Review Article Heart Failure: Advanced Development …downloads.hindawi.com/journals/bmri/2015/352734.pdfMyosin heavy chain % Cardiacmusclebetaisoform MYBPC Myosin-binding protein

Review ArticleHeart Failure Advanced Development inGenetics and Epigenetics

Jian Yang Wei-wei Xu and Shen-jiang Hu

Department of Cardiology The First Affiliated Hospital College of Medicine Zhejiang University No 79 Qing-Chun RoadHangzhou 310003 China

Correspondence should be addressed to Shen-jiang Hu s0hu0001hotmailcom

Received 27 November 2014 Revised 25 February 2015 Accepted 19 March 2015

Academic Editor Daniele Catalucci

Copyright copy 2015 Jian Yang et alThis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Heart failure (HF) is a complex pathophysiological syndrome that arises from a primary defect in the ability of the heart to take inandor eject sufficient blood Genetic mutations associated with familial dilated cardiomyopathy hypertrophic cardiomyopathyand arrhythmogenic right ventricular cardiomyopathy can contribute to the various pathologies of HF Therefore geneticscreening could be an approach for guiding individualized therapies and surveillance In addition epigenetic regulation occursvia key mechanisms including ATP-dependent chromatin remodeling DNA methylation histone modification and RNA-basedmechanisms MicroRNA is also a hot spot in HF research This review gives an overview of genetic mutations associated withcardiomyopathy and the roles of some epigenetic mechanisms in HF

1 Background

Heart failure (HF) is a complex pathophysiological syn-drome that arises from a primary defect in the ability ofthe heart to take in andor eject sufficient blood [1] Theclinical manifestations of HF mainly arise from the primarymyocardial disease most commonly coronary artery diseasehypertension and inherited cardiomyopathy Although theetiology is highly variable HF represents a derangementof the interplay between the cardiac renal and vascularsystemsWithout successful intervention inadequate systolicor diastolic cardiac function causes poor systemic blood flowleading to compensatory neurohormone release vasocon-striction and fluid retention HF remains the most devastat-ing cardiovascular disease in terms of morbidity mortalityquality of life and health care costs and is still the number onekiller in the western world It is estimated that symptomaticHF currently affects 04ndash2 of the general population inthe western world [2] However importantly the incidence ofsymptomatic HF increases substantially with increasing ageand the prevalence of symptomatic HF in individuals over 65years of age is estimated to be 6ndash10 Up to 50 of patients

diagnosed with HFwill die within four years and for patientswith end-stage HF the one-year-survival rate is 50 whichis worse than most advanced malignancies [2]

2 Genetics

Genetic mutations can contribute to the various pathologiesof HF by altering the structures and functions of the pro-teins responsible for various cellular activities The currentclassification of cardiomyopathies by the European Society ofCardiology recognizes fourmajor types of cardiomyopathieshypertrophic cardiomyopathy (HCM) dilated cardiomyopa-thy (DCM) restrictive cardiomyopathy (RCM) and arrhyth-mogenic right ventricular cardiomyopathy (ARVC) as wellas unclassified cardiomyopathies such as noncompactioncardiomyopathy (NCCM) [3] In the past few years over 100cardiomyopathy-related genes have been identified Approx-imately 30 genes have been identified that are associated withHCM 40 with DCM 10 with RCM five with ARVC and 10with NCCM [4ndash6] Here we present detailed introductionsto familial dilated cardiomyopathy (FDCM) familial hyper-trophic cardiomyopathy (FHCM) and ARVC

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 352734 11 pageshttpdxdoiorg1011552015352734

2 BioMed Research International

Table 1 Main dilated cardiomyopathy-causing genes dilated cardiomyopathy

Gene Protein OMIM of familial DCM cases InheritancepatternTTN Titin 188840 15ndash27 ADLMNA Lamin AC 150330 6 ADMYH7 120573-myosin heavy chain 160760 420 ADMYPN Myopalladin 608517 350 ADTNNT2 Cardiac troponin T 191045 290 AD

Table 2 Main dilated cardiomyopathy-causing genes hypertrophic cardiomyopathy

Gene Protein OMIM of familial HCM cases

MYH7 Myosin heavy chain 160760 40Cardiac muscle beta isoform 192600

MYBPC3 Myosin-binding protein C cardiac-type 600958 40TNNT2 Troponin T cardiac muscle 115195 5TNNI3 Troponin I cardiac muscle 191044 5

TPM1 Tropomyosin 1 alpha chain 115196 2191010

MYL2 Myosin regulatory light chain 2 160781 Unknownventricularcardiac muscle isoform 608758

MYL3 Myosin light polypeptide 3 160790 1608751

21 Dilated Cardiomyopathy Modern familial screeningstudies have shown that up to 48 of DCMmay be inherited[7] To date mutations in more than 40 genes have beenimplicated in the development ofDCM[8] InheritedDCM isusually transmitted as an autosomal dominant trait althoughall other single inheritance patterns have been identified(autosomal recessive X-linked and mitochondrial) [7] In arecent study of 312 patients FDCMwith a phenotype of highage penetrance andworse outcomes inmales which occurredin 27 was attributed to truncationmutations in titin (TTN)[9 10] Genome-wide mapping and exome sequencing in aunique affected family have identifiedGATAD1 encoding theGATA zinc finger domain containing protein 1 as anotherpathogenic gene causing autosomal recessive DCM [11 12]The main DCM-causing genes are shown in Table 1

22 Hypertrophic Cardiomyopathy HCM is characterizedas left ventricular hypertrophy in the absence of abnormalloading conditions sufficient to explain the observed degreeof hypertrophy [13] Recent studies have shown that 67 ofHCM is inherited [14] HCM is caused by mutations in genesencoding myofilament proteins of the sarcomere Z-discproteins Ca2+ -handling proteins and other proteins relatedto the sarcomere The majority of patients with FHCM showautosomal dominant mutations in genes encoding sarcomereproteins such as 120573-myosin heavy chain (MYH7) cardiacmyosin-binding protein C (MYBPC3) cardiac troponin T(TNNT2) troponin I (TNNI3) alpha-tropomyosin (TPM1)myosin light chains (MYL2 and MYL3) and cardiac actin(ACTC1) [15ndash17]Mutations in genes encoding other sarcom-ere or related proteins including alpha-myosin heavy chain(MYH6) and titin (TTN) genes encoding Z-disc proteins

such as muscle LIM protein (CSRP3) or genes encodingcalcium-handling proteins (eg phospholamban) individu-ally account for less than 1 of cases Recently the mito-chondrial 16S rRNA 2336TgtCmutation has been reported tobe another pathogenic gene alteration associated with HCMwhen the RNA of another unique family was sequenced[18]

The main HCM-related genes are shown in Table 2

23 Arrhythmogenic Right Ventricular CardiomyopathyArrhythmogenic right ventricular cardiomyopathy (ARVC)is increasingly designated arrhythmogenic cardiomyopathybecause biventricular and left-dominant forms arerecognized [19] Around 40 of patients with ARVC carrypathogenic mutations in the similar genes as observed forother myocardium such as HCM and DCM [20] In mostpatients the disease is inherited as an autosomal dominantdisease caused bymutations in one of the five genes encodingdesmosomal proteins plakophilin-2 (PKP2) desmoplakin(DSP) plakoglobin (JUP) desmoglein-2 (DSG2) anddesmocollin-2 (DSC2) Nondesmosomal genes implicated inthe disease include the transforming growth factor 3(TGFB3) cardiac ryanodine receptor 2 (RYR2) andtransmembrane protein 43 (TMEM43) [21] A novel geneticvariant in the transcription factor Islet-1 has been shownin recent studies to be associated with the onset of ARVC[22ndash24] The main genes which are involved in ARVC areshown in Table 3

Interestingly the genes causing different types of car-diomyopathy overlap to a large extent and mutations in thesame gene may in some instances exert opposite functionaleffects [25 26] How the variations in a single gene generate

BioMed Research International 3

Table 3 Main arrhythmogenic right ventricular cardiomyopathy-causing genes hypertrophic cardiomyopathy

Gene Protein OMIM of familial ARVC casesDSP Desmoplakin 125647 6ndash16PKP2 Plakophilin 2 602861 11ndash43DSG2 Desmoglein 2 125671 12ndash40

Table 4 Cardiomyopathy Genes and Associated Clinical Features

Gene DCM HCM ARVC Inheritance LocationroleAbcc9 X AD Potassium channelACTC1 X X AD SarcomereACTN2 X X AD Z-diskDES X X AD Intermediate filamentDSC2 X X AD DesmosomeDSG2 X X AD DesmosomeDSP X X AD AR DesmosomeLAMP2 X X XL LysosomeLMNA X AD Nuclear membraneMYBPC3 X X AD SarcomereMYH7 X X X AD SarcomerePKP2 X X AD DesmosomeTNNC1 X X AD SarcomereTNNI3 X X AD SarcomereTNNT2 X X AD SarcomereTTN X X X AD Sarcomere

different cardiomyopathic phenotypes is unknown but cur-rent hypotheses under investigation involve transcriptionalregulation posttranslational modification modifier variantsof other genes environmental influences and the differentialeffects of the specific regions of the protein affected by themutations Detailed information is shown in Table 4

24 Future Development Gene Screening Epidemiologicalstudies that include family histories and echocardiographicscreening of first-degree relatives have found that left ven-tricular remodeling and depressed fractional shortening arecommon in the asymptomatic relatives of patients with inher-ited cardiomyopathy and are associated with a statisticallysignificant medium-term risk of disease progression [27ndash31]Thus genetic screening is extremely important because it canidentify relatives at risk of developing the disease allowingtheir early treatment and correct surveillance [28 32 33]Family screening and genetic testing in families with a historyof cardiomyopathy are recommended in clinical guidelines[34 35] In the last few years next-generation sequencingtechniques have improved the efficiency and speed of genesequencing and extensive and cheaper panels of DCM genesare now available giving hope for the early detection offamilial cardiomyopathy [36 37]

Next-generation sequencing (NGS) technologies allowmassively parallel DNA sequencing of gene panels the wholecoding sequence (exome) or the whole genome sequence(WGS) in a single experiment at an affordable price anda timeline of days or weeks a significant advantage over

traditional Sanger sequencing [38] NGS technologies offerthe advantage of unbiased genome-wide variant detectionin small nuclear families and sporadic cases that previouslycould not be used effectively with traditional linkage analysisPresently the speed at which NGS can identify novel geneticvariants of unknown significance is far greater than the speedat which functional assays can be used to assess variantpathogenicity [20]

However the use of genetic testing in clinical practiceis not common today for reasons including the cost andcomplexity of the sequencing technologies Moreover therelatively low quality of genetic testing can detect pathogenicvariants in only about 50 of individuals with familial HCMDCM or ARVC [8 35 39] Another factor that limits theclinical application of genetics is our poor understanding ofgenotype-phenotype relationships [36] Many of the clinicalassociations initially established for individual mutationshave not been reproducible [40 41] An exceptionmay be thepoor prognoses for compound or double heterozygotes [4243] especially in individuals with HCM or ARVC Patientscarrying multiple mutations are more likely to present earlierand with more-severe disease A genotype-phenotype asso-ciation recently proposed in HCM showed increased cardio-vascular events and the more frequent evolution to a dilatedphenotype in the presence of any sarcomere-related genemutation compared to genotype-negative patients [44 45]Finally it is increasingly recognized that the genetic back-grounds of different inherited cardiomyopathies overlapsubstantially This further challenges current attempts to


establish genotype-phenotype relationships Widely differentphenotypes (dilation noncompaction and hypertrophy) canbe caused bymutations in the same genes or even by the samemutations [36 46]

In the future continuing advances in the field willincrease the uptake of genetic testing when lower costs makeit a routine technology in daily clinical practice As the num-ber of patients who undergo genetic testing increases and theavailability of genetic databases improves the interpretationof genetic findings will become easier and more robust Theinformation obtained from large cohorts of patients carryingthe same mutated genes will be the first step towards thedesign and adoption of genetically individualized therapiesand surveillance

3 Epigenetics

31 Chromatin Remodeling There are four different familiesof ATP-dependent chromatin remodeling complexes switch-ing defectivesucrose nonfermenting complexes (SWISNF)imitation switch complexes chromodomain-helicase-DNA-binding complexes and inositol-requiring 80 complexes[47ndash49] In this section we will focus on the brahma-associated factor (BAF) complex the vertebrate orthologueof the SWISNF complex which was initially identified inSaccharomyces cerevisiae In mammals there are 14 BAFsubunits which contain either brahma (BRM) or brahma-related gene 1 (BRG1) as the ATPase subunit Certain BAFsubunits are only expressed in specific cell types definingthe tissue- or cell-type-specific BAF complexes The BAFcomplex is involved in several cellular processes includingheart and muscle development [50] BRG1 plays a key role inthe switch from the fetal myosin heavy chain isoform (ie120573-MHC or MYH7) to the adult MHC (120572-MHC or MYH6)during cardiac hypertrophy BRG1 is activated in HCM andits levels correlate with disease severityTherefore preventingthe reexpression of BRG1 reduces hypertrophy and reversesthe shift in myosin isoforms [51]

32 DNA Methylation DNA methylation is the most com-mon epigenetic modification in the mammalian genome[52 53] A genome-wide study of DNA methylation inthe hearts of end-stage cardiomyopathic patients showedthat methylation was significantly reduced in the promotersof upregulated genes but unchanged in the promoters ofdownregulated genes [54] A recent genome-wide analysisof repetitive element methylation in the cardiac genomerevealed that the hypomethylation of satellite elements wasassociated with significant upregulation of juxtacentromericSATELLITE transcripts in diseased hearts compared withhealthy controls [55] Researchers also found an altered DNAmethylation pattern in the myocardia of patients with idio-pathic DCM causing the misexpression of the genes for lym-phocyte antigen 75 (LY75) and the tyrosine kinase-type cellsurface receptor HER3 (ERBB3) the zebrafish orthologuesof which are important for both adaptive and maladaptiveresponses in HF [56] There is new evidence that increasedDNA methylation plays a causative role in programming

heart hypertrophy and reducing cardiac contractility sug-gesting that demethylation is a potential therapeutic strategyin the treatment of HF and ischemic heart disease [57]Thesestudies support the possible role of DNA methylation inregulating the changes in gene expression that underlie HFMovassagh et al identified three angiogenic factors whoseexpression could be regulated byDNAmethylation in humanheart failure Plateletendothelial cell adhesion molecule 1(PECAM1) angiomotin-like 2 (AMOTL2) and Rho GTPaseactivating protein 24 (ARHGAP24) showed possible novelgenetic pathways through the process of methylation [54]Expression of these methylating enzymes was shown to beregulated by hypoxia-inducible factor- (HIF-) 1alpha whichmay prove to be a valuable therapeutic approach [58]DNMT3A likely plays an essential role in RASSF1Amediatedupregulation of ERK12 in rat cardiac fibrosis [59] Howeverthey do not clearly demonstrate whether these epigeneticmarkers are involved in regulating gene expression in cardiachypertrophy or the stage in the pathology at which they areinvolved Despite this inhibitors of DNA methylation area potential therapy for preventing cardiac hypertrophy andtreating HF because they reverse norepinephrine-inducedand calcium-induced cardiac hypertrophy in rats [57 60ndash62]Further studies are still required

33 Histone Modification Histone acetylation occurs atthe lysine residues of the histone tails resulting in thedecondensation of the chromatin structure and acting asbinding sites for bromodomain proteins and transcriptionalactivators eventually leading to transcriptional activation[63] A genome-wide analysis of histone markers that iden-tify the epigenetic signatures of promoters and enhancersunderlying cardiac hypertrophy indicated that the epigeneticlandscape is a key determinant of the reprogramming ofgene expression that occurs in cardiac hypertrophy [64]The acetylation of histones is a dynamic process regulatedby two enzyme families the histone acetyltransferases andthe histone deacetylases (HDACs) The balance between theactivities of these two sets of enzymes is crucial for theregulation of gene expression and its deregulation is linkedto several pathological conditions in the development of HFFor example sirtuins are a highly conserved family of his-toneprotein deacetylases and have been shown to participatein biological functions related to the development of heartfailure including regulation of energy production oxidativestress intracellular signaling angiogenesis autophagy andcell deathsurvival Emerging evidence indicates that twosirtuins (SIRT1 and SIRT3) play protective roles in failinghearts [65]

ThusHDAC inhibitors have been suggested to restore thecorrect gene expression program in hypertrophied cardiaccells as a prophylactic treatment for HF Studies showedthat cardiac fibrosis and hypertrophy were prevented bytreatment with class I HDAC inhibitors [66ndash68] HDACinhibitors increase the acetylation of the sarcomeric proteinsthat enhance myofilament calcium sensitivity in cardiac cells[69] Identifying the molecular targets of HDAC inhibitorscould provide important information for the development ofnew drugs for cardiac hypertrophy and HF


Table 5 Main involved miRNAs in heart failure

MicroRNA Expression in HF Function in cardiac vascular system1 Downregulated Development and function of cardiac and skeletal muscle1516 Upregulated Apoptosis induction

21 Upregulated Induced in endothelial cells by shear stress modulates theapoptosis and eNOS activity

195 Upregulated Involved in myocyte hypertrophy and dilatedcardiomyopathy

199a Upregulated Essential for maintaining the cardiomyocytes size

133 Downregulated Development and function of cardiac and skeletal muscleRegulation of beta-adrenergic receptors

23a Upregulated Involved in the regulation of cardiac hypertrophy320 Upregulated Involved in the regulation of cardiac ischemia injury

208 Upregulated Stress-induced cardiac hypertrophy Reduced 120573-MHCexpression

Surprisingly another study revealed that estrogenic com-pounds derepressed the opposite effects of angiotensin II onthe same parameters for HDAC4 and 5 (class II) [70] Thismechanism potentially supports the use of ER120573 agonists asHDAC modulators to treat cardiac disease

The methylation of histones is a dynamic process medi-ated by histone methyltransferases and histone demethylases[71] and unlike acetylation histone methylation can eitheractivate or repress gene expression depending on the targetsite and the degree of methylationThe genome-wide histonemethylation profile for HF showed that the trimethylationof histone H3 on lysine 4 (K4TM) or lysine 9 (K9TM) ismarkedly affected in cardiomyocytes during the developmentof HF in a rat disease model [72] Another study concludedthat HDAC4 plays an essential role in an acute increaseof cardiac preload induced HDAC4 nuclear export H3K9demethylation HP1 dissociation from the promoter regionand activation of the ANP gene and may represent a targetfor pharmacological interventions that prevent maladaptiveremodeling in patients with HF [73]

34 MicroRNA-Based Mechanisms MicroRNAs are single-stranded about 22 nt-long ncRNAs that regulate gene expres-sion mainly by forming partial hybrids with target mRNAsand thereby lowering their translation andor stability [74]A microRNA is transcribed as a long primary miRNA(primiRNA) which is cleaved by themicroprocessor complexto generate a miRNA precursor (premiRNA) that is exportedto the cytoplasm [75] In the last two decades miRNAhas fundamentally transformed our understanding of howgene networks are regulated and has become one of themost exciting areas in modern cardiological research Itwas first discovered in 2007 that the increased expressionof miR-21 miR-29b miR-129 miR-210 miR-211 miR-212and miR-423 and the reduced expression of miR-30 miR-182 and miR-526 are associated with human HF [76] Sincethen many miRNAs have been shown to be deregulated inspecific tissues playing critical roles in the pathogenesis andprogression of HF Four miRNAs are highly expressed in theheart miR-1 miR-133 miR-208 and miR-499

ThemainmiRNAs involved are shown in Table 5 In stud-ies by Ikeda et al [77] and Sucharov et al [78] the expressionpatterns of miRNAs in samples of myocardia from patientswith ischemic cardiomyopathy idiopathic cardiomyopathyor aortic stenosis were analyzed Interestingly their resultsshowed that subsets of miRNAs are differentially regulated ineach of these etiologies

Cardiac contractility depends on the expression of thetwo MHC isoforms 120572- and 120573-MHC and changes in theirproportions may lead to hypertrophy fibrosis and theserious disruption of the contractile function of the heartThe increased expression of 120573-MHC in the myocardium acommon feature of cardiac hypertrophy and HF may reducethe power output and can contribute to the depressed systolicfunction in end-stage HF [79] Recently an increase in 120573-MHC was associated with the overexpression of miR-208a inthe heart leading to arrhythmia fibrosis and hypertrophicgrowth in mice and poor clinical outcomes in humans withDCM [80] miR-208a also controls systemic energy home-ostasis by regulating the expression of MED13 suggesting arole for the heart in systemic metabolic control [81]

The downregulation of miR-1 is necessary to relievethe repression of growth-related target genes and induceshypertrophy [82] miR-1 downregulates calcium-calmodulinsignaling through calcineurin to nuclear factor of activatedT-cells (NFAT) [83] The reduction of miR-1 and increasein ANXA5 appear to be important modulators of NCX1expression and activity during HF [84]

miR-195 is upregulated during hypertrophy The cardiacoverexpression of miR-195 in vivo can drive cardiac hyper-trophy which rapidly transitions to HF [85] However themechanism by which miR-195 promotes hypertrophy is notwell understood Recent studies have shown that miR-195potentially targets several genes involved in multiple signal-ing pathways for example GADD45GMAP2K1MRAS andRAF1 which are involved in the MAPK signaling pathway[81] Meanwhile miR-195 targets the HMGA MO25 genewhich is involved in apoptosis signaling [82 83] Thesefindings suggest the potential mechanisms underlying thepathological role of miR-195 in hypertrophy


miR-499 has been shown to enhance cardiomyogenesisin vitro and after infarction in vivo which indicates that itenhances myocyte differentiationhypertrophy [86] Anotherstudy found that increased miR-499 in cardiac hypertro-phy and cardiomyopathy is sufficient to cause murine HFand accelerates the maladaptation to pressure overloadingin mice and humans [87] These findings are similar toour finding that the expression of miR-499 increases aftersurgery for transverse aortic constriction A bioinformaticsanalysis indicated that miR-499 might interfere with theWNT JAKSTAT and apoptosis signaling pathways duringthe development of hypertrophy [87 88] miR-23 and miR-24were recently shown to be upregulated in hypertrophic andischemic cardiomyopathy [77]They show similar expressionpatterns and were predicted in this study to regulate MAPKand WNT signaling

miR-21 is a miRNA that shows a consistent overex-pression pattern in HF The expression of miR-21 seemsto be induced in endothelial cells by shear stress andregulates the function of vascular smooth muscle cells bymodulating endothelial nitric oxide synthase (eNOS) activity[89] Another study identified fibroblast exosomal-derivedmiR-21 3p (miR-21lowast) as a potent paracrine-acting RNAmolecule that induces cardiomyocyte hypertrophy Proteomeprofiling identified sorbin SH3 domain-containing protein2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) asmiR-21lowast targets and miR-21lowast silences SORBS2 or PDLIM5expression in cardiomyocyte-induced hypertrophy [90]Fibroblast-derivedmiR-21lowast is a paracrine signalingmediatorof cardiomyocyte hypertrophy and a potential therapeutictarget

NFAT and miR-25 cooperate to reactivate the transcrip-tion factor HAND2 in HF [91] Recently Wahlquist et alreported the pathological upregulation of miR-25 during HFand showed that its inhibition blocked and reversed thedisease in mice Although an increase in cardiac miR-25levels caused a decline in cardiac function antimiRNA-basedinhibition of miR-25 halted established HF at least in partby increasing themRNA of SERCA2a [92] suggesting that aninhibitor ofmiR-25will be a potential therapeutic agent in thefutureThe above two studies show controversial data becauseof different chemistries and dose and at different times afterthe initiation of pressure-overload stress it is conceivablethat miR-25 could play a beneficial role acutely by helpingthe heart adapt to pressure stress but produce long-termmaladaptive effects Future studies with expanded group sizeswill be vitally important to further explore the therapeuticrelevance of miR-25 inhibition in the setting of heart failure

miR-133 is expressed in adult cardiomyocytes and skeletalmuscle Research showed that miR-133 levels reduced in theinfarcted areas of the heart [93] Among the miRNA alteredin pressure-overload cardiac hypertrophy models miR-133was singularly downregulated [94] Overexpressing miR-133reduced apoptosis and increased viability of H9c2 cells afterexposure to H

2O2 whereas downregulating miR-133 expres-

sion with an inhibitory oligonucleotide promoted apoptosisin these cells and in neonatal rat ventricular cardiomyocytes[95] Heart function has been restored by reprogramming

nonmyocytes into cardiomyocytes by expressing transcrip-tion factors (GATA4 HAND2 myocyte-specific enhancerfactor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs(miR-1 miR-133 miR-208 and miR-499) [96] indicatingthat miR-133 could be a potential drug target for cardiacremodeling

Expression of miR-199b was shown to be elevated inmouse models with pathological hypertrophy and in humanfailing hearts da CostaMartins et al recently describedmiR-199b involvement in an autoamplification loop promotingCNNFAT signaling Modulation of Dyrk1a by miR-199bconstitutes a feed forward mechanism that enhances patho-logical cardiomyocyte hypertrophy processes [97] Admin-istration of antagomiR-199b to mice after transverse aor-tic constriction could reverse andor attenuate pathologicalhypertrophy and fibrosis [97] Further we identified thatthe TWIST1miR-199214 axis is downregulated in dilatedcardiomyopathy which is likely to play a role in the increasedactivity of the UPS [98] This may contribute to the lossof cardiac mass during dilatation of the heart Besidesin vivo experiments using endothelial cell-specific MeCP2null or Sirt1 transgenic mice confirmed the involvementof MeCP2Sirt1 in the regulation of angiogenic functionsof endothelial cells TGF-120573 impairs endothelial angiogenicresponses partly by downregulating miR-30a-3p and subse-quent derepression of MeCP2-mediated epigenetic silencingof Sirt1 [99]

Recent evidence has shown that a proportion of circulat-ing miRNAs are secreted from normal healthy or damagedcells as microvesicles The fact that these circulating miRNAscan be detected in the peripheral blood makes them poten-tially useful in diagnosis or to guide therapy with rapid andsimple tests that eliminate the need for invasive proceduressuch as biopsies [100]

Recent studies have shown that miR-103 miR-142-3pmiR-199a-3p miR-23a miR-27b miR-324-5p and miR-342-3p can be used to distinguish between HF exacerbatedchronic obstructive pulmonary disease other causes of dys-pnea and controls [101] The miRNAs miR-126 and miR-508-5p could also be useful in the diagnosis of chronic HFpatients and might provide novel targets for the preventionand treatment of chronic HF [102] FABP3 a miRNA targetcan be used as an indicator of myocardial miRNA expressionand function in humanHFpatients [103] OthermiRNAs thatcan be used as biomarkers for the diagnosis and prognosis ofHF must be identified in future studies

Currently two therapeutic strategies involving miRNAshave been studied the use of antimiRs and miRNA mimics(miR-mimics) In a pioneering study Thum et al found thatan antimiR functionally designed to inhibit miR-21 signifi-cantly reversed the progression of cardiac hypertrophy andfibrosis and attenuated the impairment of cardiac function[104] Another study by Montgomery et al showed that thetherapeutic inhibition of miR-208a prevented pathologicalmyosin changes and cardiac remodeling improving car-diac function and increasing survival [105] The therapeuticefficacy of miR-mimics has also been studied Suckau etal successfully used a viral vector expressing optimizedmiR-mimics in mice to normalize cardiac dilation and


significantly reduce cardiac hypertrophy and cardiac fibrosis[106] Wahlquist et al demonstrated that the increasedexpression of endogenous miR-25 contributes to the declinein cardiac function during HF and suggested that it might betargeted therapeutically to restore cardiac function [92]Morerecently Castaldi et al found that miR-133 controls multiplecomponents of the beta1AR transduction cascade and iscardioprotective during heart failure which indicated over-expression ofmicroRNAs in vivo is also a therapeutic strategyin the treatment of HF [107]

35 Long-Noncoding-RNA-Based Mechanisms LncRNAswere discovered in the early 1990s and are nowadaysdefined as RNA molecules of gt200 nucleotides in length[13] LncRNAs regulate the expression of genes at theepigenetic transcriptional and posttranscriptional levelsand play important roles in physiological processes Thefact that some lncRNAs have been found to be differentiallyregulated in the developing or diseased heart provides astrong indication for their involvement in cardiac (patho)physiology [13]

Wang et al first demonstrated a novel cardiac-hypertrophy-regulating complex composed of the lncRNACHRFmiR-489 andMYD88 [108] Han et al discovered thatlncRNA protects the heart from hypertrophy through theBRG1-HDAC-PARP pathway and MHRT-BRG1 feedbackSimilarly the circulating lncRNA LIPCAR is a novelbiomarker of cardiac remodeling and predicts the survivalof patients with HF [109] Mhrt is the first example toour knowledge of a lncRNA that inhibits myopathy andchromatin remodelers [109] Moreover transcription in theheart of Kcnq1 depends on the expression of the lncRNAKcnq1ot1 which could be responsible for abnormal heartfunction [16] ANRIL can also repress the expressionof suppressor genes INK4b ARF and INK4a which isinvolved in the development of coronary heart disease[15 19 110] Also it is reported nowadays that the expressionprofiles of lncRNAs but not mRNAs or miRNAs candiscriminate failing hearts of different pathologies and aremarkedly altered in response to LVAD support [111] Themitochondrial long noncoding RNA LIPCAR has beenproven to be a novel biomarker of cardiac remodeling andpredicts future death in patients with heart failure [112]CARL a cardiac apoptosis-related lncRNA can suppressmitochondrial fission and apoptosis by targeting miR-539and PHB2 which may provide a new approach for tacklingapoptosis and myocardial infarction [113]

Indeed future studies on the role of lncRNA in HFand heart development will improve our understanding ofthe ncRNA network involved in regulating gene expressionchanges underlying HF and thus allow the development ofspecific therapeutic strategies based on the interference notonly of miRNAs but also of lncRNA important for HF Thesestudies will greatly benefit from the combination of next-generation sequencing technologies applied to RNA (RNA-seq) with bioinformatic tools developed to identify lncRNAsthat are differentially expressed in different biological condi-tions and for the redirection of their mechanism of action

4 Conclusion

To understand the genetics and epigenetics of HF and theirrole in pathogenic cardiovascular processes is an excitingnew frontier in cardiovascular medicine Understanding thegenetics of HF may not only allow its early detection but alsomake possible personalizedmedical care forHFThedynamicaspects of epigenetics will provide more accurate evidenceof the roles of changing environmental factors in drugresponses thereby linking the environment with the genomeand will also provide a way to reactivate silenced genes Thepotential ofmiRNAs as new tools for diagnosis and prognosisis increasingly clear and they offer promising therapeuticstrategies for HF Additional research is obviously requiredto clarify how epigenetic mechanisms affect the onset anddevelopment of heart disease and heart regeneration to iden-tify new drug targets forHF and to allow disease classificationand risk stratification

Conflict of Interests

All authors declare that they have no conflict of interestsregarding the submitted paper to BioMed Research Interna-tional

Acknowledgments

This work was supported by the National Natural SciencesFoundation of China (Project no 81400295) the ResearchFund of the Health Agency of Zhejiang Province (Project no2014KYB099) and Zhejiang Provincial Natural ScienceFoundation of China (Project no LQ14H020004)

References

[1] A S Go D Mozaffarian V L Roger et al ldquoHeart diseaseand stroke statisticsmdash2014 update a report from the AmericanHeart Associationrdquo Circulation vol 129 no 3 pp e28ndashe2922014

[2] C W Yancy M Jessup B Bozkurt et al ldquo2013 ACCFAHAguideline for the management of heart failure executive sum-mary a report of the American College of Cardiology Foun-dationAmerican Heart Association Task Force on practiceguidelinesrdquo Circulation vol 128 no 16 pp 1810ndash1852 2013

[3] P Elliott B Andersson E Arbustini et al ldquoClassification of thecardiomyopathies a position statement from the european soci-ety of cardiology working group on myocardial and pericardialdiseasesrdquo European Heart Journal vol 29 no 2 pp 270ndash2762008

[4] A Posafalvi J C Herkert R J Sinke et al ldquoClinical utility genecard for dilated cardiomyopathy (CMD)rdquo European Journal ofHuman Genetics vol 21 no 10 2013

[5] P Teekakirikul M A Kelly H L Rehm N K Lakdawala andB H Funke ldquoInherited cardiomyopathies molecular geneticsand clinical genetic testing in the postgenomic erardquoThe Journalof Molecular Diagnostics vol 15 no 2 pp 158ndash170 2013

[6] W P Te Rijdt J D H Jongbloed R A de Boer et al ldquoClinicalutility gene card for arrhythmogenic right ventricular car-diomyopathy (ARVC)rdquo European Journal of Human Geneticsvol 22 no 2 2014


[7] R E Hershberger and J D Siegfried ldquoUpdate 2011 clinical andgenetic issues in familial dilated cardiomyopathyrdquo Journal of theAmerican College of Cardiology vol 57 no 16 pp 1641ndash16492011

[8] P Garcia-Pavia M Cobo-Marcos G Guzzo-Merello et alldquoGenetics in dilated cardiomyopathyrdquo Biomarkers in Medicinevol 7 no 4 pp 517ndash533 2013

[9] D S Herman L Lam M R G Taylor et al ldquoTruncations oftitin causing dilated cardiomyopathyrdquoTheNew England Journalof Medicine vol 366 no 7 pp 619ndash628 2012

[10] K Y van Spaendonck-Zwarts A Posafalvi M P van den Berget al ldquoTitin gene mutations are common in families withboth peripartum cardiomyopathy and dilated cardiomyopathyrdquoEuropean Heart Journal vol 35 no 32 pp 2165ndash2173 2014

[11] J LTheis KM SharpeM EMatsumoto et al ldquoHomozygositymapping and exome sequencing reveal GATAD1 mutationin autosomal recessive dilated cardiomyopathyrdquo CirculationCardiovascular Genetics vol 4 no 6 pp 585ndash594 2011

[12] Z Liu W Li X Ma et al ldquoEssential role of the zinc finger tran-scription factor casz1 for Mammalian cardiac morphogenesisand developmentrdquoThe Journal of Biological Chemistry vol 289no 43 pp 29801ndash29816 2014

[13] P Elliott and W J McKenna ldquoHypertrophic cardiomyopathyrdquoThe Lancet vol 363 no 9424 pp 1881ndash1891 2004

[14] E Biagini I Olivotto M Iascone et al ldquoSignificance ofsarcomere gene mutations analysis in the end-stage phaseof hypertrophic cardiomyopathyrdquo The American Journal ofCardiology vol 114 no 5 pp 769ndash776 2014

[15] H Morita H L Rehm A Menesses et al ldquoShared geneticcauses of cardiac hypertrophy in children and adultsrdquoThe NewEngland Journal of Medicine vol 358 no 18 pp 1899ndash19082008

[16] H Morita R Nagai J G Seidman and C E SeidmanldquoSarcomere gene mutations in hypertrophy and heart failurerdquoJournal of Cardiovascular Translational Research vol 3 no 4pp 297ndash303 2010

[17] L R Lopes and P M Elliott ldquoGenetics of heart failurerdquoBiochimica et Biophysica ActamdashMolecular Basis of Disease vol1832 no 12 pp 2451ndash2461 2013

[18] Z Liu Y Song D Li et al ldquoThe novel mitochondrial 16S rRNA2336TgtC mutation is associated with hypertrophic cardiomy-opathyrdquo Journal of Medical Genetics vol 51 no 3 pp 176ndash1842014

[19] S Sen-Chowdhry R D Morgan J C Chambers and W JMcKenna ldquoArrhythmogenic cardiomyopathy etiology diagno-sis and treatmentrdquo Annual Review of Medicine vol 61 pp 233ndash253 2010

[20] A Azaouagh S Churzidse T Konorza and R Erbel ldquoArrhyth-mogenic right ventricular cardiomyopathydysplasia a reviewand updaterdquo Clinical Research in Cardiology vol 100 no 5 pp383ndash394 2011

[21] A M Lahtinen A S Havulinna P A Noseworthy et alldquoPrevalence of arrhythmia-associated gene mutations and riskof sudden cardiac death in the Finnish populationrdquo Annals ofMedicine vol 45 no 4 pp 328ndash335 2013

[22] F W Friedrich G Dilanian P Khattar et al ldquoA novel geneticvariant in the transcription factor Islet-1 exerts gain of functionon myocyte enhancer factor 2C promoter activityrdquo EuropeanJournal of Heart Failure vol 15 no 3 pp 267ndash276 2013

[23] N Okudaira M Kuwahara Y Hirata Y Oku and H NishioldquoA knock-in mouse model of N-terminal R420W mutation

of cardiac ryanodine receptor exhibits arrhythmogenesis withabnormal calcium dynamics in cardiomyocytesrdquo Biochemicaland Biophysical Research Communications vol 452 no 3 pp665ndash668 2014

[24] V Siragam X Cui S Masse et al ldquoTMEM43 mutationpS358L alters intercalated disc protein expression and reducesconduction velocity in arrhythmogenic right ventricular car-diomyopathyrdquoPLoSONE vol 9 no 10 Article ID e109128 2014

[25] S Sen-Chowdhry P Syrris A Pantazis G Quarta W JMcKenna and J C Chambers ldquoMutational heterogeneitymodifier genes and environmental influences contribute tophenotypic diversity of arrhythmogenic cardiomyopathyrdquo Cir-culation Cardiovascular Genetics vol 3 no 4 pp 323ndash3302010

[26] H Watkins H Ashrafian and C Redwood ldquoInherited car-diomyopathiesrdquoTheNew England Journal of Medicine vol 364no 17 pp 1643ndash1656 2011

[27] NGMahon R TMurphy C AMacRae A L P Caforio PMElliott and W J McKenna ldquoEchocardiographic evaluation inasymptomatic relatives of patients with dilated cardiomyopathyreveals preclinical diseaserdquoAnnals of InternalMedicine vol 143no 2 pp 108ndash115 2005

[28] Y M Hoedemaekers K Caliskan M Michels et al ldquoTheimportance of genetic counseling DNA diagnostics and car-diologic family screening in left ventricular noncompactioncardiomyopathyrdquo Circulation Cardiovascular Genetics vol 3no 3 pp 232ndash239 2010

[29] J-R Bao J-Z Wang Y Yao et al ldquoScreening of pathogenicgenes in Chinese patients with arrhythmogenic right ventric-ular cardiomyopathyrdquo Chinese Medical Journal vol 126 no 22pp 4238ndash4241 2013

[30] E Gandjbakhch A Vite F Gary et al ldquoScreening of genesencoding junctional candidates in arrhythmogenic right ven-tricular cardiomyopathydysplasiardquo Europace vol 15 no 10 pp1522ndash1525 2013

[31] L Mestroni and M R G Taylor ldquoGenetics and genetic test-ing of dilated cardiomyopathy a new perspectiverdquo DiscoveryMedicine vol 15 no 80 pp 43ndash49 2013

[32] D P Judge ldquoUse of genetics in the clinical evaluation of car-diomyopathyrdquoThe Journal of the AmericanMedical Associationvol 302 no 22 pp 2471ndash2476 2009

[33] N Hofman I van Langen and A AMWilde ldquoGenetic testingin cardiovascular diseasesrdquo Current Opinion in Cardiology vol25 no 3 pp 243ndash248 2010

[34] P Charron M Arad E Arbustini et al ldquoGenetic counsellingand testing in cardiomyopathies a position statement of theEuropean Society of CardiologyWorking Group onMyocardialand Pericardial Diseasesrdquo European Heart Journal vol 31 no22 pp 2715ndash2726 2010

[35] F I Marcus S Edson and J A Towbin ldquoGenetics of arrhyth-mogenic right ventricular cardiomyopathy a practical guide forphysiciansrdquo Journal of the American College of Cardiology vol61 no 19 pp 1945ndash1948 2013

[36] D J Tester and M J Ackerman ldquoGenetic testingfor potentially lethal highly treatable inheritedcardiomyopathieschannelopathies in clinical practicerdquoCirculation vol 123 no 9 pp 1021ndash1037 2011

[37] J S Ware A M Roberts and S A Cook ldquoNext generationsequencing for clinical diagnostics and personalised medicineimplications for the next generation cardiologistrdquoHeart vol 98no 4 pp 276ndash281 2012


[38] T Vrijenhoek K Kraaijeveld M Elferink et al ldquoNext-generation sequencing-based genome diagnostics across clin-ical genetics centers implementation choices and their effectsrdquoEuropean Journal of Human Genetics 2015

[39] B J Maron T S Haas and J S Goodman ldquoHypertrophiccardiomyopathy one genemdashbut many phenotypesrdquo AmericanJournal of Cardiology vol 113 no 10 pp 1772ndash1773 2014

[40] S P Page S Kounas P Syrris et al ldquoCardiac myosin bindingprotein-C mutations in families with hypertrophic cardiomy-opathy disease expression in relation to age gender and longterm outcomerdquo Circulation Cardiovascular Genetics vol 5 no2 pp 156ndash166 2012

[41] F Pasquale P Syrris J P Kaski J Mogensen W J McKennaand P Elliott ldquoLong-term outcomes in hypertrophic cardiomy-opathy caused by mutations in the cardiac troponin T generdquoCirculation Cardiovascular Genetics vol 5 no 1 pp 10ndash17 2012

[42] B Bauce A Nava G Beffagna et al ldquoMultiple mutations indesmosomal proteins encoding genes in arrhythmogenic rightventricular cardiomyopathydysplasiardquo Heart Rhythm vol 7no 1 pp 22ndash29 2010

[43] F Girolami C Y Ho C Semsarian et al ldquoClinical features andoutcome of hypertrophic cardiomyopathy associated with triplesarcomere protein gene mutationsrdquo Journal of the AmericanCollege of Cardiology vol 55 no 14 pp 1444ndash1453 2010

[44] I Olivotto F Girolami M J Ackerman et al ldquoMyofilamentprotein gene mutation screening and outcome of patients withhypertrophic cardiomyopathyrdquoMayoClinic Proceedings vol 83no 6 pp 630ndash638 2008

[45] I Olivotto F Girolami R Sciagr et al ldquoMicrovascular functionis selectively impaired in patients with hypertrophic cardiomy-opathy and sarcomere myofilament gene mutationsrdquo Journal ofthe American College of Cardiology vol 58 no 8 pp 839ndash8482011


[47] L Ho and G R Crabtree ldquoChromatin remodelling duringdevelopmentrdquo Nature vol 463 no 7280 pp 474ndash484 2010

[48] K Ohtani and S Dimmeler ldquoEpigenetic regulation of cardio-vascular differentiationrdquo Cardiovascular Research vol 90 no3 pp 404ndash412 2011

[49] C P Chang and B G Bruneau ldquoEpigenetics and cardiovasculardevelopmentrdquo Annual Review of Physiology vol 74 pp 41ndash682012

[50] P Han C T Hang J Yang and C-P Chang ldquoChromatinremodeling in cardiovascular development and physiologyrdquoCirculation Research vol 108 no 3 pp 378ndash396 2011

[51] C T Hang J Yang P Han et al ldquoChromatin regulation by Brg1underlies heart muscle development and diseaserdquo Nature vol466 no 7302 pp 62ndash67 2010

[52] S Saxonov P Berg and D L Brutlag ldquoA genome-wide analysisof CpG dinucleotides in the human genome distinguishestwo distinct classes of promotersrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 103 no5 pp 1412ndash1417 2006

[53] A M Deaton and A Bird ldquoCpG islands and the regulation oftranscriptionrdquo Genes amp Development vol 25 no 10 pp 1010ndash1022 2011

[54] M Movassagh M-K Choy D A Knowles et al ldquoDistinctepigenomic features in end-stage failing human heartsrdquo Circu-lation vol 124 no 22 pp 2411ndash2422 2011

[55] S Haider L Cordeddu E Robinson et al ldquoThe landscape ofDNA repeat elements in human heart failurerdquo Genome Biologyvol 13 no 10 article R90 2012

[56] T F Whayne ldquoEpigenetics in the development modificationand prevention of cardiovascular diseaserdquo Molecular BiologyReports vol 42 no 4 pp 765ndash776 2015

[57] DXiao CDasguptaMChen et al ldquoInhibition ofDNAmethy-lation reverses norepinephrine-induced cardiac hypertrophy inratsrdquo Cardiovascular Research vol 101 no 3 pp 373ndash382 2014

[58] C J Watson P Collier I Tea et al ldquoHypoxia-induced epi-genetic modifications are associated with cardiac tissue fibro-sis and the development of a myofibroblast-like phenotyperdquoHuman Molecular Genetics vol 23 no 8 pp 2176ndash2188 2014

[59] H Tao J J Yang Z W Chen et al ldquoDNMT3A silencingRASSF1A promotes cardiac fibrosis through upregulation ofERK12rdquo Toxicology vol 323 pp 42ndash50 2014

[60] E Orenes-Pinero S Montoro-Garcıa J V Patel M ValdesF Marın and G Y H Lip ldquoRole of microRNAs in cardiacremodelling new insights and future perspectivesrdquo Interna-tional Journal of Cardiology vol 167 no 5 pp 1651ndash1659 2013

[61] S Turdi W Sun Y Tan X Yang L Cai and J Ren ldquoInhibitionof DNA methylation attenuates low-dose cadmium-inducedcardiac contractile and intracellular Ca2+ anomaliesrdquo Clinicaland Experimental Pharmacology amp Physiology vol 40 no 10pp 706ndash712 2013

[62] Y H Kao G S Lien T F Chao and Y J Chen ldquoDNAmethylation inhibition a novel therapeutic strategy for heartfailurerdquo International Journal of Cardiology vol 176 no 1 pp232ndash233 2014

[63] A G Rigopoulos and H Seggewiss ldquoHypertrophic cardiomy-opathyrdquoThe Lancet vol 381 no 9876 p 1456 2013

[64] R Papait P Cattaneo P Kunderfranco et al ldquoGenome-wideanalysis of histone marks identifying an epigenetic signatureof promoters and enhancers underlying cardiac hypertrophyrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 110 no 50 pp 20164ndash20169 2013

[65] V B Pillai N R Sundaresan G Kim et al ldquoExogenousNAD blocks cardiac hypertrophic response via activation ofthe SIRT3-LKB1-AMP-activated kinase pathwayrdquo Journal ofBiological Chemistry vol 285 no 5 pp 3133ndash3144 2010

[66] B S Ferguson B C Harrison M Y Jeong et al ldquoSignal-dependent repression of DUSP5 by class I HDACs controlsnuclear ERK activity and cardiomyocyte hypertrophyrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 110 no 24 pp 9806ndash9811 2013

[67] Y H Kao J P Liou C C Chung et al ldquoHistone deacetylaseinhibition improved cardiac functions with direct antifibroticactivity in heart failurerdquo International Journal of Cardiology vol168 no 4 pp 4178ndash4183 2013

[68] H F Nural-Guvener L Zakharova J Nimlos S PopovicD Mastroeni and M A Gaballa ldquoHDAC class I inhibitorMocetinostat reverses cardiac fibrosis in heart failure anddiminishes CD90+ cardiac myofibroblast activationrdquo Fibroge-nesis amp Tissue Repair vol 7 no 1 p 10 2014

[69] M P Gupta S A Samant S H Smith and S G ShroffldquoHDAC4 and PCAF bind to cardiac sarcomeres and play a rolein regulating myofilament contractile activityrdquo The Journal ofBiological Chemistry vol 283 no 15 pp 10135ndash10146 2008


[70] A PedramaM Razandi R Narayanan J T Dalton T AMcK-insey and E R Levin ldquoEstrogen regulates histone deacetylasesto prevent cardiac hypertrophyrdquo Molecular Biology of the Cellvol 24 no 24 pp 3805ndash3818 2013

[71] R Teperino K Schoonjans and J Auwerx ldquoHistone methyltransferases and demethylases can they link metabolism andtranscriptionrdquo Cell Metabolism vol 12 no 4 pp 321ndash327 2010

[72] RKaneda S Takada Y Yamashita et al ldquoGenome-wide histonemethylation profile for heart failurerdquo Genes to Cells vol 14 no1 pp 69ndash77 2009

[73] M Hohl M Wagner J-C Reil et al ldquoHDAC4 controls histonemethylation in response to elevated cardiac loadrdquoThe Journal ofClinical Investigation vol 123 no 3 pp 1359ndash1370 2013

[74] M R Fabian N Sonenberg and W Filipowicz ldquoRegulation ofmRNA translation and stability bymicroRNAsrdquoAnnual Reviewof Biochemistry vol 79 pp 351ndash379 2010

[75] J Krol I Loedige and W Filipowicz ldquoThe widespread reg-ulation of microRNA biogenesis function and decayrdquo NatureReviews Genetics vol 11 no 9 pp 597ndash610 2010

[76] T Thum P Galuppo C Wolf et al ldquoMicroRNAs in the humanheart a clue to fetal gene reprogramming in heart failurerdquoCirculation vol 116 no 3 pp 258ndash267 2007

[77] S Ikeda S W Kong J Lu et al ldquoAltered microRNA expressionin human heart diseaserdquo Physiological Genomics vol 31 no 3pp 367ndash373 2007

[78] C Sucharov M R Bristow and J D Port ldquomiRNA expressionin the failing human heart functional correlatesrdquo Journal ofMolecular and Cellular Cardiology vol 45 no 2 pp 185ndash1922008

[79] D M Bers ldquoCardiac excitation-contraction couplingrdquo Naturevol 415 no 6868 pp 198ndash205 2002

[80] M Jessup B Greenberg D Mancini et al ldquoCalcium upreg-ulation by percutaneous administration of gene therapy incardiac disease (CUPID) a phase 2 trial of intracoronary genetherapy of sarcoplasmic reticulumCa2+-ATPase in patients withadvanced heart failurerdquo Circulation vol 124 no 3 pp 304ndash3132011

[81] C E Grueter E van Rooij B A Johnson et al ldquoA cardiacMicroRNA governs systemic energy homeostasis by regulationof MED13rdquo Cell vol 149 no 3 pp 671ndash683 2012

[82] R Fiore and G Schratt ldquoMicroRNAs in synapse developmenttiny molecules to rememberrdquo Expert Opinion on BiologicalTherapy vol 7 no 12 pp 1823ndash1831 2007

[83] S Ikeda A He S W Kong et al ldquoMicroRNA-1 negativelyregulates expression of the hypertrophy-associated calmodulinandMef2a genesrdquoMolecular and Cellular Biology vol 29 no 8pp 2193ndash2204 2009

[84] Q Dai M Guo Y Guo X Liu Y Liu and Z Teng ldquoA leastsquare method based model for identifying protein complexesin protein-protein interaction networkrdquo BioMed Research Inter-national vol 2014 Article ID 720960 9 pages 2014

[85] E Van Rooij L B Sutherland N Liu et al ldquoA signaturepattern of stress-responsive microRNAs that can evoke cardiachypertrophy and heart failurerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 103 no48 pp 18255ndash18260 2006

[86] T Hosoda H Zheng M Cabral-Da-Silva et al ldquoHumancardiac stem cell differentiation is regulated by a mircrinemechanismrdquo Circulation vol 123 no 12 pp 1287ndash1296 2011

[87] S J Matkovich Y Hu W H Eschenbacher L E Dorn andG W Dorn ldquoDirect and indirect involvement of MicroRNA-499 in clinical and experimental cardiomyopathyrdquo CirculationResearch vol 111 no 5 pp 521ndash531 2012

[88] GW Dorn S J MatkovichW H Eschenbacher and Y ZhangldquoA human 31015840 miR-499 mutation alters cardiac mRNA targetingand functionrdquo Circulation Research vol 110 no 7 pp 958ndash9672012

[89] M Weber M B Baker J P Moore and C D Searles ldquoMiR-21 is induced in endothelial cells by shear stress and modulatesapoptosis and eNOS activityrdquo Biochemical and BiophysicalResearch Communications vol 393 no 4 pp 643ndash648 2010

[90] C Bang S Batkai S Dangwal et al ldquoCardiac fibroblast-derivedmicroRNA passenger strand-enriched exosomes mediate car-diomyocyte hypertrophyrdquo The Journal of Clinical Investigationvol 124 no 5 pp 2136ndash2146 2014

[91] E Dirkx M M Gladka L E Philippen et al ldquoNfat and miR-25cooperate to reactivate the transcription factor Hand2 in heartfailurerdquo Nature Cell Biology vol 15 no 11 pp 1282ndash1293 2013

[92] C Wahlquist D Jeong A Rojas-Munoz et al ldquoInhibitionof miR-25 improves cardiac contractility in the failing heartrdquoNature vol 508 no 7497 pp 531ndash535 2014

[93] E Bostjancic N Zidar D Stajer and D Glavac ldquoMicroRNAsmiR-1 miR-133a miR-133b and miR-208 are dysregulated inhuman myocardial infarctionrdquo Cardiology vol 115 no 3 pp163ndash169 2010

[94] A Care D Catalucci F Felicetti et al ldquoMicroRNA-133 controlscardiac hypertrophyrdquo Nature Medicine vol 13 no 5 pp 613ndash618 2007

[95] C Xu Y Lu Z Pan et al ldquoThe muscle-specific microRNAsmiR-1 and miR-133 produce opposing effects on apoptosis bytargeting HSP60 HSP70 and caspase-9 in cardiomyocytesrdquoJournal of Cell Science vol 124 part 18 p 3187 2011

[96] M Xin E N Olson and R Bassel-Duby ldquoMending brokenhearts cardiac development as a basis for adult heart regenera-tion and repairrdquo Nature Reviews Molecular Cell Biology vol 14no 8 pp 529ndash541 2013

[97] P A da Costa Martins K Salic M M Gladka et alldquoMicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurinNFAT signallingrdquoNature Cell Biology vol 12 no 12 pp 1220ndash1227 2010

[98] A Baumgarten C Bang A Tschirner et al ldquoTWIST1 regulatesthe activity of ubiquitin proteasome system via the miR-199214 cluster in human end-stage dilated cardiomyopathyrdquoInternational Journal of Cardiology vol 168 no 2 pp 1447ndash14522013

[99] I Volkmann R Kumarswamy N Pfaff et al ldquoMicroRNA-mediated epigenetic silencing of sirtuin1 contributes toimpaired angiogenic responsesrdquo Circulation Research vol 113no 8 pp 997ndash1003 2013

[100] V Oliveira-Carvalho V O Carvalho M M Silva G VGuimaraes and E A Bocchi ldquoMicroRNAs a new paradigmin the treatment and diagnosis of heart failurerdquo ArquivosBrasileiros de Cardiologia vol 98 no 4 pp 362ndash369 2012

[101] K L Ellis V A Cameron R W Troughton C M FramptonL J Ellmers and A M Richards ldquoCirculating microRNAsas candidate markers to distinguish heart failure in breathlesspatientsrdquo European Journal of Heart Failure vol 15 no 10 pp1138ndash1147 2013

[102] L Qiang L HongW Ningfu et al ldquoExpression of miR-126 andmiR-508-5p in endothelial progenitor cells is associated with


the prognosis of chronic heart failure patientsrdquo InternationalJournal of Cardiology vol 168 no 3 pp 2082ndash2088 2013

[103] F Varrone B Gargano P Carullo et al ldquoThe circulating level ofFABP3 is an indirect biomarker of microRNA-1rdquo Journal of theAmerican College of Cardiology vol 61 no 1 pp 88ndash95 2013

[104] T Thum C Gross J Fiedler et al ldquoMicroRNA-21 contributesto myocardial disease by stimulating MAP kinase signalling infibroblastsrdquo Nature vol 456 no 7224 pp 980ndash984 2008

[105] R L Montgomery T G Hullinger H M Semus et alldquoTherapeutic inhibition of miR-208a improves cardiac functionand survival during heart failurerdquo Circulation vol 124 no 14pp 1537ndash1547 2011

[106] L Suckau H Fechner E Chemaly et al ldquoLong-term cardiac-targeted RNA interference for the treatment of heart failurerestores cardiac function and reduces pathological hypertro-phyrdquo Circulation vol 119 no 9 pp 1241ndash1252 2009

[107] A Castaldi T Zaglia V di Mauro et al ldquoMicroRNA-133modulates the beta1-adrenergic receptor transduction cascaderdquoCirculation Research vol 115 no 2 pp 273ndash283 2014

[108] K Wang F Liu L Y Zhou et al ldquoThe long noncoding RNACHRF regulates cardiac hypertrophy by targeting miR-489rdquoCirculation Research vol 114 no 9 pp 1377ndash1388 2014

[109] P Han W Li C H Lin et al ldquoA long noncoding RNA protectsthe heart from pathological hypertrophyrdquo Nature vol 514 no7520 pp 102ndash106 2014

[110] A Dutta W Henley I A Lang et al ldquoThe coronary arterydisease-associated 9p21 variant and later life 20-Year survival tocohort extinctionrdquo Circulation Cardiovascular Genetics vol 4no 5 pp 542ndash548 2011

[111] K Yang K A Yamada A Y Patel et al ldquoDeep RNA sequencingreveals dynamic regulation of myocardial noncoding RNAs infailing human heart and remodeling with mechanical circula-tory supportrdquo Circulation vol 129 no 9 pp 1009ndash1021 2014

[112] R Kumarswamy C Bauters I Volkmann et al ldquoCirculatinglong noncoding RNA LIPCAR predicts survival in patientswith heart failurerdquo Circulation Research vol 114 no 10 pp1569ndash1575 2014

[113] K Wang B Long L Y Zhou et al ldquoCARL lncRNA inhibitsanoxia-induced mitochondrial fission and apoptosis in car-diomyocytes by impairingmiR-539-dependent PHB2 downreg-ulationrdquo Nature Communications vol 5 article 3596 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Main dilated cardiomyopathy-causing genes dilated cardiomyopathy

Gene Protein OMIM of familial DCM cases InheritancepatternTTN Titin 188840 15ndash27 ADLMNA Lamin AC 150330 6 ADMYH7 120573-myosin heavy chain 160760 420 ADMYPN Myopalladin 608517 350 ADTNNT2 Cardiac troponin T 191045 290 AD

Table 2 Main dilated cardiomyopathy-causing genes hypertrophic cardiomyopathy

Gene Protein OMIM of familial HCM cases

MYH7 Myosin heavy chain 160760 40Cardiac muscle beta isoform 192600

MYBPC3 Myosin-binding protein C cardiac-type 600958 40TNNT2 Troponin T cardiac muscle 115195 5TNNI3 Troponin I cardiac muscle 191044 5

TPM1 Tropomyosin 1 alpha chain 115196 2191010

MYL2 Myosin regulatory light chain 2 160781 Unknownventricularcardiac muscle isoform 608758

MYL3 Myosin light polypeptide 3 160790 1608751

21 Dilated Cardiomyopathy Modern familial screeningstudies have shown that up to 48 of DCMmay be inherited[7] To date mutations in more than 40 genes have beenimplicated in the development ofDCM[8] InheritedDCM isusually transmitted as an autosomal dominant trait althoughall other single inheritance patterns have been identified(autosomal recessive X-linked and mitochondrial) [7] In arecent study of 312 patients FDCMwith a phenotype of highage penetrance andworse outcomes inmales which occurredin 27 was attributed to truncationmutations in titin (TTN)[9 10] Genome-wide mapping and exome sequencing in aunique affected family have identifiedGATAD1 encoding theGATA zinc finger domain containing protein 1 as anotherpathogenic gene causing autosomal recessive DCM [11 12]The main DCM-causing genes are shown in Table 1

22 Hypertrophic Cardiomyopathy HCM is characterizedas left ventricular hypertrophy in the absence of abnormalloading conditions sufficient to explain the observed degreeof hypertrophy [13] Recent studies have shown that 67 ofHCM is inherited [14] HCM is caused by mutations in genesencoding myofilament proteins of the sarcomere Z-discproteins Ca2+ -handling proteins and other proteins relatedto the sarcomere The majority of patients with FHCM showautosomal dominant mutations in genes encoding sarcomereproteins such as 120573-myosin heavy chain (MYH7) cardiacmyosin-binding protein C (MYBPC3) cardiac troponin T(TNNT2) troponin I (TNNI3) alpha-tropomyosin (TPM1)myosin light chains (MYL2 and MYL3) and cardiac actin(ACTC1) [15ndash17]Mutations in genes encoding other sarcom-ere or related proteins including alpha-myosin heavy chain(MYH6) and titin (TTN) genes encoding Z-disc proteins

such as muscle LIM protein (CSRP3) or genes encodingcalcium-handling proteins (eg phospholamban) individu-ally account for less than 1 of cases Recently the mito-chondrial 16S rRNA 2336TgtCmutation has been reported tobe another pathogenic gene alteration associated with HCMwhen the RNA of another unique family was sequenced[18]

The main HCM-related genes are shown in Table 2

23 Arrhythmogenic Right Ventricular CardiomyopathyArrhythmogenic right ventricular cardiomyopathy (ARVC)is increasingly designated arrhythmogenic cardiomyopathybecause biventricular and left-dominant forms arerecognized [19] Around 40 of patients with ARVC carrypathogenic mutations in the similar genes as observed forother myocardium such as HCM and DCM [20] In mostpatients the disease is inherited as an autosomal dominantdisease caused bymutations in one of the five genes encodingdesmosomal proteins plakophilin-2 (PKP2) desmoplakin(DSP) plakoglobin (JUP) desmoglein-2 (DSG2) anddesmocollin-2 (DSC2) Nondesmosomal genes implicated inthe disease include the transforming growth factor 3(TGFB3) cardiac ryanodine receptor 2 (RYR2) andtransmembrane protein 43 (TMEM43) [21] A novel geneticvariant in the transcription factor Islet-1 has been shownin recent studies to be associated with the onset of ARVC[22ndash24] The main genes which are involved in ARVC areshown in Table 3

Interestingly the genes causing different types of car-diomyopathy overlap to a large extent and mutations in thesame gene may in some instances exert opposite functionaleffects [25 26] How the variations in a single gene generate














3 Epigenetics







































4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























3 Epigenetics







































4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















3 Epigenetics







































4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















4 Conclusion




Acknowledgments


References





























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Heart Failure: Advanced Development …downloads.hindawi.com/journals/bmri/2015/352734.pdfMyosin heavy chain % Cardiacmusclebetaisoform MYBPC Myosin-binding protein