Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

Alexander Berezin

Alexander Berezin, Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University for Zaporozhye, 26, Mayakovsky Av., Zaporozhye, Postcode 69035, Ukraine

Correspondence to: Alexander Berezin, Professor, MD, PhD, Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University for Zaporozhye, 26, Mayakovsky Av., Zaporozhye, Postcode 69035, Ukraine.
Email: dr_berezin@mail.ru
Telephone: +38 061 2894585
Fax: +38 0612894585
Received: March 30, 2016
Revised: May 5, 2016
Accepted: May 12, 2016
Published online: August 10, 2016


Chronic heart failure (HF) is a leading clinical and public problem affected higher risk of morbidity and mortality in different population. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved left ventricular ejection fraction (HFpEF). Although both HF phenotypes are distinguished in clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context investigation of various molecular and cellular mechanisms leading to development and progression of both HF phenotypes are very important. There is emerging evidence regarding that the epigenetic regulation may have a clue in the pathogenesis of HF. The review is represented current available evidence regarding an implication of epigenetic modifications in development of different HF phenotypes.

Key words: Heart failure with reduced ejection fraction; Heart failure with preserved ejection fraction; Epigenetic modifications; Chromatin remodeling

© 2016 The Author. Published by ACT Group Ltd.

Berezin A. Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes? Journal of Cardiology and Therapy 2016; 3(4): 554-559 Available from: URL: http: //www.ghrnet.org/index.php/jct/article/view/1812

Abbreviations α-MHC: the alpha-myosin heavy chain gene; CV: cardiovascular; DNA: deoxyribonucleic acid; ECREM: Epigenetic Code REplication Machinery; HFrEF: heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; miRNA: micro ribonucleic acid; MHC: myosin heavy chain; SPR-Ca2+ ATPase: sarcoplasmic reticulum Ca2+ ATPase genes.


Chronic heart failure (HF) has remained to be a serious clinical and public problem[1]; despite the prevalence of chronic HF especially HF with reduced left ventricular ejection fraction (HFrEF) seems to have a tendency to decrease within the last decade in the development countries[2]. Contrary, a frequency of newly HF with preserved left ventricular ejection fraction (HFpEF) is on the rise and HFpEF is considered more common than HFrEF predominantly in the older population and among subjects with hypertension, diabetes, respiratory diseases[3]. Currently, more than 50% of patients with the clinical syndrome of HF might have a preserved left ventricular ejection fraction[4]. Nevertheless, recent clinical studies have shown a sufficient distinguish between presentation of both HF phenotypes (HFrEF or HFpEF) in individuals at risk for HF development in a primary care setting[5,6]. Although HFpEF patients might have lower levels of predictive biomarkers[7], the clinical outcomes in HFpEF individuals, i.e. cardiovascular (CV) death, HF-related death, sudden death and readmission, are not better than in patients with HFrEF[8,9].

Current clinical HF guidelines are recommended to use early identification and treatment of the underlying cause of cardiac dysfunction to prevent HF manifestation[10,11], whereas no evidence that HF phenotypes’ development is preventable with specific medical care[12]. Taken together, all these data clarify the importance of stratification of individuals at risk of HFrEF or HFpEF development and progression[13,14].

Various molecular and cellular mechanisms are involved in the development and progression of both HF phenotypes. There is emerging evidence regarding that the epigenetic regulation may take an important part in the pathogenesis of HF playing a pivotal role in phenotypic response of failing heart and prognosis[15,16]. There is experimental and clinical evidence that advance of HF might associate with autonomic imbalance with increased sympathetic nerve activity and a withdrawal of parasympathetic activity, with the target of involvement being the heart which may be of epigenetic origin[16-18]. The increase in angiotensin II signaling enhances sympathetic nerve activity through actions on both central and peripheral sites causing increased contractility of the heart, as an adaptation, during chronic HF[17]. Angiotensin II signaling is enhanced in different brain sites such as the paraventricular nucleus, rostral ventrolateral medulla and area postrema via neuregulin-brain natriuretic peptide release from these sites which influences the function of cardiomyocytes and the heart[18]. It is suggested that blocking angiotensin II type 1 receptors decreases sympathetic nerve activity and cardiac sympathetic afferent reflex when therapy is administered to the PVN which may be due to epigenetic modulation[19].

Epigenetic modifications affected DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and microRNA-related mechanisms are considered a sufficient factor contributing to adverse cardiac remodeling and preceding cardiac dysfunction[20]. Probably, in the future epigenetic modifications of cardiomyocytes would be a target for personalized management and much more effective tools for prevention of HF development[21]. The review is summarized the knowledge regarding implication of epigenetic modifications in development of different HF phenotypes.


A classical definition of epigenetics was proposed by Conrad Waddington in the 1950s, which believed that organism’ phenotype arises from its genotype through so called “programmed epigenetic” event. Epigenetics was considered neither as the study of changes in states of any gene activity or inherited activity states only[22]. In some definitions, only those activity states that are inherited across cell division were defined[23]. In the Roadmap Epigenomics Project epigenetics is used as an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence[24]. Accordingly Banbury Conference Center and Cold Spring Harbor Laboratory chromatin-based epigenetic trait has defined as a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence[25]. By now, it has been suggested that the basis of epigenetics is non-genetic cellular memory that expressed or non-expressed in specific developmental and environmental situations[26].

Berger SL et al[27] have suggested to use at least three categories of signals that modulate epigenetic state: “Epigenator”, “Epigenetic Initiator” and “Epigenetic Maintainer”. Authors suggested that signal that is proposed to name the “Epigenator” might be atribute of the environment and it could be a trigger an intracellular pathway. The signal that is called “Epigenetic Initiator”, corresponds to “Epigenator” signal and is essential for define the precise arrangement of the epigenetic chromatin environment. Finally, “Epigenetic Maintainer” signal is deemed as the chromatin environment contributing to the first and subsequent generations. The role of different classes of potential signals affected epigenetic modifications of chromatin is not well defined and is widely discussed.

In this context, discrete chemical modifications of DNA and primarily histones might regulate expression or repression of target genes and can be transmitted to the descent via epigenetic memory[28]. It has suggested that the macro-molecular complex, called “Epigenetic Code REplication Machinery” (ECREM), as being involved in the inheritance of the epigenetic code. The main the members of ECREM could be enzymes involved in epigenetic modification of chromatin, i.e. DNA methyltransferases, histone deacetylases, histone acetyltransferases, and sirtuins. Moreover, deregulated ECREM is considered a clue of cell reprogramming[27,28]. However, epigenetic events in various cells provide closely control of gene expression and genomic regulation through multiple generations leading to phenotypes’ variability.


Epigenetics are referred a modification of the non-DNA sequences related heritable changes in gene expression of target cells that is currently recognized as a key to understanding of pathogenesis CV diseases[29]. Epigenetic modifications are based on different molecular mechanisms, which affect DNA methylation and deactylation, ATP-dependent chromatin remodeling, histone modifications, and microRNA regulation (Figure 1). All these processes coordinate modulating of chromatin structure and thereby might effect of modalities and expression of target genes[30]. It has been found the proliferative capability of human cardiac cells is under tight epigenetic regulation that mediates a dynamic adaptation of the structure and functionality of wide spectrum of cells, i.e. cardiomyocytes, fibroblasts, endothelial cells, progenitor cells, for environmental challenges and to respond to biochemical stress. It is suggested that dysregulation in epigenetic signals, messengers and molecular targets is a clue for pathological remodeling of heart and vessels, progenitor cell dysfunction, worsening of endogenous repair system, metabolic memory manifestation[31]. It is now becoming evident that cumulative effect of these factors may culminate in HF, cardiac hypertrophy, arrhythmia, dyslipidemia, atherosclerosis/atherothrombosis, and associates with increased risk of CV death[32-37]. Whether interactions between features of transcriptomics, proteomics and metabolomics are specifically for HFrEF and HFpEF remains still not clear. Moreover, different mechanisms of epigenetic modifications may relate to various HF-depended settings, i.e. cardiac hypertrophy, myocardial infarction, atrial fibrillation, sudden death, and play controversial role (Table 1). However, the innate mechanisms regarding causal pathway to HF phenotypes’ development are nor fully understood and require more investigations[38].

DNA methylation

DNA methylation is the most common epigenetic chromatin modification[39]. Movassagh M et al[40] suggested that there is distinct global pattern of the epigenome leading to regulate the expression of underlying genes. Authors investigated genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation enrichment for cardiomyopathic and normal human hearts. It has found a sufficient difference in DNA methylation in promoters of up-regulated genes, but not down-regulated genes in end-stage cardiomyopathy [40]. Furthermore, the process of DNA methylation was under regulation through several genetic pathways that are modulating by platelet/endothelial cell adhesion molecule 1, hypoxia-inducible factor- 1alpha, angiomotin-like 2, and Rho GTPase activating protein 24[40,41]. Authors suggested that epigenetic modifications identified in failing heart might affect cardiac function directly through regulation of structure protein synthesis and, however, indirectly via increased activity of cardiac fibroblasts due to prolonged hypoxia contributing to the pro-fibrotic nature of the ischemic milieu.

Contrary, satellite repeat element transcripts, a form of non-coding RNA that is heavily methylated in post-natal tissue, have putative functions in maintaining genomic stability and chromosomal integrity[42]. Moreover, the hypomethylation of satellite elements exhibited closely association with significant up-regulation of satellite transcripts[42]. Finally, there is evidence that methylation-regulated, alternative transcripts might express in a tissue- and cell type-specific manner and they may regulate intragenic promoter activity via enhancing transcription elongation efficiency[39,43]. Thus, DNA methylations may enhance transcription of the underlying satellite repeat element transcripts.

Xiao D et al[44] reported that increased DNA methylation might have a causative role in programming of heart hypertrophy and reduced global cardiac contractility function. Moreover, impaired contractility of the left ventricle has associated with an increase in the susceptibility to ischemic injury[44]. Contrary, Haas J et al[45] did not find evidence regarding participation of DNA methylation in genes suspected to HF development. However, DNA methylation has exhibited a causality role in diabetes-induced HFpEF[46]. Unfortunately, the data regarding the role of DNA methylation in development of both phenotypes of HF beyond inhered forms in are very limited. More investigations are required to understand the underlying mechanisms linked DNA methylation and HF presentation.

ATP-dependent enzymes in chromatin remodeling

The ATP-dependent chromatin remodeling complexes are not able to directly modify DNA or histones, whereas they may use energy of ATP hydrolysis in processes regarding destabilize, eject or restructure of nucleosomes, which is functional unit of chromatin[47]. Because nucleosomes actively participate in transcription, chromosome segregation, DNA replication, and DNA repair, the chromosomal DNA packaging by nucleosomes is crucial for the regulation of these processes[48]. The dynamic access to DNA packaging performs by specialized chromatin remodeling complexes[49]. There are four different families of ATP-dependent chromatin remodeling complexes: switching defective/sucrose non-fermenting complexes (SWI/SNF), imitation switch complexes, chromodomain-helicase-DNA-binding complexes, and inositol-requiring eighty complexes[50,51]. All members of each family exhibit distinct unique domains that are served to histone-DNA contacts for DNA movement and chromatin restructuring[52]. The covalently modified histones are recognized by these domains of ATP-dependent chromatin remodelers and thereby regulate an expression of distinct gene programs tailored to specificity and biological functions of each family of chromatin remodeling complexes[53].

Histone modifications

Histone modification represents a dynamic process affected histone proteins (H2A, H2B, H3, and H4) that are composed in the nucleosomes and mediated by several enzymes[54]. As a result, distinct histone amino-terminal modifications appear to be able to induce synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states[55]. By now more than 150 post-translation modifications of histones have been reported, including methylations, acetylations, sumoylation, ubiquitinations, ADP-ribosylation, proline isomerization, and phosphorylations[56]. Appearance of conformational changes in the chromatin resulting in alteration due to histone modifications regulates gene expression depending on depending on whether DNA has been became accessible (defined as euchromatin) or inaccessible (called as heterochromatin) for further transcription process[57].

Recent studies have shown that histone modification predominantly methylation is closely regulates inflammatory and metabolic disorders, as well as links CV disease and vascular homeostasis[58-60]. There is evidence that altered redox signaling might mediate trimethylation of histones H3K4 and H3K9 and thereby links an oxidative stress pathway with biochemical mechanisms underlying HFrEF development[61]. Probably, aging might affect on development neither HFpEF nor HFrEF through so-called "epigenetic drift" via markedly regulation of DNA and histone methylation[62]. However, further investigations are needed to explain in details the role of histone modification in impairment of cardiac structure and functionality.


MicroRNAs (miRNAs) are small non-coding RNAs that exert their function by both transcript degradation and translational inhibition, resulting in changes in target gene and protein expression[63]. It has been suggested that reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart. Indeed, recent studies have shown that the increased expression of miRNA-1, miRNA-21, miRNA-29b, miRNA-129, miRNA-133, miRNA-208, miRNA-210, miRNA-211, miRNA-212, and miRNA-423 and miRNA-499 the reduced expression of miRNA-30, miRNA-182, and miRNA-526 are associated with HF development and progression[64-66]. Therefore, altered microRNA expression in human heart was found in ischemic cardiomyopathy, dilated cardiomyopathy, and aortic stenosis[67,68]. There is evidence that the disproportion between myocardial expressions of alpha- and beta-myosin heavy chain (MHC) might be associated with over-expression of heart-specific miRNA-208a leading to arrhythmia, fibrosis, and cardiac hypertrophy[69]. Nevertheless, miRNA-208a expression is under negatively control of MED13, a subunit of the mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors[70]. The down-regulation of miRNA-1 and up-regulation of miRNA-195 are necessary for cardiac hypertrophy and HFpEF development, while the underlying molecular mechanisms of these effects are not still clear[65,71]. Finally, cardiac hypertrophy may associate with the activation of Nppa, Nppb, and Acta1 (skeletal α-actin) fetal gene program[72]. It has deemed that the key components of cardiomyocyte hypertrophy mediator might be miRNA-dependent regulator of calcium signaling pathways[73]. Whether altered signature of miRNA is considered a clue for cardiac hypertrophy and dysfunction, low number of direct clinical evidence regarding specifically HF phenotypes’ development relating to miRNA signature remains a part of scientific discussion[59].

In conclusion, the current available data preliminary clarify that epigenetic modifications might be discussed as a clue of forming phenotypes of HF, whereas there is no strong evidence regarding epigenetic signatures represent causal pathways leading to specific forms of cardiac remodeling associated with HFrEF or HFpEF. More investigations are required to discover epigenetic regulation features, because of progress in this setting appears to be more much promised for individualized translation medical care.


There are no conflicts of interest with regard to the present study.


1Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016; 133(4): 447-54.

2Güder G, Gelbrich G, Edelmann F, Wachter R, Pieske B, Pankuweit S, Maisch B, Prettin C, Brenner S, Morbach C, Berliner D, Deubner N, Ertl G, Angermann CE, Störk S; Competence Network Heart Failure Germany. Reverse epidemiology in different stages of heart failure. Int J Cardiol. 2015; 184: 216-24.

3van Riet EE, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016; 18(3): 242-52.

4Edelmann F. Epidemiology and prognosis of heart failure. Herz. 2015; 40(2):176-84.

5Jorge AL, Rosa ML, Martins WA, Correia DM, Fernandes LC, Costa JA, Moscavitch SD, Jorge BA, Mesquita ET. The Prevalence of Stages of Heart Failure in Primary Care: A Population-Based Study. J Card Fail. 2016; 22(2): 153-7.

6van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol. 2013; 61(14): 1498-506.

7Bettencourt P, Azevedo A, Fonseca L, Araújo JP, Ferreira S, Almeida R, Rocha-Goncalves F, Ferreira A. Prognosis of decompensated heart failure patients with preserved systolic function is predicted by NT-proBNP variations during hospitalization. Int J Cardiol. 2007; 117(1): 75-9.

8Kang SH, Park JJ, Choi DJ, Yoon CH, Oh IY, Kang SM, Yoo BS, Jeon ES, Kim JJ, Cho MC, Chae SC, Ryu KH, Oh BH; KorHF Registry. Prognostic value of NT-proBNP in heart failure with preserved versus reduced EF. Heart. 2015; 101(23): 1881-8.

9Nichols GA, Reynolds K, Kimes TM, Rosales AG, Chan WW. Comparison of Risk of Re-hospitalization, All-Cause Mortality, and Medical Care Resource Utilization in Patients With Heart Failure and Preserved Versus Reduced Ejection Fraction. Am J Cardiol. 2015; 116(7): 1088-92.

10McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012; 33(14): 1787-847

11Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62(16): e147-239.

12Fischer C, Steyerberg EW, Fonarow GC, Ganiats TG, Lingsma HF. A systematic review and meta-analysis on the association between quality of hospital care and readmission rates in patients with heart failure. Am Heart J. 2015; 170(5): 1005-1017.e2.

13Berezin AE. Predicting Heart Failure Phenotypes using Cardiac Biomarkers: Hype and Hope. J Dis Markers. 2015; 2(4): 1035-1041

14Berezin AE. Prognostication in different heart failure phenotypes: the role of circulating biomarkers. J Circulating Biomarkers. 2016; 5 [ahead of print] doi: 10.5772/62797.

15Napoli C, Grimaldi V, De Pascale MR, Sommese L, Infante T, Soricelli A. Novel epigenetic-based therapies useful in cardiovascular medicine. World J Cardiol. 2016; 8(2): 211-9.

16Hristova K, Singh RB, Fedacko J, Toda E, Kumar A, Saxena M, Baby A, Singh R, Toru T, Wilson DW. Causes and risk factors of congestive heart failure in India. World Heart J. 2013; 5: 13-20.

17Fedacko J, Singh RB, Gupta A, Hristova K, Toda E, Kumar A, Saxena M, Baby A, Singh R, Toru T, Wilson DW. Inflammatory mediators in chronic heart failure in North India. Acta Cardiol. 2014; 69: 391-8.

18Singh N, Gupta N, Gupta R, Ahehab A. Hristova K, Elkilany G, Dherange P. Heart failure biomarkers: importance in prognosis of disease. Editorial, World Heart J 2015; 6: 7-12

19Singh RB, Cornelissen G, Takahashi T, Shastun S. Brain-heart interactions and circadian rhythms in chronic heart failure. World Heart J 2015; 7: 129-142

20Di Salvo TG, Haldar SM. Epigenetic mechanisms in heart failure pathogenesis. Circ Heart Fail. 2014; 7(5): 850-63.

21Mollova MY, Katus HA, Backs J. Regulation of CaMKII signaling in cardiovascular disease. Front Pharmacol. 2015; 6: 178.

22Mann JR. Epigenetics and memigenetics. Cell Mol Life Sci. 2014; 71(7): 1117-22.

23Roloff TC, Nuber UA. Chromatin, epigenetics and stem cells. Eur J Cell Biol. 2005; 84(2-3): 123-35.

24Romanoski CE, Glass CK, Stunnenberg HG, Wilson L, Almouzni G. Epigenomics: Roadmap for regulation. Nature. 2015; 518(7539): 314-6.

25Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009; 23(7): 781-3.

26Cao Y, Lu L, Liu M, Li XC, Sun RR, Zheng Y, Zhang PY. Impact of epigenetics in the management of cardiovascular disease: a review. Eur Rev Med Pharmacol Sci. 2014; 18(20): 3097-104.

27Bronner C, Chataigneau T, Schini-Kerth VB, Landry Y. The "Epigenetic Code Replication Machinery", ECREM: a promising drugable target of the epigenetic cell memory. Curr Med Chem. 2007; 14(25): 2629-41.

28Swaminathan V, Reddy BA, Ruthrotha Selvi B, Sukanya MS, Kundu TK. Small molecule modulators in epigenetics: implications in gene expression and therapeutics. Subcell Biochem. 2007; 41: 397-428.

29Marín-García J, Akhmedov AT. Epigenetics of the failing heart. Heart Fail Rev. 2015; 20(4): 435-59.

30Yang J, Xu WW, Hu SJ. Heart failure: advanced development in genetics and epigenetics. Biomed Res Int. 2015; 2015: 352734.

31Schiano C, Vietri MT, Grimaldi V, Picascia A, Pascale MR, Napoli C. Epigenetic-related therapeutic challenges in cardiovascular disease. Trends Pharmacol Sci. 2015; 36(4): 226-35.

32Berezin AE. Circulating Cell-Free Mitochondrial DNA as Biomarker of Cardiovascular risk: New Challenges of Old Findings. Angiology. 2015; 3: 161-163.

33Berezin AE. Impaired Phenotype of Circulating Endothelial-Derived Microparticles: Novel Marker of Cardiovascular Risk. Journal of Cardiology and Therapy. 2015; 2(4): 273-278.

34Berezin AE. Endothelial Derived Micro Particles: Biomarkers for Heart Failure Diagnosis and Management. J Clin Trial Cardiol. 2015; 2(3): 1-3.

35Berezin A, Kremzer A, Berezina T, Martovotskaya Yu, Gromenko O. Pattern of endothelial progenitor cells and apoptotic endothelial cell-derived microparticles in chronic heart failure patients with preserved and reduced left ventricular ejection fraction. EBioMedicine. 2016; 4: 86-94. doi: 10.1016/j.ebiom.2016.01.018

36Berezin A, Kremzer A, Berezina T, Martovotskaya Yu. Pattern of circulating microparticles in chronic heart failure patients with metabolic syndrome: Relevance to neurohumoral and inflammatory activation. BBA Clinical. 2015; 4: 69-75.

37Duygu B, Poels EM, da Costa Martins PA. Genetics and epigenetics of arrhythmia and heart failure. Front Genet. 2013; 4: 219. doi: 10.3389/fgene.2013.00219.

38Piran S, Liu P, Morales A, Hershberger RE. Where genome meets phenome: rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure. J Am Coll Cardiol. 2012; 60(4): 283-9.

39Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010; 466(7303): 253-7.

40Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, Foo RS. Distinct epigenomic features in end-stage failing human hearts. Circulation. 2011; 124(22): 2411-22.

41Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C, Phelan D, Ledwidge MT, McDonald KM, McCann A, Sharaf O, Baugh JA. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 2014; 23(8): 2176-88.

42 Haider S, Cordeddu L, Robinson E, Movassagh M, Siggens L, Vujic A, Choy MK, Goddard M, Lio P, Foo R. The landscape of DNA repeat elements in human heart failure. Genome Biol. 2012; 13(10): R90.

43 Jones PA. The DNA methylation paradox. Trends Genet. 1999; 15(1): 34-7.

44 Xiao D, Dasgupta C, Chen M, Zhang K, Buchholz J, Xu Z, Zhang L. Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertrophy in rats. Cardiovasc Res. 2014; 101(3): 373-82.

45 Haas J, Frese KS, Park YJ, Keller A, Vogel B, Lindroth AM, Weichenhan D, Franke J, Fischer S, Bauer A, Marquart S, Sedaghat-Hamedani F, Kayvanpour E, Köhler D, Wolf NM, Hassel S, Nietsch R, Wieland T, Ehlermann P, Schultz JH, Dösch A, Mereles D, Hardt S, Backs J, Hoheisel JD, Plass C, Katus HA, Meder B. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol Med 2013; 5(3): 413-29

46 Konig A, Bode C, Bugger H. Diabetes mellitus and myocardial mitochondrial dysfunction: bench to bedside. Heart Fail Clin 2012; 8(4): 551-61

47 Varga-Weisz P. Chromatin remodeling factors and DNA replication. Prog Mol Subcell Biol. 2005; 38: 1-30.

48 Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009; 78: 273-304.

49 Saha A, Wittmeyer J, Cairns BR. Mechanisms for nucleosome movement by ATP-dependent chromatin remodeling complexes. Results Probl Cell Differ. 2006; 41: 127-48.

50 Lange M, Demajo S, Jain P, Di Croce L. Combinatorial assembly and function of chromatin regulatory complexes. Epigenomics. 2011; 3(5): 567-80.

51Ho L, Crabtree GR. Chromatin remodelling during development. Nature. 2010; 463(7280): 474-84.

52 Newell-Price J, Clark AJ, King P. DNA methylation and silencing of gene expression. Trends Endocrinol Metab. 2000;11(4):142–8

53 Chodavarapu RK, Feng S, Bernatavichute YV, Chen PY, Stroud H, Yu Y, Yu Y, Hetzel JA, Kuo F, Kim J, Cokus SJ, Casero D, Bernal M, Huijser P, Clark AT, Krämer U, Merchant SS, Zhang X, Jacobsen SE, Pellegrini M. Relationship between nucleosome positioning and DNA methylation. Nature. 2010; 466(7304): 388–92.

54 Zhang Y, Fatima N, Dufau ML. Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription. Mol Cell Biol. 2005; 25(18): 7929-39.

55 Jenuwein T, Allis CD. Translating the histone code. Science. 2001; 293(5532): 1074-80.

56 Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011; 123(19): 2145-56.

57 Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010; 11(4): 285-96.

58 Robb GB, Carson AR, Tai SC, Fish JE, Singh S, Yamada T, Scherer SW, Nakabayashi K, Marsden PA. Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem. 2004; 279(36): 37982-96.

59 Tai SC, Robb GB, Marsden PA. Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel. Arterioscler Thromb Vasc Biol. 2004; 24(3): 405-12.

60 Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007; 25(1): 1-14.

61 Kim GH, Ryan JJ, Archer SL. The role of redox signaling in epigenetics and cardiovascular disease. Antioxid Redox Signal. 2013; 18(15): 1920-36.

62 Illi B, Ciarapica R, Capogrossi MC. Chromatin methylation and cardiovascular aging. J Mol Cell Cardiol. 2015; 83: 21-31

63 Ambros V. microRNAs: tiny regulators with great potential. Cell. 2001; 107: 823–826

64 Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007; 116(3): 258-67.

65 van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006; 103: 18255–18260.

66 Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 2007; 100: 416–424.

67 Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD, Golub TR, Pieske B, Pu WT. Altered microRNA expression in human heart disease. Physiol Genomics. 2007; 31(3): 367-73.

68 Sucharov C, Bristow MR, Port JD. miRNA expression in the failing human heart: functional correlates. J Mol Cell Cardiol. 2008; 45(2): 185-92.

69 Udali S, Guarini P, Moruzzi S, Choi SW, Friso S. Cardiovascular epigenetics: from DNA methylation to microRNAs. Mol Aspects Med. 2013; 34(4): 883-901.

70 Grueter CE, van Rooij E, Johnson BA, DeLeon SM, Sutherland LB, Qi X, Gautron L, Elmquist JK, Bassel-Duby R, Olson EN. A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell. 2012; 149(3): 671-83.

71 Ikeda S, He A, Kong SW, Lu J, Bejar R, Bodyaket N, Lee KH, Ma Q, Kang PM, Golub TR, Pu WT. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Molecular and Cellular Biology. 2009; 29(8): 2193–2204.

72 Izumo S, Nadal-Ginard B, Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc. Natl. Acad. Sci. USA 1988; 85: 339-343.

73 Bagnall RD, Tsoutsman T, Shephard RE, Ritchie W, Semsarian C. Global microRNA profiling of the mouse ventricles during development of severe hypertrophic cardiomyopathy and heart failure. PLoS ONE 2012; 7: e44744.

Peer reviewers: Ram B Singh, MD, Professor, Internal Medicine and Neurocardiology, Halberg Hospital and Research Institute, Civil Lines, Moradabad (UP) Pin =244001, India; Kartikeya Bhargava, Senior Consultant Cardiology, Medanta Heart Institute, Medanta-The Medicity, Sector 38, Gurgaon – 122001, Haryana, India.


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.