volume":"14","author":"Hartupee","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s11883-014-0403-7","article-title":"Modulation of the renin-angiotensin-aldosterone system in heart failure","volume":"16","author":"George","year":"2014","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.jacc.2017.04.025","article-title":"2017 ACC\/AHA\/HFSA Focused Update of the 2013 ACCF\/AHA Guideline for the Management of Heart Failure","volume":"70","author":"Yancy","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(10)61198-1","article-title":"Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study","volume":"376","author":"Swedberg","year":"2010","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1056\/NEJMoa1915928","article-title":"Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction","volume":"382","author":"Armstrong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(16)31713-5","article-title":"Dilated cardiomyopathy","volume":"390","author":"Weintraub","year":"2017","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"CONSENSUS Trial Study Group (1987). Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N. Engl. J. Med., 316, 1429\u20131435.","DOI":"10.1056\/NEJM198706043162301"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1093\/oxfordjournals.eurheartj.a060844","article-title":"Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy\/Safety Trial (FEST) Study Group","volume":"16","author":"Erhardt","year":"1995","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1056\/NEJM199209033271001","article-title":"Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction","volume":"327","author":"Pfeffer","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"The SOLVD Investigators (1991). Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure. N. Engl. J. Med., 325, 293\u2013302.","DOI":"10.1056\/NEJM199108013250501"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1093\/eurheartj\/ehl250","article-title":"The perindopril in elderly people with chronic heart failure (PEP-CHF) study","volume":"27","author":"Cleland","year":"2006","journal-title":"Eur. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators (1993). Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet, 342, 821\u2013828.","DOI":"10.1016\/0140-6736(93)92693-N"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1056\/NEJM199512213332503","article-title":"A Clinical Trial of the Angiotensin-Converting-Enzyme Inhibitor Trandolapril in Patients with Left Ventricular Dysfunction after Myocardial Infarction","volume":"333","author":"Carlsen","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1161\/01.CIR.0000146819.43235.A9","article-title":"Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: Results of the CHARM low-left ventricular ejection fraction trials","volume":"110","author":"Young","year":"2004","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/S0140-6736(00)02213-3","article-title":"Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial\u2014The Losartan Heart Failure Survival Study ELITE II","volume":"355","author":"Pitt","year":"2000","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1056\/NEJMoa010713","article-title":"A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure","volume":"345","author":"Cohn","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0140-6736(98)11181-9","article-title":"The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial","volume":"353","author":"Lechat","year":"1999","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1056\/NEJM199605233342101","article-title":"The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure","volume":"334","author":"Packer","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"MERIT-HF Study Group (1999). Effect of metoprolol CR\/XL in chronic heart failure: Metoprolol CR\/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet, 353, 2001\u20132007.","DOI":"10.1016\/S0140-6736(99)04440-2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/eurheartj\/ehi115","article-title":"Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)","volume":"26","author":"Flather","year":"2005","journal-title":"Eur. Heart J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure","volume":"341","author":"Pitt","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms","volume":"364","author":"Zannad","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJM198606123142404","article-title":"Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure","volume":"314","author":"Cohn","year":"1986","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and Excitation-Contraction Coupling in the Heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.abb.2016.02.016","article-title":"Structural determinants of muscle thin filament cooperativity","volume":"594","author":"Moore","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"237","DOI":"10.5483\/BMBRep.2013.46.5.077","article-title":"SERCA2a: A prime target for modulation of cardiac contractility during heart failure","volume":"46","author":"Park","year":"2013","journal-title":"BMB Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1016\/j.jacc.2016.08.079","article-title":"Clinical and Mechanistic Insights into the Genetics of Cardiomyopathy","volume":"68","author":"Burke","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","first-page":"972","article-title":"Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy","volume":"15","author":"Ingles","year":"2013","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated Cardiomyopathy: Genetic Determinants and Mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1136\/hrt.2004.040337","article-title":"New insights into the pathology of inherited cardiomyopathy","volume":"91","author":"Hughes","year":"2005","journal-title":"Heart Br. Card. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Vikhorev, P.G., and Vikhoreva, N.N. (2018). Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082234"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ameri, P., Schiattarella, G.G., Crotti, L., Torchio, M., Bertero, E., Rodolico, D., Forte, M., Di Mauro, V., Paolillo, R., and Chimenti, C. (2020). Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041192"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1161\/CIRCULATIONAHA.109.904557","article-title":"Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies","volume":"121","author":"Predmore","year":"2010","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bbadis.2014.11.003","article-title":"Sarcomeric protein isoform transitions in cardiac muscle: A journey to heart failure","volume":"1852","author":"Yin","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s10974-010-9205-x","article-title":"A piece of the human heart: Variance of protein phosphorylation in left ventricular samples from end-stage primary cardiomyopathy patients","volume":"30","author":"Holewijn","year":"2009","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.yjmcc.2009.12.017","article-title":"Myofilament length dependent activation","volume":"48","author":"Mateja","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Alamo, L., and Ware, J.S. (2017). Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. eLife, 6.","DOI":"10.7554\/eLife.24634"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nsmb.3408","article-title":"The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations","volume":"24","author":"Nag","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jmb.2011.09.017","article-title":"A molecular model of phosphorylation-based activation and potentiation of tarantula muscle thick filaments","volume":"414","author":"Brito","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1073\/pnas.0909468107","article-title":"Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers","volume":"107","author":"Stewart","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yjmcc.2016.03.009","article-title":"Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes","volume":"94","author":"McNamara","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_51","first-page":"3461","article-title":"Defining the genetic architecture of hypertrophic cardiomyopathy: Re-evaluating the role of non-sarcomeric genes","volume":"38","author":"Walsh","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/jhg.2009.138","article-title":"Molecular basis of hereditary cardiomyopathy: Abnormalities in calcium sensitivity, stretch response, stress response and beyond","volume":"55","author":"Kimura","year":"2010","journal-title":"J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s10974-013-9358-5","article-title":"Alpha-tropomyosin mutations in inherited cardiomyopathies","volume":"34","author":"Redwood","year":"2013","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1161\/CIRCGENETICS.111.959973","article-title":"Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene","volume":"5","author":"Pasquale","year":"2012","journal-title":"Circulation. Cardiovasc. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/cvr\/cvr320","article-title":"Mutations of ventricular essential myosin light chain disturb myosin binding and sarcomeric sorting","volume":"93","author":"Lossie","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1093\/eurheartj\/ehv522","article-title":"Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers","volume":"37","author":"Claes","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/ng0897-379","article-title":"Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy","volume":"16","author":"Kimura","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3389\/fphys.2018.00405","article-title":"Classifying Cardiac Actin Mutations Associated with Hypertrophic Cardiomyopathy","volume":"9","author":"Despond","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/S0021-9258(17)42067-9","article-title":"Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction","volume":"269","author":"Sweeney","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/0092-8674(94)90054-X","article-title":"Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere","volume":"77","author":"Thierfelder","year":"1994","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1074\/jbc.M008691200","article-title":"Hypercontractile properties of cardiac muscle fibers in a knock-in mouse model of cardiac myosin-binding protein-C","volume":"276","author":"Witt","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/S0006-3495(03)75048-6","article-title":"Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy","volume":"84","author":"Roopnarine","year":"2003","journal-title":"Biophys. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19090","DOI":"10.1074\/jbc.M109.007021","article-title":"A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy","volume":"284","author":"Pinto","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1016\/j.bpj.2011.02.061","article-title":"A new state of cardiac myosin with very slow ATP turnover: A potential cardioprotective mechanism in the heart","volume":"100","author":"Hooijman","year":"2011","journal-title":"Biophys. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1161\/CIRCULATIONAHA.119.042339","article-title":"Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy","volume":"141","author":"Toepfer","year":"2020","journal-title":"Circulation"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200012073432304","article-title":"Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy","volume":"343","author":"Kamisago","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.ejheart.2004.04.017","article-title":"Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy","volume":"6","author":"Miettinen","year":"2004","journal-title":"Eur. J. Heart Fail."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1111\/febs.13286","article-title":"Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain","volume":"282","author":"Huang","year":"2015","journal-title":"FEBS J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"14525","DOI":"10.1073\/pnas.0606383103","article-title":"Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function","volume":"103","author":"Schmitt","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"E2338","DOI":"10.1073\/pnas.1716925115","article-title":"Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice","volume":"115","author":"Yuan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10741-005-5252-6","article-title":"Sarcomeric protein mutations in dilated cardiomyopathy","volume":"10","author":"Chang","year":"2005","journal-title":"Heart Fail. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1111\/j.1742-4658.2005.04630.x","article-title":"Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation","volume":"272","author":"Vang","year":"2005","journal-title":"FEBS J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1073\/pnas.022628899","article-title":"Ca(2+)-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy","volume":"99","author":"Morimoto","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16571","DOI":"10.1074\/jbc.M117.776815","article-title":"A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle","volume":"292","author":"Kawas","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1080\/00498254.2018.1495856","article-title":"In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin","volume":"49","author":"Grillo","year":"2019","journal-title":"Xenobiotica Fate Foreign Compd. Biol. Syst."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1126\/science.aad3456","article-title":"A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice","volume":"351","author":"Green","year":"2016","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0140-6736(20)31792-X","article-title":"Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"396","author":"Olivotto","year":"2020","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"McNamara, J.W., Li, A., Lal, S., Bos, J.M., Harris, S.P., van der Velden, J., Ackerman, M.J., Cooke, R., and Dos Remedios, C.G. (2017). MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180064"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"E7486","DOI":"10.1073\/pnas.1720342115","article-title":"Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin","volume":"115","author":"Rohde","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"E8143","DOI":"10.1073\/pnas.1809540115","article-title":"Deciphering the super relaxed state of human \u03b2-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers","volume":"115","author":"Anderson","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/S0140-6736(17)31071-1","article-title":"Heart failure","volume":"390","author":"Metra","year":"2017","journal-title":"Lancet"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"The Xamoterol in Severe Heart Failure Study Group (1990). Xamoterol in severe heart failure. Lancet, 336, 1\u20136.","DOI":"10.1016\/0140-6736(90)91517-E"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1056\/NEJM199111213252103","article-title":"Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group","volume":"325","author":"Packer","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jchf.2017.03.003","article-title":"Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients with Severe Chronic Heart Failure: Primary Results of the PROFILE Trial After 24 Years","volume":"5","author":"Packer","year":"2017","journal-title":"JACC Heart Fail."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1136\/hrt.76.3.223","article-title":"Effect of pimobendan on exercise capacity in patients with heart failure: Main results from the Pimobendan in Congestive Heart Failure (PICO) trial","volume":"76","author":"Lubsen","year":"1996","journal-title":"Heart Br. Card. Soc."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(96)10488-8","article-title":"Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators","volume":"349","author":"Hampton","year":"1997","journal-title":"Lancet"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.ahj.2007.06.044","article-title":"Low-dose oral enoximone enhances the ability to wean patients with ultra-advanced heart failure from intravenous inotropic support: Results of the oral enoximone in intravenous inotrope-dependent subjects trial","volume":"154","author":"Feldman","year":"2007","journal-title":"Am. Heart J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1093\/eurheartj\/ehp338","article-title":"Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: The randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials","volume":"30","author":"Metra","year":"2009","journal-title":"Eur. Heart J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1126\/science.1200113","article-title":"Cardiac myosin activation: A potential therapeutic approach for systolic heart failure","volume":"331","author":"Malik","year":"2011","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41467-017-00176-5","article-title":"Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil","volume":"8","author":"Hartman","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1016\/j.jacc.2019.02.051","article-title":"Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week","volume":"73","author":"Psotka","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_92","first-page":"483","article-title":"Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes","volume":"67","author":"Szentandrassy","year":"2016","journal-title":"J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1016\/j.jacc.2016.01.031","article-title":"Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study","volume":"67","author":"Teerlink","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/S0140-6736(16)32049-9","article-title":"Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A phase 2, pharmacokinetic, randomised, placebo-controlled trial","volume":"388","author":"Teerlink","year":"2016","journal-title":"Lancet"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1002\/ejhf.928","article-title":"Left ventricular ejection time is an independent predictor of incident heart failure in a community-based cohort","volume":"20","author":"Hegde","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/ejhf.2022","article-title":"Left ventricular systolic ejection time is an independent predictor of all-cause mortality in heart failure with reduced ejection fraction","volume":"23","author":"Alhakak","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.jchf.2019.12.001","article-title":"Omecamtiv Mecarbil in Chronic Heart Failure with Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF","volume":"8","author":"Teerlink","year":"2020","journal-title":"JACC Heart Fail."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1056\/NEJMoa2025797","article-title":"Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure","volume":"384","author":"Teerlink","year":"2020","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:20:00Z","timestamp":1760163600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,21]]},"references-count":98,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22126617"],"URL":"https:\/\/doi.org\/10.3390\/ijms22126617","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,21]]}}}