Advertisement

Clinical applications of epigenetics in cardiovascular disease: the long road ahead

Published:April 09, 2014DOI:https://doi.org/10.1016/j.trsl.2014.04.004
      Epigenetic processes, defined as heritable changes in gene expression that occur without changes to the DNA sequence, have emerged as a promising area of cardiovascular disease research. Epigenetic information transcends that of the genotype alone and provides for an integrated etiologic picture of cardiovascular disease pathogenesis because of the interaction of the epigenome with the environment. Epigenetic biomarkers, which include DNA methylation, histone modifications, and RNA-based mechanisms, are both modifiable and cell-type specific, which makes them not only responsive to the environment, but also an attractive target for drug development. However, the enthusiasm surrounding possible applications of cardiovascular epigenetics currently outpaces available evidence. In this review, the authors synthesize the evidence linking epigenetic changes with cardiovascular disease, emphasizing the gap between the translational potential and the clinical reality of cardiovascular epigenetics.

      Abbreviations:

      apoA-I (apolipoprotein A-I), ASSURE (ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation), BET (bromodomain and extraterminal), CpG (cytosine-phosphate-guanine), CVD (cardiovascular disease), HDAC (histone deacetylase), HDL (high-density lipoprotein), LINE-1 (long interspersed nucleotide element 1), SUSTAIN (Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Di Angelantonio E.
        • Butterworth A.S.
        Clinical utility of genetic variants for cardiovascular risk prediction: a futile exercise or insufficient data?.
        Circ Cardiovasc Genet. 2012; 5: 387-390
        • Egger G.
        • Liang G.
        • Aparicio A.
        • et al.
        Epigenetics in human disease and prospects for epigenetic therapy.
        Nature. 2004; 429: 457-463
        • Kaikkonen M.U.
        • Lam M.T.
        • Glass C.K.
        Non-coding RNAs as regulators of gene expression and epigenetics.
        Cardiovasc Res. 2011; 90: 430-440
        • Duygu B.
        • Poels E.M.
        • da Costa Martins P.A.
        Genetics and epigenetics of arrhythmia and heart failure.
        Front Genet. 2013; 4: 219
        • Udali S.
        • Guarini P.
        • Moruzzi S.
        • et al.
        Cardiovascular epigenetics: from DNA methylation to microRNAs.
        Mol Aspects Med. 2013; 34: 883-901
        • Baccarelli A.
        • Rienstra M.
        • Benjamin E.J.
        Cardiovascular epigenetics: basic concepts and results from animal and human studies.
        Circ Cardiovasc Genet. 2010; 3: 567-573
        • Ordovas J.M.
        • Smith C.E.
        Epigenetics and cardiovascular disease.
        Nat Rev Cardiol. 2010; 7: 510-519
        • Grabiec A.M.
        • Reedquist K.A.
        Histone deacetylases in RA: epigenetics and epiphenomena.
        Arthritis Res Ther. 2010; 12: 142
        • Ratan R.R.
        Epigenetics and the nervous system: epiphenomenon or missing piece of the neurotherapeutic puzzle?.
        Lancet Neurol. 2009; 8: 975-977
        • Gopalakrishnan S.
        • Van Emburgh B.O.
        • Robertson K.D.
        DNA methylation in development and human disease.
        Mutat Res. 2008; 647: 30-38
        • Robertson K.D.
        DNA methylation and human disease.
        Nat Rev Genet. 2005; 6: 597-610
        • Jones P.A.
        • Baylin S.B.
        The fundamental role of epigenetic events in cancer.
        Nat Rev Genet. 2002; 3: 415-428
        • Vaissiere T.
        • Sawan C.
        • Herceg Z.
        Epigenetic interplay between histone modifications and DNA methylation in gene silencing.
        Mutat Res. 2008; 659: 40-48
        • Heijmans B.T.
        • Kremer D.
        • Tobi E.W.
        • et al.
        Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus.
        Hum Mol Genet. 2007; 16: 547-554
        • Huh I.
        • Zeng J.
        • Park T.
        • et al.
        DNA methylation and transcriptional noise.
        Epigenetics Chromatin. 2013; 6: 9
        • Hsiung D.T.
        • Marsit C.J.
        • Houseman E.A.
        • et al.
        Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 108-114
        • Handy D.E.
        • Castro R.
        • Loscalzo J.
        Epigenetic modifications: basic mechanisms and role in cardiovascular disease.
        Circulation. 2011; 123: 2145-2156
        • Castro R.
        • Rivera I.
        • Struys E.A.
        • et al.
        Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease.
        Clin Chem. 2003; 49: 1292-1296
        • Sharma P.
        • Kumar J.
        • Garg G.
        • et al.
        Detection of altered global DNA methylation in coronary artery disease patients.
        DNA Cell Biol. 2008; 27: 357-365
        • Stenvinkel P.
        • Karimi M.
        • Johansson S.
        • et al.
        Impact of inflammation on epigenetic DNA methylation: a novel risk factor for cardiovascular disease?.
        J Intern Med. 2007; 261: 488-499
        • Bind M.A.
        • Baccarelli A.
        • Zanobetti A.
        • et al.
        Air pollution and markers of coagulation, inflammation, and endothelial function: associations and epigene-environment interactions in an elderly cohort.
        Epidemiology. 2012; 23: 332-340
        • Baccarelli A.
        • Tarantini L.
        • Wright R.O.
        • et al.
        Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA Normative Aging Study.
        Epigenetics. 2010; 5: 222-228
        • Baccarelli A.
        • Wright R.
        • Bollati V.
        • et al.
        Ischemic heart disease and stroke in relation to blood DNA methylation.
        Epidemiology. 2010; 21: 819-828
        • Cash H.L.
        • McGarvey S.T.
        • Houseman E.A.
        • et al.
        Cardiovascular disease risk factors and DNA methylation at the LINE-1 repeat region in peripheral blood from Samoan islanders.
        Epigenetics. 2011; 6: 1257-1264
        • Turcot V.
        • Tchernof A.
        • Deshaies Y.
        • et al.
        LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes.
        Clin Epigenetics. 2012; 4: 10
        • Bell C.G.
        • Finer S.
        • Lindgren C.M.
        • et al.
        Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.
        PLoS One. 2010; 5: e14040
        • Almen M.S.
        • Jacobsson J.A.
        • Moschonis G.
        • et al.
        Genome wide analysis reveals association of a FTO gene variant with epigenetic changes.
        Genomics. 2012; 99: 132-137
        • Breitling L.P.
        • Salzmann K.
        • Rothenbacher D.
        • et al.
        Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease.
        Eur Heart J. 2012; 33: 2841-2848
        • Talens R.P.
        • Jukema J.W.
        • Trompet S.
        • et al.
        Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction.
        Int J Epidemiol. 2012; 41: 106-115
        • Jiang D.
        • Zheng D.
        • Wang L.
        • et al.
        Elevated PLA2G7 gene promoter methylation as a gender-specific marker of aging increases the risk of coronary heart disease in females.
        PLoS One. 2013; 8: e59752
        • Perkins E.
        • Murphy S.K.
        • Murtha A.P.
        • et al.
        Insulin-like growth factor 2/H19 methylation at birth and risk of overweight and obesity in children.
        J Pediatr. 2012; 161: 31-39
        • Deodati A.
        • Inzaghi E.
        • Liguori A.
        • et al.
        IGF2 methylation is associated with lipid profile in obese children.
        Horm Res Paediatr. 2013; 79: 361-367
        • Yoo J.Y.
        • Lee S.
        • Lee H.A.
        • et al.
        Can proopiomelanocortin methylation be used as an early predictor of metabolic syndrome?.
        Diabetes Care. 2014; 37: 734-739
        • Alexeeff S.E.
        • Baccarelli A.A.
        • Halonen J.
        • et al.
        Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes.
        Int J Epidemiol. 2013; 42: 270-280
        • Friso S.
        • Pizzolo F.
        • Choi S.W.
        • et al.
        Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension.
        Atherosclerosis. 2008; 199: 323-327
        • Guay S.P.
        • Voisin G.
        • Brisson D.
        • et al.
        Epigenome-wide analysis in familial hypercholesterolemia identified new loci associated with high-density lipoprotein cholesterol concentration.
        Epigenomics. 2012; 4: 623-639
        • Xu X.
        • Su S.
        • Barnes V.A.
        • et al.
        A genome-wide methylation study on obesity: differential variability and differential methylation.
        Epigenetics. 2013; 8: 522-533
        • Hidalgo B.
        • Irvin M.R.
        • Sha J.
        • et al.
        Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study.
        Diabetes. 2014; 63: 801-807
        • Haas J.
        • Frese K.S.
        • Park Y.J.
        • et al.
        Alterations in cardiac DNA methylation in human dilated cardiomyopathy.
        EMBO Mol Med. 2013; 5: 413-429
        • Movassagh M.
        • Choy M.K.
        • Knowles D.A.
        • et al.
        Distinct epigenomic features in end-stage failing human hearts.
        Circulation. 2011; 124: 2411-2422
        • Kim M.
        • Long T.I.
        • Arakawa K.
        • et al.
        DNA methylation as a biomarker for cardiovascular disease risk.
        PLoS One. 2010; 5: e9692
        • Cordaux R.
        • Batzer M.A.
        The impact of retrotransposons on human genome evolution.
        Nat Rev Genet. 2009; 10: 691-703
        • Zhu Z.Z.
        • Hou L.
        • Bollati V.
        • et al.
        Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis.
        Int J Epidemiol. 2012; 41: 126-139
        • Liu C.
        • Mou S.
        • Pan C.
        The FTO gene rs9939609 polymorphism predicts risk of cardiovascular disease: a systematic review and meta-analysis.
        PLoS One. 2013; 8: e71901
        • Vimaleswaran K.S.
        • Li S.
        • Zhao J.H.
        • et al.
        Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene.
        Am J Clin Nutr. 2009; 90: 425-428
        • Ronn T.
        • Volkov P.
        • Davegardh C.
        • et al.
        A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.
        PLoS Genet. 2013; 9: e1003572
        • Fu Y.
        • Jia G.
        • Pang X.
        • et al.
        FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA.
        Nat Commun. 2013; 4: 1798
        • Jia G.
        • Fu Y.
        • Zhao X.
        • et al.
        N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
        Nat Chem Biol. 2011; 7: 885-887
        • Smemo S.
        • Tena J.J.
        • Kim K.H.
        • et al.
        Obesity-associated variants within FTO form long-range functional connections with IRX3.
        Nature. 2014; 507: 371-375
        • Zhuang J.
        • Peng W.
        • Li H.
        • et al.
        Methylation of p15INK4b and expression of ANRIL on chromosome 9p21 are associated with coronary artery disease.
        PLoS One. 2012; 7: e47193
        • Kelsall C.J.
        • Hoile S.P.
        • Irvine N.A.
        • et al.
        Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis.
        PLoS One. 2012; 7: e34492
        • Hoile S.P.
        • Irvine N.A.
        • Kelsall C.J.
        • et al.
        Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver.
        J Nutr Biochem. 2013; 24: 1213-1220
        • Rakyan V.K.
        • Down T.A.
        • Balding D.J.
        • et al.
        Epigenome-wide association studies for common human diseases.
        Nat Rev Genet. 2011; 12: 529-541
        • Papait R.
        • Cattaneo P.
        • Kunderfranco P.
        • et al.
        Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy.
        Proc Natl Acad Sci U S A. 2013; 110: 20164-20169
        • Florath I.
        • Butterbach K.
        • Muller H.
        • et al.
        Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites.
        Hum Mol Genet. 2014; 23: 1186-1201
        • Wilhelm-Benartzi C.S.
        • Houseman E.A.
        • Maccani M.A.
        • et al.
        In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta.
        Environ Health Perspect. 2012; 120: 296-302
        • Shenker N.S.
        • Polidoro S.
        • van Veldhoven K.
        • et al.
        Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking.
        Hum Mol Genet. 2013; 22: 843-851
        • Zeilinger S.
        • Kuhnel B.
        • Klopp N.
        • et al.
        Tobacco smoking leads to extensive genome-wide changes in DNA methylation.
        PLoS One. 2013; 8: e63812
        • Zhi D.
        • Aslibekyan S.
        • Irvin M.R.
        • et al.
        SNPs located at CpG sites modulate genome-epigenome interaction.
        Epigenetics. 2013; 8: 802-806
        • Gibbs J.R.
        • van der Brug M.P.
        • Hernandez D.G.
        • et al.
        Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain.
        PLoS Genet. 2010; 6: e1000952
        • Meaburn E.L.
        • Schalkwyk L.C.
        • Mill J.
        Allele-specific methylation in the human genome: implications for genetic studies of complex disease.
        Epigenetics. 2010; 5: 578-582
        • Pickrell J.K.
        • Marioni J.C.
        • Pai A.A.
        • et al.
        Understanding mechanisms underlying human gene expression variation with RNA sequencing.
        Nature. 2010; 464: 768-772
        • Sengupta N.
        • Seto E.
        Regulation of histone deacetylase activities.
        J Cell Biochem. 2004; 93: 57-67
        • van Eijk K.R.
        • de Jong S.
        • Boks M.P.
        • et al.
        Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects.
        BMC Genomics. 2012; 13: 636
        • Zhang D.
        • Cheng L.
        • Badner J.A.
        • et al.
        Genetic control of individual differences in gene-specific methylation in human brain.
        Am J Hum Genet. 2010; 86: 411-419
        • Yu C.E.
        • Cudaback E.
        • Foraker J.
        • et al.
        Epigenetic signature and enhancer activity of the human APOE gene.
        Hum Mol Genet. 2013; 22: 5036-5047
        • Joo J.E.
        • Hiden U.
        • Lassance L.
        • et al.
        Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells.
        BMC Genomics. 2013; 14: 475
        • Johansson A.
        • Enroth S.
        • Gyllensten U.
        Continuous aging of the human DNA methylome throughout the human lifespan.
        PLoS One. 2013; 8: e67378
        • Heyn H.
        • Li N.
        • Ferreira H.J.
        • et al.
        Distinct DNA methylomes of newborns and centenarians.
        Proc Natl Acad Sci U S A. 2012; 109: 10522-10527
        • Kaminsky Z.A.
        • Tang T.
        • Wang S.C.
        • et al.
        DNA methylation profiles in monozygotic and dizygotic twins.
        Nat Genet. 2009; 41: 240-245
        • Marczylo E.L.
        • Amoako A.A.
        • Konje J.C.
        • et al.
        Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern?.
        Epigenetics. 2012; 7: 432-439
        • Laubenthal J.
        • Zlobinskaya O.
        • Poterlowicz K.
        • et al.
        Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring.
        FASEB J. 2012; 26: 3946-3956
        • Zaina S.
        • Lund G.
        Epigenetics: a tool to understand diet-related cardiovascular risk?.
        J Nutrigenet Nutrigenomics. 2011; 4: 261-274
        • Szarc vel Szic K.
        • Ndlovu M.N.
        • Haegeman G.
        • et al.
        Nature or nurture: let food be your epigenetic medicine in chronic inflammatory disorders.
        Biochem Pharmacol. 2010; 80: 1816-1832
        • Newman P.E.
        Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis?.
        Med Hypotheses. 1999; 53: 421-424
        • Esteller M.
        Epigenetics in biology and medicine.
        CRC Press, Boca Raton, FL2008:: 212
        • Fang M.
        • Chen D.
        • Yang C.S.
        Dietary polyphenols may affect DNA methylation.
        J Nutr. 2007; 137: 223s-228s
        • Lee W.J.
        • Shim J.Y.
        • Zhu B.T.
        Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids.
        Mol Pharmacol. 2005; 68: 1018-1030
        • Pilsner J.R.
        • Hall M.N.
        • Liu X.
        • et al.
        Associations of plasma selenium with arsenic and genomic methylation of leukocyte DNA in Bangladesh.
        Environ Health Perspect. 2011; 119: 113-118
        • Crescenti A.
        • Sola R.
        • Valls R.M.
        • et al.
        Cocoa consumption alters the global DNA methylation of peripheral leukocytes in humans with cardiovascular disease risk factors: a randomized controlled trial.
        PLoS One. 2013; 8: e65744
        • Milagro F.I.
        • Campion J.
        • Cordero P.
        • et al.
        A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss.
        FASEB J. 2011; 25: 1378-1389
        • Moleres A.
        • Campion J.
        • Milagro F.I.
        • et al.
        Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON Study.
        FASEB J. 2013; 27: 2504-2512
        • Lopez-Legarrea P.
        • Mansego M.L.
        • Zulet M.A.
        • et al.
        SERPINE1, PAI-1 protein coding gene, methylation levels and epigenetic relationships with adiposity changes in obese subjects with metabolic syndrome features under dietary restriction.
        J Clin Biochem Nutr. 2013; 53: 139-144
        • Bell J.T.
        • Tsai P.C.
        • Yang T.P.
        • et al.
        Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
        PLoS Genet. 2012; 8: e1002629
        • Tobi E.W.
        • Lumey L.H.
        • Talens R.P.
        • et al.
        DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.
        Hum Mol Genet. 2009; 18: 4046-4053
        • Csoka A.B.
        • Szyf M.
        Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology.
        Med Hypotheses. 2009; 73: 770-780
        • Napoli C.
        • Infante T.
        • Casamassimi A.
        Maternal-foetal epigenetic interactions in the beginning of cardiovascular damage.
        Cardiovasc Res. 2011; 92: 367-374
        • Arce C.
        • Segura-Pacheco B.
        • Perez-Cardenas E.
        • et al.
        Hydralazine target: from blood vessels to the epigenome.
        J Transl Med. 2006; 4: 10
        • Lee B.H.
        • Yegnasubramanian S.
        • Lin X.
        • et al.
        Procainamide is a specific inhibitor of DNA methyltransferase 1.
        J Biol Chem. 2005; 280: 40749-40756
        • Cornacchia E.
        • Golbus J.
        • Maybaum J.
        • et al.
        Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.
        J Immunol. 1988; 140: 2197-2200
        • Zhou Y.
        • Lu Q.
        DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients.
        Autoimmun Rev. 2008; 7: 376-383
        • Singh V.
        • Sharma P.
        • Capalash N.
        DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer.
        Curr Cancer Drug Targets. 2013; 13: 379-399
        • Lin Y.C.
        • Lin J.H.
        • Chou C.W.
        • et al.
        Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.
        Cancer Res. 2008; 68: 2375-2383
        • Mitro N.
        • Godio C.
        • De Fabiani E.
        • et al.
        Insights in the regulation of cholesterol 7alpha-hydroxylase gene reveal a target for modulating bile acid synthesis.
        Hepatology. 2007; 46: 885-897
        • Haberland M.
        • Montgomery R.L.
        • Olson E.N.
        The many roles of histone deacetylases in development and physiology: implications for disease and therapy.
        Nat Rev Genet. 2009; 10: 32-42
        • Lehmann L.H.
        • Worst B.C.
        • Stanmore D.A.
        • et al.
        Histone deacetylase signaling in cardioprotection.
        Cell Mol Life Sci. 2014; 71: 1673-1690
        • Choi M.C.
        • Cohen T.J.
        • Barrientos T.
        • et al.
        A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.
        Mol Cell. 2012; 47: 122-132
        • McKinsey T.A.
        Therapeutic potential for HDAC inhibitors in the heart.
        Annu Rev Pharmacol Toxicol. 2012; 52: 303-319
        • Zhao T.C.
        • Du J.
        • Zhuang S.
        • et al.
        HDAC inhibition elicits myocardial protective effect through modulation of MKK3/Akt-1.
        PLoS One. 2013; 8: e65474
        • Zhao T.C.
        • Zhang L.X.
        • Cheng G.
        • et al.
        gp-91 mediates histone deacetylase inhibition-induced cardioprotection.
        Biochim Biophys Acta. 2010; 1803: 872-880
        • Meng X.
        • Zhang K.
        • Li J.
        • et al.
        Statins induce the accumulation of regulatory T cells in atherosclerotic plaque.
        Mol Med. 2012; 18: 598-605
        • Tao H.
        • Shi K.H.
        • Yang J.J.
        • et al.
        Histone deacetylases in cardiac fibrosis: current perspectives for therapy.
        Cell Signal. 2014; 26: 521-527
        • Verdin E.
        • Dequiedt F.
        • Kasler H.G.
        Class II histone deacetylases: versatile regulators.
        Trends Genet. 2003; 19: 286-293
        • Vojinovic J.
        • Damjanov N.
        HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis.
        Mol Med. 2011; 17: 397-403
        • Dje N’Guessan P.
        • Riediger F.
        • Vardarova K.
        • et al.
        Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells.
        Arterioscler Thromb Vasc Biol. 2009; 29: 380-386
        • Chen J.B.
        • Chern T.R.
        • Wei T.T.
        • et al.
        Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment.
        J Med Chem. 2013; 56: 3645-3655
        • Hanai J.
        • Cao P.
        • Tanksale P.
        • et al.
        The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity.
        J Clin Invest. 2007; 117: 3940-3951
        • Buettner C.
        • Lecker S.H.
        Molecular basis for statin-induced muscle toxicity: implications and possibilities.
        Pharmacogenomics. 2008; 9: 1133-1142
        • Bailey D.
        • Jahagirdar R.
        • Gordon A.
        • et al.
        RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo.
        J Am Coll Cardiol. 2010; 55: 2580-2589
        • Anand P.
        • Brown J.D.
        • Lin C.Y.
        • et al.
        BET bromodomains mediate transcriptional pause release in heart failure.
        Cell. 2013; 154: 569-582
        • Nicholls S.J.
        • Gordon A.
        • Johannson J.
        • et al.
        ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies.
        Cardiovasc Drugs Ther. 2012; 26: 181-187
      1. Resverlogix Corp. Resverlogix’s BET protein inhibitor RVX-208 meets primary endpoint in SUSTAIN clinical trial in patients with high risk cardiovascular disease. 2012. Available at: http://www.resverlogix.com/media/press-release.html?id=475. Accessed on January 16, 2014.

        • Nicholls S.J.
        • Chapman J.
        ASSURE: effect of an oral agent inducing Apo A-I synthesis on progression of coronary atherosclerosis: results of the ASSURE study.
        European Society of Cardiology Congress, Amsterdam2013
      2. Resverlogix Corp. Resverlogix announces combined RVX-208 findings from SUSTAIN & ASSURE phase 2b trials. 2014. Available at: http://www.resverlogix.com/media/press-release.html?id=497. Accessed on January 16, 2014.

        • Jaguszewski M.
        • Osipova J.
        • Ghadri J.R.
        • et al.
        A signature of circulating microRNAs differentiates Takotsubo cardiomyopathy from acute myocardial infarction.
        Eur Heart J. 2014; 35: 999-1006
        • Raizman J.E.
        • Diamandis E.P.
        • Rayner K.
        • et al.
        Novel biomarkers for acute myocardial infarction: is microRNA the new kid on the block?.
        Clin Chem. 2013;