the human being has only 12% of its genome that codes for mrnas building the basis for protein synthesis . in contrast , there are many more noncoding rnas ( ncrnas ) in the genome , most of them with unknown function . based on their size , ncrnas are subdivided into ( i ) small ncrnas ( < 200 nucleotides long ) including micrornas ( mirna ) and ( ii ) long ncrnas ( lncrna ) , having a length between 0.2 and 2  kb.1 virtually all cellular functions are being linked to ncrnas and they have been identified to be important players in human pathology , including that of the cardiovascular system . about 1,5002,000 human mirnas have been identified that regulate at least half of all mrnas.2 as there are a number of reviews published on the mechanistic role of mirnas and their potential use as therapeutic targets,3 , 4 , 5 , 6 , 7 i here focus on some fundamental studies and novel aspects of mirnas in heart failure . a pioneering work about a first mirna to play a role in cardiac hypertrophy stems from the olson laboratory , showing mir208 to be crucially involved in hypertrophic signalling.8 most mirnas are more ubiquitously expressed and are not celltype specific . thus , many mirnas are expressed at relatively low levels under basal conditions but during pathological stress are strongly upregulated . an example is the neurologicenriched mirna mir212/132 family , which becomes activated during heart failure ( hf ) in humans9 and animal models.10 these mirnas have been shown to regulate cardiac hypertrophy in cardiomyocytes by targeting the antihypertrophic transcription factor forkhead box o3 ( foxo3 ) , leading to hyperactivation of the prohypertrophic calcineurin / nfat signalling pathway . importantly , inhibition of mir132 rescued cardiac hypertrophy and hf in mice , suggesting a novel therapeutic approach for this pathology.10 another hallmark of adverse cardiac remodelling is cardiac fibrosis.11 this is accompanied with increased secretion of extracellular matrix proteins and growth factors . an mirna enriched in cardiac fibroblasts is mir21.12 this mirna is an endogenous brake for the erk map kinase inhibitor sprouty1 , which is mechanistically involved in fibrosis development.13 both mir21 and mir29 have been shown to serve as potential therapeutic targets for cardiac fibrosis . recently , circulating levels of mir29 were found to directly correlate with different forms of cardiac hypertrophy . 14 thus , monitoring the level of this mirna family may be useful for prognostic / therapeutic purposes in adverse cardiac remodelling disease entities . next to cardiomyocytes and cardiac firbroblasts , the cardiac endothelium plays a major role in cardiac ( patho)biology especially as recently suggested in heart failure with preserved ejection fraction ( hfpef).15 our group recently identified an mirna involved in the regulation of cardiac vascularization , that is , mir24.16 this mirna is highly expressed in cardiac endothelial cells . blockade of endothelial mir24 limits myocardial infarction ( mi ) size in mice , via an increase of vascularity leading to improved cardiac function and survival . 16 in terms of diagnostics , a recent publication showed also the use of circulating mirna patterns in distinguishing heart failure with reduced ejection fraction ( hfref ) and heart failure with preserved ejection fraction ( hfpef ) . long noncoding rnas are defined as transcripts more than 200 nucleotides long that do not code for proteins.18 important to note is the fact that this definition may be preliminary as indeed some lncrnas have been reported to encode short peptides in human tissues , which also may have functional effects.19 a classification of lncrnas can be viewed in the work of thum and condorelli . 1 mechanistically , there are numerous ways how lncrnas may function in the regulation of the genome . for instance , lncrnas can interact with all macromolecules within the cell , including other rna species , proteins , and dna . long noncoding rnas also have the ability for conformational switching , which can either activate or silence interaction with other molecules.20 long noncoding rnas can be found in the nucleus of a cell or in the cytoplasm or in both compartments . bvht ( braveheart ) and fendrr ( foxf1 adjacent noncoding developmental regulatory rna).21 , 22 
 bvht seems to be a master gene required for cardiomyocyte differentiation . unfortunately , bvht seems to be specific to the mouse , making translations into humans difficult . the lncrna fendrr is higher conserved and regulates the expression of important cardiac transcription factors with knockout mice showing defects in cardiac development.22 only few studies have started to identify potential roles of lncrnas in the pathogenesis of cardiac diseases . deep sequencing studies revealed the profile of myocardial lncrnas to be altered in hf in humans.23 the lncrna chrf ( cardiac hypertrophyrelated factor ) was found to act as a sequence able to sequester mir489.24 interestingly , there are several lncrnas associated to the locus of the cardiacspecific gene myosin heavy chain 7 ( myh7 ) ; inhibition of the lncrna mhrt was mechanistically shown to induce cardiomyopathy subsequent to pressure overload , whereas restoring mhrt protected the heart from hf.25 another lncrna recently linked to cardiac pathology is carl ( cardiac apoptosisrelated lncrna).26 
 carl binds mir539 , an mirna found to target the mrna of a subunit of prohibitin , where it seems to have a role in mitochondrial homeostasis . by this , carl serves as an endogenous sponge regulating mitochondrial morphology and cell death in cardiomyocytes . cells are usually able to produce different forms of vesicles including apoptotic bodies , microvesicles , and exosomes . these vesicles contain proteins , mirna , mrna , and lncrnas ( unpublished results ) . exosomes , for example , are particularity enriched in small rnas , such as mirnas.27 of clinical interest , secreted exosomes can be isolated from biological fluids and their mirna profile can be assessed , thus emerging as potential biomarkers for diseases.28 this has been suggested also for extracellular longer rnas , which can be detected in the plasma of patients with mi.29 recently , our group screened circulating mirnas in no hf ( nohf ) , hfref , and hfpef patients using taqman mirna arrays ( life technologies , grand island , ny , usa ) . a selected mirna panel ( mir30c , mir146a , mir221 , mir328 , and mir375 ) was further verified and validated in an independent cohort consisting of 225 patients . indeed , this approach improved the discriminative value of bnp as an hf diagnostic . combinations of two or more mirna candidates with bnp had the ability to improve significantly predictive models to distinguish hfpef from hfref compared with bnp alone ( area under the receiver operating characteristic curve > 0.82).17 whether these mirnas are also mechanistically important for hfpef or hfref , disease pathologies are interesting and require further investigations . locally , cells might also communicate with each other by shuttling noncoding rnas back and forth ; for instance , cardiac fibroblasts can secrete exosomes that are enriched with mirnas that could be taken up by recipient cardiomyocytes , provoking hypertrophy.30 there is increasing evidence that cardiovascular cells are able to communicate via ncrna transfer , and this also could lead into new strategies aiming at modulation of extracellular noncoding rna species . there has been a tremendous increase in knowledge about noncoding rnas in cardiovascular biology and disease within the last years . however , this represents only the tip of the iceberg that needs to be discovered to fully understand the importance of noncoding rnas . likely , new noncoding rnas will help not only to understand better the mechanisms of heart failure but will develop into new concepts of theragnostic approaches . a variety of endeavours is currently undertaken by various groups worldwide to bring mirna therapeutics into the clinics within the next 58  years . this includes target and drug candidate optimization , efficacy studies in small and large animals , toxicology and safety studies , and absorption , distribution , metabolism , and excretion studies leading to phase i , phase ii , and phase iii studies until the market will be reached ( figure  1 ) . clinical development plan for noncoding rnabased therapeutics of which
abstractabout 11% of all deaths include heart failure as a contributing cause . 
 the annual cost of heart failure amounts to us $ 34,000,000,000 in the united states alone . with the exception of heart transplantation 
 , there is no curative therapy available . 
 only occasionally there are new areas in science that develop into completely new research fields . 
 the topic on noncoding rnas , including micrornas , long noncoding rnas , and circular rnas , is such a field . in this short review 
 , we will discuss the latest developments about noncoding rnas in cardiovascular disease . 
 micrornas are short regulatory noncoding endogenous rna species that are involved in virtually all cellular processes . 
 long noncoding rnas also regulate gene and protein levels ; however , by much more complicated and diverse mechanisms . in general , noncoding rnas have been shown to be of great value as therapeutic targets in adverse cardiac remodelling and also as diagnostic and prognostic biomarkers for heart failure . in the future , noncoding rnabased therapeutics are likely to enter the clinical reality offering a new treatment approach of heart failure .