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This study sought to evaluate the potential of circulating long non‐coding RNAs (lncRNAs) as biomarkers for heart failure (HF). We measured the circulating levels of 13 individual lncRNAs which are known to be relevant to cardiovascular disease in the plasma samples from 72 HF patients and 60 non‐HF control participants using real‐time reverse transcription‐polymerase chain reaction (real‐time RT‐PCR) methods. We found that out of the 13 lncRNAs tested, non‐coding repressor of NFAT (NRON) and myosin heavy‐chain‐associated RNA transcripts (MHRT) had significantly higher plasma levels in HF than in non‐HF subjects: 3.17 ± 0.30 versus 1.0 ± 0.07 for NRON (P < 0.0001) and 1.66 ± 0.14 versus 1.0 ± 0.12 for MHRT (P < 0.0001). The area under the ROC curve was 0.865 for NRON and 0.702 for MHRT. Univariate and multivariate analyses identified NRON and MHRT as independent predictors for HF. Spearman's rank correlation analysis showed that NRON was negatively correlated with HDL and positively correlated with LDH, whereas MHRT was positively correlated with AST and LDH. Hence, elevation of circulating NRON and MHRT predicts HF and may be considered as novel biomarkers of HF.

(5, 6). FADD has a carboxylterminal DD and an amino-terminal death effector domain (DED). Through its DED, FADD recruits the DED-containing apoptosis-initiating proteases caspase-8 (7, 8) and caspase-10 (9 -11) to the Fas receptor to assemble a DISC (12). In the DISC, caspase-8 is cleaved through autoproteolysis of caspase-8 molecules in close proximity (13). Active caspase-8 subunits are released into the cytoplasm to cleave downstream effector caspases such as caspase-3 (14), which subsequently cleaves its substrates such as DNA fragmentation factor 45 (DFF45) (15), to execute programmed cell death.Recently, the recruitment of other DED-containing proteins to the Fas-mediated DISC, which has been described, modulates DISC functions. These include a family of virus-encoded proteins referred to as v-FLIP (16, 17). v-FLIP contains two DEDs that can bind to the Fas/FADD complex to inhibit Fasmediated apoptosis by interfering with the recruitment of caspase-8 to the DISC. A mammalian cellular homolog of v-FLIP is termed c-FLIP (18), CASH (19), CASPER (20), CLARP (21), FLAME1 (22), I-FLICE (23), MRIT (24), and Usurpin (25). These studies, however, have generated controversy as to the functions of c-FLIP in apoptosis. Some groups have described it as pro-apoptotic (19 -21, 24), whereas others as anti-apoptotic (18,22,25). Recent analysis of Fas-mediated DISC in c-FLIPtransfected BJAB cells has shown that c-FLIP proteins are recruited to the Fas-mediated DISC to inhibit caspase-8 cleavage (26, 27), which supports the role of c-FLIP as an antiapoptotic molecule.The c-FLIP gene is composed of 13 exons that are clustered within ϳ200 kilobases within the caspase-8 and caspase-10 genes on human chromosome 2q33 to 34 (25, 28). c-FLIP is expressed as four main mRNA splice variants but only two forms of protein in human tissues (18,20). The short form protein (c-FLIP S , M r ϳ28) contains two DEDs and is structurally related to v-FLIP; the longer form (c-FLIP L , M r ϳ55) is structurally similar to caspase-8 and contains two DEDs and a caspase-like domain that lacks catalytic activity (18). c-FLIP L is expressed in many tissues, but c-FLIP S is found mainly in lymphatic tissue (18). Expression of c-FLIP mRNA and proteins is regulated by mitogen-activated protein kinase kinase in T lymphocytes (29)