evrazkarЕвразийский Кардиологический ЖурналEurasian heart journal2225-16852305-0748Евразийская ассоциация кардиологов10.38109/2225-1685-2023-4-76-82evrazkar-6429Research ArticleОБЗОРREVIEWЭпигенетические лекарства: новый рубеж в лечении сердечной недостаточностиEpigenetic drugs: a new frontier in the treatment of heart failurehttps://orcid.org/0000-0003-4973-039XАйтбаевК. А.AitbaevK. A.

Кубаныч Авенович Айтбаев, д.м.н., профессор, заведующий отделением патологической физиологии, НИИ молекулярной биологии и медицины

ул. Тоголок молдо, дом 3, г. Бишкек 720040

Kubanych A. Aitbaev, Dr. of Sci. (Med.), Professor, Head of the Department of pathological physiology

3 Togolok Moldo street, Bishkek 720040

https://orcid.org/0000-0001-8513-9279МуркамиловИ. Т.MurkamilovI. T.

Илхом Торобекович Муркамилов, д.м.н., доцент кафедры факультетской терапии

ул. И. Ахунбаева, 92, Бишкек 720020

ул. Киевская, 44, г. Бишкек 720000

Ilkhom T. Murkamilov, Dr. of Sci. (Med.), Associate Professor, the Department of Faculty Therapy

92 Akhunbaev Street, Bishkek 720020, Kyrgyzstan

44 Kyiv Street, Bishkek 720000

murkamilov.i@mail.ruhttps://orcid.org/0000-0002-7653-0433МуркамиловаЖ. А.MurkamilovaZh. A.

Жамила Абдилалимовна Муркамилова, аспирант

ул. Киевская, 44, г. Бишкек 720000

Zhamila A. Murkamilova, graduate student

44 Kyiv Street, Bishkek 720000

https://orcid.org/0000-0002-2682-4417ФоминВ. В.FominV. V.

Виктор Викторович Фомин, д.м.н., профессор, член-корр. РАН, Проректор по научно-исследовательской и клинической работе

ул. Трубецкая, д. 8, стр. 2, г. Москва 

Viktor V. Fomin, Dr. of Sci. (Med.), Professor, Corresponding Member of RAS, Vice-Rector for Research and Clinical Work

8 Trubetskaya street, building 2, Moscow 119048

https://orcid.org/0000-0003-3007-8127КудайбергеноваИ. О.KudaibergenovaI. O.

Индира Орозобаевна Кудайбергенова, д.м.н., профессор, ректор

ул. И. Ахунбаева, 92, Бишкек 720020

Indira O. Kudaibergenova, Dr. of Sci. (Med.), Professor, Rector

92 Akhunbaev Street, Bishkek 720020, Kyrgyzstan

https://orcid.org/0000-0002-8502-2203ЮсуповаТ. Ф.YusupovaT. F.

Турсуной Фуркатовна Юсупова, Студентка 5-го курса, медицинский факультет

ул. Ленина, 331, г. Ош 723500

Tursunoy F. Yusupova, 5th year student, Faculty of Medicine

331 Lenin street, Osh city 723500

https://orcid.org/0000-0003-0632-6653ЮсуповФ. А.YusupovF. A.

Фуркат Абдулахатович Юсупов, д.м.н., профессор, зав каф. неврологии, нейрохирургии и психиатрии

ул. Ленина, 331, г. Ош 723500

Furkat A. Yusupov, Dr. of Sci. (Med.), Professor, Head of Department of Neurology, Neurosurgery and Psychiatry

331 Lenin street, Osh city 723500

Научно-исследовательский институт молекулярной биологии и медициныКыргызстанResearch Institute of Molecular Biology and MedicineKyrgyzstanКыргызская государственная медицинская академия имени и.к. Ахунбаева; Кыргызско-российский славянский университет им. Б.Н. ЕльцинаКыргызстанI.K. Akhunbaev Kyrgyz State Medical Academy; Kyrgyz Russian Slavic UniversityKyrgyzstanКыргызско-российский славянский университет им. Б.Н. ЕльцинаКыргызстанKyrgyz Russian Slavic UniversityKyrgyzstanПервый МГМУ имени И. М. Сеченова (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical University (Sechenov University)Russian FederationКыргызская государственная медицинская академия имени и.к. АхунбаеваКыргызстанI.K. Akhunbaev Kyrgyz State Medical AcademyKyrgyzstanОшский государственный университетКыргызстанOsh State UniversityKyrgyzstan202322112023047682Copyright © Айтбаев К.А., Муркамилов И.Т., Муркамилова Ж.А., Фомин В.В., Кудайбергенова И.О., Юсупова Т.Ф., Юсупов Ф.А., 20232023Айтбаев К.А., Муркамилов И.Т., Муркамилова Ж.А., Фомин В.В., Кудайбергенова И.О., Юсупова Т.Ф., Юсупов Ф.А.Aitbaev K.A., Murkamilov I.T., Murkamilova Z.A., Fomin V.V., Kudaibergenova I.O., Yusupova T.F., Yusupov F.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.heartj.asia/jour/article/view/6429

Раскрытие секретов гибкости генома не только способствовало развитию исследований в этой области, но также послужило толчком к разработке новых методов лечения болезней человека. Лучшее понимание биологии хроматина (комплексы ДНК/гистоны) и некодирующих РНК (нкРНК) позволило разработать эпигенетические (эпи) препараты, способные модулировать программы транскрипции, связанные с сердечно-сосудистыми заболеваниями. Это особенно относится к сердечной недостаточности, где было показано, что эпигенетические механизмы лежат в основе развития некоторых патологических процессов, таких как гипертрофия левого желудочка, фиброз, апоптоз кардиомиоцитов и дисфункция микрососудов. Ориентация на эпигенетические сигналы может представлять собой многообещающий подход, особенно у пациентов с сердечной недостаточностью с сохраненной фракцией выброса (СНсФВ), где прогноз остается неблагоприятным, а эффективных методов лечения пока не существует. В этих условиях эпигенетика может использоваться для разработки индивидуальных терапевтических подходов, что прокладывает путь к персонализированной медицине. Несмотря на то, что благоприятные эффекты эпи-препаратов привлекают всё большее внимание, количество эпигенетических соединений, используемых в клинической практике, остается низким, что свидетельствует о необходимости разработки более селективных эпи-препаратов. В настоящем обзоре мы приводим перечень новых перспективных эпи-препаратов для лечения сердечно-сосудистых заболеваний, с акцентом, главным образом, на СНсФВ. Терапевтический эффект этих препаратов обусловлен воздействием как минимум на один из трёх основных эпигенетических механизмов: метилирование ДНК, модификация гистонов и некодирующие РНК. 

Uncovering the secrets of genome flexibility not only contributed to the development of research in this area, but also served as an impetus for the development of new treatments for human diseases. A better understanding of the biology of chromatin (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic (epi) preparations capable of modulating transcriptional programs associated with cardiovascular disease. This is especially true in heart failure, where epigenetic mechanisms have been shown to underlie the development of several pathological processes such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis, and microvascular dysfunction. Targeting epigenetic signals may represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where the prognosis remains poor and effective treatments are not yet available. Under these conditions, epigenetics can be used to develop individualized therapeutic approaches, paving the way for personalized medicine. Although the beneficial effects of epi-drugs are gaining more attention, the number of epigenetic compounds used in clinical practice remains low, suggesting the need to develop more selective epi-drugs. In this review, we present a list of new promising epi-drugs for the treatment of cardiovascular diseases, with a focus mainly on HFpEF. The therapeutic effect of these drugs is due to the impact on at least one of the three main epigenetic mechanisms: DNA methylation, histone modification, and non-coding RNA.

сердечная недостаточностьэпи-терапияперсонализированная медицинаheart failureepi-therapypersonalized medicineReferencesWeinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114:A160–7. https://doi.org/10.1289/ehp.114-a160Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114:A160–7. https://doi.org/10.1289/ehp.114-a160Rozek LS, Dolinoy DC, Sartor MA, Omenn GS. Epigenetics: relevance and implications for public health. Annu Rev Public Health. 2014;35:105– 22. https://doi.org/10.1146/annurev-publhealth-032013-182513Rozek LS, Dolinoy DC, Sartor MA, Omenn GS. Epigenetics: relevance and implications for public health. Annu Rev Public Health. 2014;35:105– 22. https://doi.org/10.1146/annurev-publhealth-032013-182513Maunakea AK, Nagarajan RP, Bilenky M et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7. https://doi.org/10.1038/nature09165Maunakea AK, Nagarajan RP, Bilenky M et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7. https://doi.org/10.1038/nature09165Mohammed SA, Ambrosini S, Lüscher T et al. Epigenetic control of mitochondrial function in the vasculature. Front Cardiovasc Med. 2020;7:28. https://doi.org/10.3389/fcvm.2020.00028Mohammed SA, Ambrosini S, Lüscher T et al. Epigenetic control of mitochondrial function in the vasculature. Front Cardiovasc Med. 2020;7:28. https://doi.org/10.3389/fcvm.2020.00028Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011;123:2145–56. https://doi.org/10.1161/CIRCULATIONAHA.110.956839Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011;123:2145–56. https://doi.org/10.1161/CIRCULATIONAHA.110.956839Gao J, Shao K, Chen X et al. The involvement of post-translational modifications in cardiovascular pathologies: focus on SUMOylation, neddylation, succinylation, and prenylation. J Mol Cell Cardiol. 2020;138:49–58. https://doi.org/10.1016/j.yjmcc.2019.11.146Gao J, Shao K, Chen X et al. The involvement of post-translational modifications in cardiovascular pathologies: focus on SUMOylation, neddylation, succinylation, and prenylation. J Mol Cell Cardiol. 2020;138:49–58. https://doi.org/10.1016/j.yjmcc.2019.11.146Das S, Shah R, Dimmeler S et al. Noncoding RNAs in cardiovascular disease: current knowledge, tools and technologies for investigation, and future directions: a scientific statement from the American heart association. Circ Genom Precis Med. 2020;13:e000062. https://doi.org/10.1161/HCG.0000000000000062Das S, Shah R, Dimmeler S et al. Noncoding RNAs in cardiovascular disease: current knowledge, tools and technologies for investigation, and future directions: a scientific statement from the American heart association. Circ Genom Precis Med. 2020;13:e000062. https://doi.org/10.1161/HCG.0000000000000062Zhong J, Agha G, Baccarelli AA. The role of DNA methylation in cardiovascular risk and disease. Circ Res. 2016;118:119–31. https://doi.org/10.1161/CIRCRESAHA.115.305206Zhong J, Agha G, Baccarelli AA. The role of DNA methylation in cardiovascular risk and disease. Circ Res. 2016;118:119–31. https://doi.org/10.1161/CIRCRESAHA.115.305206Aggarwal R, Jha M, Shrivastava A, Jha AK. Natural compounds: role in reversal of epigenetic changes. Biochemistry. 2015;80:972–89. https://doi.org/10.1134/S0006297915080027Aggarwal R, Jha M, Shrivastava A, Jha AK. Natural compounds: role in reversal of epigenetic changes. Biochemistry. 2015;80:972–89. https://doi.org/10.1134/S0006297915080027Ganesan A, Arimondo PB, Rots MG et al. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenet. 2019;11:174. https://doi.org/10.1186/s13148-019-0776-0Ganesan A, Arimondo PB, Rots MG et al. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenet. 2019;11:174. https://doi.org/10.1186/s13148-019-0776-0Savarese G, Becher PM, Lund LH et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023 Jan 18;118(17):3272-3287. https://doi.org/10.1093/cvr/cvac013Savarese G, Becher PM, Lund LH et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023 Jan 18;118(17):3272-3287. https://doi.org/10.1093/cvr/cvac013Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction: A Review. JAMA. 2023 Mar 14;329(10):827-838. https://doi.org/10.1001/jama.2023.2020Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction: A Review. JAMA. 2023 Mar 14;329(10):827-838. https://doi.org/10.1001/jama.2023.2020Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Res C Embryo Today. 2011;93:51–5. https://doi.org/10.1002/bdrc.20199Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Res C Embryo Today. 2011;93:51–5. https://doi.org/10.1002/bdrc.20199From AM, Leibson CL, Bursi F et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006;119:591–9. https://doi.org/10.1016/j.amjmed.2006.05.024From AM, Leibson CL, Bursi F et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006;119:591–9. https://doi.org/10.1016/j.amjmed.2006.05.024Liu CF, Tang WHW. Epigenetics in cardiac hypertrophy and heart failure. Basic Transl Sci. 2019;4:976–93. https://doi.org/10.1016/j.jacbts.2019.05.011Liu CF, Tang WHW. Epigenetics in cardiac hypertrophy and heart failure. Basic Transl Sci. 2019;4:976–93. https://doi.org/10.1016/j.jacbts.2019.05.011Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;30:30–41. https://doi.org/10.1038/nrcardio.2010.165Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;30:30–41. https://doi.org/10.1038/nrcardio.2010.165Rich MW. Heart failure in the 21st century: a cardiogeriatric syndrome. J Gerontol A Biol Sci Med Sci. 2001;56:M88–96. https://doi.org/10.1093/gerona/56.2.M88Rich MW. Heart failure in the 21st century: a cardiogeriatric syndrome. J Gerontol A Biol Sci Med Sci. 2001;56:M88–96. https://doi.org/10.1093/gerona/56.2.M88Backs J, Olson EN. Control of cardiac growth by histone acetylation/ deacetylation. Circ Res. 2006;98:15–24. https://doi.org/10.1161/01.RES.0000197782.21444.8fBacks J, Olson EN. Control of cardiac growth by histone acetylation/ deacetylation. Circ Res. 2006;98:15–24. https://doi.org/10.1161/01.RES.0000197782.21444.8fFrey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004; 109:1580–9. doi:10.1161/01.CIR.0000120390.68287.BBFrey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004; 109:1580–9. doi:10.1161/01.CIR.0000120390.68287.BBHill JA, Olson EN, Biology M-L. Mechanisms of disease cardiac plasticity. N Engl J Med. 2008;58:1370–80. https://doi.org/10.1056/NEJMra072139Hill JA, Olson EN, Biology M-L. Mechanisms of disease cardiac plasticity. N Engl J Med. 2008;58:1370–80. https://doi.org/10.1056/NEJMra072139Duygu B, de Windt LJ, da Costa Martins PA. Targeting microRNAs in heart failure. Trends Cardiovasc Med. 2016;26:99–110. https://doi.org/10.1016/j.tcm.2015.05.008Duygu B, de Windt LJ, da Costa Martins PA. Targeting microRNAs in heart failure. Trends Cardiovasc Med. 2016;26:99–110. https://doi.org/10.1016/j.tcm.2015.05.008Ganesan A. Multitarget drugs: an epigenetic epiphany. ChemMedChem. 2016;11:1227–41. https://doi.org/10.1002/cmdc.201500394Ganesan A. Multitarget drugs: an epigenetic epiphany. ChemMedChem. 2016;11:1227–41. https://doi.org/10.1002/cmdc.201500394Madsen A, Höppner G, Krause J et al. An important role for DNMT3amediated DNA methylation in cardiomyocyte metabolism and contractility. Circulation. 2020;142:1562–78. https://doi.org/10.1161/CIRCULATIONAHA.119.044444Madsen A, Höppner G, Krause J et al. An important role for DNMT3amediated DNA methylation in cardiomyocyte metabolism and contractility. Circulation. 2020;142:1562–78. https://doi.org/10.1161/CIRCULATIONAHA.119.044444Stenzig J, Schneeberger Y, Löser A et al. Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. J Mol Cell Cardiol. 2018;120:53–63. https://doi.org/10.1016/j.yjmcc.2018.05.012Stenzig J, Schneeberger Y, Löser A et al. Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. J Mol Cell Cardiol. 2018;120:53–63. https://doi.org/10.1016/j.yjmcc.2018.05.012Gnyszka A, Jastrzebski Z, Flis S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013;33:2989–96.Gnyszka A, Jastrzebski Z, Flis S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013;33:2989–96.Fraineau S, Palii CG, Allan DS, Brand M. Epigenetic regulation of endothelial-cell-mediated vascular repair. FEBS J. 2015;282:1605–29. https://doi.org/10.1111/febs.13183Fraineau S, Palii CG, Allan DS, Brand M. Epigenetic regulation of endothelial-cell-mediated vascular repair. FEBS J. 2015;282:1605–29. https://doi.org/10.1111/febs.13183Plácido R, Heinonen IHA, Volpe M et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2018;10:1347. https://doi.org/10.3389/fphys.2019.01347Plácido R, Heinonen IHA, Volpe M et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2018;10:1347. https://doi.org/10.3389/fphys.2019.01347Rajan A, Shi H, Xue B. Class I and II histone deacetylase inhibitors differentially regulate thermogenic gene expression in brown adipocytes open. Sci Rep. 2018;8:13072. https://doi.org/10.1038/s41598-018-31560-wRajan A, Shi H, Xue B. Class I and II histone deacetylase inhibitors differentially regulate thermogenic gene expression in brown adipocytes open. Sci Rep. 2018;8:13072. https://doi.org/10.1038/s41598-018-31560-wNapoli C, Benincasa G, Donatelli F, Ambrosio G. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113–28. https://doi.org/10.1016/j.ahj.2020.03.007Napoli C, Benincasa G, Donatelli F, Ambrosio G. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113–28. https://doi.org/10.1016/j.ahj.2020.03.007Wang Y, Miao X, Liu Y et al. Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases. Oxid Med Cell Longev. 2014;2014:641979. https://doi.org/10.1155/2014/641979Wang Y, Miao X, Liu Y et al. Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases. Oxid Med Cell Longev. 2014;2014:641979. https://doi.org/10.1155/2014/641979Kong Y, Tannous P, Lu G et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation. 2006;113:2579–88. https://doi.org/10.1161/CIRCULATIONAHA.106.625467Kong Y, Tannous P, Lu G et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation. 2006;113:2579–88. https://doi.org/10.1161/CIRCULATIONAHA.106.625467Granger A, Abdullah I, Huebner F et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22:3549–60. https://doi.org/10.1096/fj.08-108548Granger A, Abdullah I, Huebner F et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22:3549–60. https://doi.org/10.1096/fj.08-108548Xie M, Kong Y, Tan W et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129:1139–51. https://doi.org/10.1161/CIRCULATIONAHA.113.002416Xie M, Kong Y, Tan W et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129:1139–51. https://doi.org/10.1161/CIRCULATIONAHA.113.002416Kee HJ, Sohn IS, Nam KI et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation. 2006 Jan 3;113(1):51-59. https://doi.org/10.1161/CIRCULATIONAHA.105.559724Kee HJ, Sohn IS, Nam KI et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation. 2006 Jan 3;113(1):51-59. https://doi.org/10.1161/CIRCULATIONAHA.105.559724Wallner M, Eaton DM, Berretta RM et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci Transl Med. 2020;12:eaay7205. https://doi.org/10.1126/scitranslmed.aay7205Wallner M, Eaton DM, Berretta RM et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci Transl Med. 2020;12:eaay7205. https://doi.org/10.1126/scitranslmed.aay7205Testai L, Sestito S, Martelli A et al. Synthesis and pharmacological characterization of mitochondrial KATP channel openers with enhanced mitochondriotropic effects. Bioorgan Chem. 2021;107:104572. https://doi.org/10.1016/j.bioorg.2020.104572Testai L, Sestito S, Martelli A et al. Synthesis and pharmacological characterization of mitochondrial KATP channel openers with enhanced mitochondriotropic effects. Bioorgan Chem. 2021;107:104572. https://doi.org/10.1016/j.bioorg.2020.104572Kelly WK, Marks P, Richon VM. CCR 20th anniversary commentary: vorinostat–gateway to epigenetic therapy. Clin Cancer Res. 2015;21:2198–200. https://doi.org/10.1158/1078-0432.CCR-14-2556Kelly WK, Marks P, Richon VM. CCR 20th anniversary commentary: vorinostat–gateway to epigenetic therapy. Clin Cancer Res. 2015;21:2198–200. https://doi.org/10.1158/1078-0432.CCR-14-2556Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem Am Chem Soc. 2020;63:12460–84. https://doi.org/10.1021/acs.jmedchem.0c00830Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem Am Chem Soc. 2020;63:12460–84. https://doi.org/10.1021/acs.jmedchem.0c00830Jeong MY, Lin YH, Wennersten SA et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med. 2018;10:eaao0144. https://doi.org/10.1126/scitranslmed.aao0144Jeong MY, Lin YH, Wennersten SA et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med. 2018;10:eaao0144. https://doi.org/10.1126/scitranslmed.aao0144Gillette T.G. HDAC inhibition in the heart: erasing hidden fibrosis. Circulation.2021;143(19):1891-1893. https://doi.org/10.1161/CIRCULATIONAHA.121.054262Gillette T.G. HDAC inhibition in the heart: erasing hidden fibrosis. Circulation.2021;143(19):1891-1893. https://doi.org/10.1161/CIRCULATIONAHA.121.054262Travers JG, Wennersten SA, Peña B, Bagchi RA, Smith HE, Hirsch RA, McKinsey TA. HDAC inhibition reverses preexisting diastolic dysfunction and blocks covert extracellular matrix remodeling. Circulation.2021;143(19):1874-1890. https://doi.org/10.1161/CIRCULATIONAHA.120.046462Travers JG, Wennersten SA, Peña B, Bagchi RA, Smith HE, Hirsch RA, McKinsey TA. HDAC inhibition reverses preexisting diastolic dysfunction and blocks covert extracellular matrix remodeling. Circulation.2021;143(19):1874-1890. https://doi.org/10.1161/CIRCULATIONAHA.120.046462Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol. 1978;3:20– 5. https://doi.org/10.1002/ana.410030105Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol. 1978;3:20– 5. https://doi.org/10.1002/ana.410030105Mokhtarani M, Diaz GA, Rhead W et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab. 2012;107:308–14. https://doi.org/10.1016/j.ymgme.2012.08.006Mokhtarani M, Diaz GA, Rhead W et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab. 2012;107:308–14. https://doi.org/10.1016/j.ymgme.2012.08.006Tian S, Lei I, Gao W et al. HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction. EBioMedicine. 2019;39:83–94. https://doi.org/10.1016/j.ebiom.2018.12.003Tian S, Lei I, Gao W et al. HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction. EBioMedicine. 2019;39:83–94. https://doi.org/10.1016/j.ebiom.2018.12.003Subramanian U, Kumar P, Mani I et al. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice. Physiol Genomics. 2016;48:477–90. https://doi.org/10.1152/physiolgenomics.00073.2015Subramanian U, Kumar P, Mani I et al. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice. Physiol Genomics. 2016;48:477–90. https://doi.org/10.1152/physiolgenomics.00073.2015Chan-Penebre E, Kuplast KG, Majer CR et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11:432–7. https://doi.org/10.1038/nchembio.1810Chan-Penebre E, Kuplast KG, Majer CR et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11:432–7. https://doi.org/10.1038/nchembio.1810Morera L, Lübbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenet. 2016;8:57. https://doi.org/10.1186/s13148-016-0223-4Morera L, Lübbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenet. 2016;8:57. https://doi.org/10.1186/s13148-016-0223-4Guo Y, Su Z-Y, Kong A-NT. Current perspectives on epigenetic modifications by dietary chemopreventive and herbal phytochemicals. Curr Pharmacol Rep. 2015;1:245–57. https://doi.org/10.1007/s40495-015-0023-0Guo Y, Su Z-Y, Kong A-NT. Current perspectives on epigenetic modifications by dietary chemopreventive and herbal phytochemicals. Curr Pharmacol Rep. 2015;1:245–57. https://doi.org/10.1007/s40495-015-0023-0Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. 2016;19:45–50. https://doi.org/10.1016/j.ddtec.2016.06.004Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. 2016;19:45–50. https://doi.org/10.1016/j.ddtec.2016.06.004Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogenomics J. 2006;6:162–5. https://doi.org/10.1038/sj.tpj.6500361Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogenomics J. 2006;6:162–5. https://doi.org/10.1038/sj.tpj.6500361Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell Cell Press. 2014;54:728–36. https://doi.org/10.1016/j.molcel.2014.05.016Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell Cell Press. 2014;54:728–36. https://doi.org/10.1016/j.molcel.2014.05.016Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:1190–208. https://doi.org/10.1161/CIRCRESAHA.120.315929Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:1190–208. https://doi.org/10.1161/CIRCRESAHA.120.315929Nicholls SJ, Ray KK, Johansson JO et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs. 2018;18:109–15. https://doi.org/10.1007/s40256-017-0250-3Nicholls SJ, Ray KK, Johansson JO et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs. 2018;18:109–15. https://doi.org/10.1007/s40256-017-0250-3Nicholls SJ, Schwartz GG, Buhr KA et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study. Cardiovasc Diabetol. 2021;20:13. https://doi.org/10.1186/s12933-020-01199-xNicholls SJ, Schwartz GG, Buhr KA et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study. Cardiovasc Diabetol. 2021;20:13. https://doi.org/10.1186/s12933-020-01199-xTsujikawa LM, Fu L, Das S et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenet. 2019;11:102. https://doi.org/10.1186/s13148-019-0696-zTsujikawa LM, Fu L, Das S et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenet. 2019;11:102. https://doi.org/10.1186/s13148-019-0696-zBrandts J, Ray KK. Apabetalone – BET protein inhibition in cardiovascular disease and type 2 diabetes. Future Cardiol. 2020;16:385–95. https://doi.org/10.2217/fca-2020-0017Brandts J, Ray KK. Apabetalone – BET protein inhibition in cardiovascular disease and type 2 diabetes. Future Cardiol. 2020;16:385–95. https://doi.org/10.2217/fca-2020-0017Chioccioli M, Roy S, Rigby K et al. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. bioRxiv [Preprint]. 2021. https://doi.org/10.1101/2021.12.22.473724Chioccioli M, Roy S, Rigby K et al. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. bioRxiv [Preprint]. 2021. https://doi.org/10.1101/2021.12.22.473724van Rooij E, Sutherland LB, Thatcher JE et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA. 2008;105:13027–32. https://doi.org/10.1073/pnas.0805038105van Rooij E, Sutherland LB, Thatcher JE et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA. 2008;105:13027–32. https://doi.org/10.1073/pnas.0805038105Landmesser U, Poller W, Tsimikas S et al. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020;41:3884–99. https://doi.org/10.1093/eurheartj/ehaa229Landmesser U, Poller W, Tsimikas S et al. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020;41:3884–99. https://doi.org/10.1093/eurheartj/ehaa229Gargiulo P, Marzano F, Salvatore M, et al. MicroRNAs: diagnostic, prognostic and therapeutic role in heart failure — a review. ESC Heart Failure. 2023;10:2:753-761. https://doi.org/10.1002/ehf2.14153Gargiulo P, Marzano F, Salvatore M, et al. MicroRNAs: diagnostic, prognostic and therapeutic role in heart failure — a review. ESC Heart Failure. 2023;10:2:753-761. https://doi.org/10.1002/ehf2.14153Ruan W, Zhao F, Zhao S et al. Knockdown of long noncoding RNA MEG3 impairs VEGF-stimulated endothelial sprouting angiogenesis via modulating VEGFR2 expression in human umbilical vein endothelial cells. Gene. 2018;649:32–9. https://doi.org/10.1016/j.gene.2018.01.072Ruan W, Zhao F, Zhao S et al. Knockdown of long noncoding RNA MEG3 impairs VEGF-stimulated endothelial sprouting angiogenesis via modulating VEGFR2 expression in human umbilical vein endothelial cells. Gene. 2018;649:32–9. https://doi.org/10.1016/j.gene.2018.01.072Leisegang MS, Fork C, Josipovic I et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136:65– 79. https://doi.org/10.1161/CIRCULATIONAHA.116.026991Leisegang MS, Fork C, Josipovic I et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136:65– 79. https://doi.org/10.1161/CIRCULATIONAHA.116.026991Man HSJ, Sukumar AN, Lam GC et al. Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA. Proc Natl Acad Sci USA. 2018;115:2401–6. https://doi.org/10.1073/pnas.1715182115Man HSJ, Sukumar AN, Lam GC et al. Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA. Proc Natl Acad Sci USA. 2018;115:2401–6. https://doi.org/10.1073/pnas.1715182115Zhang X, Tang X, Hamblin MH, Yin K-J. Long non-coding RNA malat1 regulates angiogenesis in hindlimb ischemia. Int J Mol Sci. 2018; 19:1723. doi:10.3390/ijms19061723Zhang X, Tang X, Hamblin MH, Yin K-J. Long non-coding RNA malat1 regulates angiogenesis in hindlimb ischemia. Int J Mol Sci. 2018; 19:1723. doi:10.3390/ijms19061723Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vasc Pharmacol. 2019;114:145–56. https://doi.org/10.1016/j.vph.2018.01.003Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vasc Pharmacol. 2019;114:145–56. https://doi.org/10.1016/j.vph.2018.01.003Miano JM, Zheng D, Bell RD et al. Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol. 2014;34:1249–59. https://doi.org/10.1161/ATVBAHA.114.303240Miano JM, Zheng D, Bell RD et al. Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol. 2014;34:1249–59. https://doi.org/10.1161/ATVBAHA.114.303240Vance KW, Schulte C, Thum T et al. Long non-coding RNAs: at the heart of cardiac dysfunction? Front Physiol. 2019;10:30. https://doi.org/10.3389/fphys.2019.00030Vance KW, Schulte C, Thum T et al. Long non-coding RNAs: at the heart of cardiac dysfunction? Front Physiol. 2019;10:30. https://doi.org/10.3389/fphys.2019.00030Zhou W, Wang C, Chang J et al. RNA methylations in cardiovascular diseases, molecular structure, biological functions and regulatory roles in cardiovascular diseases. Front Pharmacol. 2021;12:722728. https://doi.org/10.3389/fphar.2021.722728Zhou W, Wang C, Chang J et al. RNA methylations in cardiovascular diseases, molecular structure, biological functions and regulatory roles in cardiovascular diseases. Front Pharmacol. 2021;12:722728. https://doi.org/10.3389/fphar.2021.722728Qin Y, Li L, Luo E et al. Role of m6A RNA methylation in cardiovascular disease (review). Int J Mol Med. 2020;46:1958–72. https://doi.org/10.3892/ijmm.2020.4746Qin Y, Li L, Luo E et al. Role of m6A RNA methylation in cardiovascular disease (review). Int J Mol Med. 2020;46:1958–72. https://doi.org/10.3892/ijmm.2020.4746Zhang B, Xu Y, Cui X et al. Alteration of m6A RNA methylation in heart failure with preserved ejection fraction. Front Cardiovasc Med. 2021;8:647806. https://doi.org/10.3389/fcvm.2021.647806Zhang B, Xu Y, Cui X et al. Alteration of m6A RNA methylation in heart failure with preserved ejection fraction. Front Cardiovasc Med. 2021;8:647806. https://doi.org/10.3389/fcvm.2021.647806Cao M, Luo H, Li D et al. Research advances on circulating long noncoding RNAs as biomarkers of cardiovascular diseases. Int J Cardiol. 2022;353:109–17. https://doi.org/10.1016/j.ijcard.2022.01.070Cao M, Luo H, Li D et al. Research advances on circulating long noncoding RNAs as biomarkers of cardiovascular diseases. Int J Cardiol. 2022;353:109–17. https://doi.org/10.1016/j.ijcard.2022.01.070

The authors declare that there are no conflicts of interest present.