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[Potential of non-coding RNA as biomarkers in heart failure]
Abstract
Heart failure is a major public health problem with an estimated prevalence of 1-2% in the adult population in developed countries. Despite some progress, the prognosis of heart failure is associated with high mortality. There is a need for prognostic markers for heart failure, such as circulating biomarkers, in order to better identify individual heart failure patients with high risk of early death, and to improve the selection of patients for invasive treatment with limited availability such as heart transplantation. Among the non coding RNA family, we investigated the potentiality of long non coding RNAs (lncRNA) as potential biomarkers in heart disease. We observed that the plasmatic levels of the lncRNA named LIPCAR may predict early mortality in patients with heart failure independently of the etiology and may improve clinical-decision making for a more personalized treatment of "high-risk" patients.
© 2015 médecine/sciences – Inserm.
... LncRNAs are differentially expressed in various human diseases, including cancer [36], heart failure [51], diabetes mellitus [51] and neuropsychiatric disorders [52]. Thus, lncRNAs are emerging as key players in disease development and progression. ...
... LncRNAs are differentially expressed in various human diseases, including cancer [36], heart failure [51], diabetes mellitus [51] and neuropsychiatric disorders [52]. Thus, lncRNAs are emerging as key players in disease development and progression. ...
Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. Therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. Recently, increasing evidence has shown that epigenetic changes, such as aberrant DNA methylation, histone modifications, and noncoding RNAs (ncRNAs) expression, play substantial roles in the development and progression of malignancies. Among these changes, long non-coding RNAs (lncRNAs), a novel class of ncRNAs, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and posttranscriptional levels. Hundreds of lncRNAs become dysregulated in the various pathological processes of gastric cancer, and multiple lncRNAs have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. Here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncRNAs; we focus on lncRNA-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncRNAs on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers.
... Accumulating evidence reveals that dysregulated GAS5 has been documented in many human diseases including malignancy 21 , childhood pneumonia 22 , autoimmune disorders 23 , heart failure, diabetes mellitus 24 , and neuropsychiatric disorders 24 . Importantly, GAS5 is widely considered as a tumor suppressor. ...
Hepatitis B virus (HBV) infection is a significant health issue worldwide.. We attempted to fulfill the molecular mechanisms of epigenetic and genetic factors associated with chronic HBV (CHBV). Expression levels of the lncRNA growth arrest-specific 5 (GAS5) and miR-137 and their corresponding SNPs, rs2067079 (C/T) and rs1625579 (G/T) were analyzed in 117 CHBV patients and 120 controls to investigate the probable association between these biomarkers and CHBV pathogenesis in the Egyptian population. Serum expression levels of GAS5 and miR-137 were significantly down-regulated in cases vs controls. Regarding GAS5 (rs2067079), the mutant TT genotype showed an increased risk of CHBV (p < 0.001), while the dominant CC was a protective factor (p = 0.004). Regarding miR-137 rs1625579, the mutant genotype TT was reported as a risk factor for CHBV (p < 0.001) and the normal GG genotype was a protective factor, p < 0.001. The serum GAS5 was significantly higher in the mutant TT genotype of GAS5 SNP as compared to the other genotypes (p = 0.007). Concerning miR-137 rs1625579, the mutant TT genotype was significantly associated with a lower serum expression level of miR-137 (p = 0.018). We revealed the dysregulated expression levels of GAS5 and miR-137 linked to their functioning SNPs were associated with CHBV risk and might act as potential therapeutic targets.
... Accumulating evidence has suggested that rather than being transcriptional noise, diverse non-coding RNAs (ncRNAs) serve as master regulators in CHF initiation and progression at the post-transcriptional level (Kumarswamy and Thum, 2013;Pinet and Bauters, 2015;Thum, 2015). Among them, long non-coding RNAs (lncRNAs) are conventionally described as transcripts longer than 200 nucleotides with no or little protein-coding capacity (Greco et al., 2016;Dangwal et al., 2017). ...
Dilated cardiomyopathy (DCM) is an important cause of sudden death and heart failure with an unknown etiology. Recent studies have suggested that long non-coding RNA (lncRNA) can interact with microRNA (miRNA) and indirectly interact with mRNA through competitive endogenous RNA (ceRNA) activities. However, the mechanism of ceRNA in DCM remains unclear. In this study, a miRNA array was first performed using heart samples from DCM patients and healthy controls. For further validation, we conducted real-time quantitative reverse transcription (RT)-PCR using samples from DCM patients and a doxorubicin-induced rodent model of cardiomyopathy, revealing that miR-144-3p and miR-451a were down-regulated, and miR-21-5p was up-regulated. Based on the ceRNA theory, we constructed a global triple network using data from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) and our miRNA array. The lncRNA-miRNA-mRNA network comprised 22 lncRNA nodes, 32 mRNA nodes, and 11 miRNA nodes. Hub nodes and the number of relationship pairs were then analyzed, and the results showed that two lncRNAs (NONHSAT001691 and NONHSAT006358) targeting miR-144/451 were highly related to DCM. Then, cluster module and random walk with restart for the ceRNA network were analyzed and identified four lncRNAs (NONHSAT026953/NONHSAT006250/NONHSAT133928/NONHSAT041662) targeting miR-21 that were significantly related to DCM. This study provides a new strategy for research on DCM or other diseases. Furthermore, lncRNA-miRNA pairs may be regarded as candidate diagnostic biomarkers or potential therapeutic targets of DCM.
... [27][28][29][30] Recent studies suggest critical roles of lncRNAs in mediating the initiation and progression of cardiovascular diseases, and lncRNAs have emerged as novel therapeutic targets in cardiovascular medicine. [31][32][33][34] Although lncRNAs play essential roles in various biological processes, hitherto, it is not yet clear whether lncRNAs are involved in the regulation of programmed necrosis in the heart. ...
Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation. However, it is not yet clear whether lncRNAs can regulate necrosis in cardiomyocytes. Here, we report that a long noncoding RNA, named necrosis-related factor (NRF), regulates cardiomyocytes necrosis by targeting miR-873 and RIPK1 (receptor-interacting serine/threonine-protein kinase 1)/RIPK3 (receptor-interacting serine/threonine-protein kinase 3). Our results show that RIPK1 and RIPK3 participate in H2O2-induced cardiomyocytes necrosis. miR-873 suppresses the translation of RIPK1/RIPK3 and inhibits RIPK1/RIPK3-mediated necrotic cell death in cardiomyocytes. miR-873 reduces myocardial infarct size upon ischemia/reperfusion (I/R) injury in the animal model. In exploring the molecular mechanism by which miR-873 expression is regulated, we identify NRF as an endogenous sponge RNA and repress miR-873 expression. NRF directly binds to miR-873 and regulates RIPK1/RIPK3 expression and necrosis. Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury. Further, we identify that p53 transcriptionally activates NRF expression. P53 regulates cardiomyocytes necrosis and myocardial I/R injury through NRF and miR-873.Our results identify a novel mechanism involving NRF and miR-873 in regulating programmed necrosis in the heart and suggest a potential therapeutic avenue for cardiovascular diseases.Cell Death and Differentiation advance online publication, 3 June 2016; doi:10.1038/cdd.2016.28.
Heart failure (HF) is the most prominent cardiovascular disease resulting from an altered cardiac homeostasis. An outstanding progress in the high-throughput sequencing technologies has demonstrated that the dynamical changes in long noncoding RNA (lncRNA) and circular RNA (circRNA) expression profiles are strongly correlated with the genesis and progression of HF. Although their function and regulation in cardiovascular system are still ambiguous, several lncRNAs and circRNAs have emerged as promising biomarkers for HF suggesting that the human noncoding secretome may provide an interesting pool of RNA molecules for the treatment of heart failure. Integration of current knowledge of lncRNAs and circRNAs with protein-coding and other noncoding genes is essential to deepen our understanding of the signaling pathways and transcriptional events involved in the pathogenesis of cardiovascular disease including HF. Undoubtedly, as much as we learn about expression patterns of lncRNAs and circRNAs, the higher chance for an improved diagnosis and therapy and better prognosis will be.
Cardiovascular diseases (CVDs) is the first cause of death worldwide, generally exhibiting a high morbidity, high disability rate and high mortality especially in the elderly persons (>50 years old). Previously, extensive studies have demonstrated that cardiac fibrosis plays cardinal roles in the pathogenesis of CVDs. However, due to the unclear underlying mechanisms of cardiac fibrosis, its clinical intervention remains very lacking. Long non-coding RNAs (lncRNAs), a class of non-coding RNA but differing from microRNAs, are generally considered as transcripts with a length ranging 200 to 100 nucleotides. Recently, accumulating evidence showed that lncRNAs involve in the pathogenesis of cardiac fibrosis. Fendrr (FOXF1 adjacent non-coding developmental regulatory RNA), is a spliced long non-coding RNA transcribed bi-directionally with FOXF1 on the opposite strand. Fendrr has been demonstrated to be essential for normal development of the heart and body wall in mouse, and shows a good anti-fibrotic activity in pulmonary fibrosis. In this study, we aimed to explore the effects of Fendrr on cardiac fibrosis. Intriguingly, we first observed that lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction (TAC) induced cardiac fibrosis mouse models, determined by RT-QPCR. Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes induced by TAC, indicating that Fendrr is required for the pathogenesis of cardiac fibrosis. In mechanism, we demonstrated experimentally that Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis (indicated by the elevation of Col1a1, Col3a1, CTGF and ACTA2 expression) in a miR-106b mediated manner. Collectively, our findings highlight the axis of Fendrr/miR-106b/Samd3 in the pathogenesis of cardiac fibrosis, which may be a promising target for clinical intervention target of cardiac fibrosis.
Multiple sclerosis (MS) is an auto-immune demyelinating disorder characterized by a chronic neuro-inflammatory process associated with an infiltration of the central nervous system (CNS) by autoreactive lymphocytes. The etiology of the disease remains unclear but the recent discovery of a dysregulated miRNA network in both cells and extracellular fluids of MS patients has brought new insights on the pathophysiological mechanisms involved in this disorder. miRNAs can induce a T cell polarization towards a pathological Th17 or Th1 phenotype and a deleterious activation of microglia, the CNS-resident macrophages. We provide here a review of the most recent data regarding miRNA dysregulation and pathophysiological roles in MS patients and in the animal model of MS, EAE (experimental autoimmune encephalomyelitis). Moreover, we discuss the putative clinical value of miRNAs as a novel biomarker and diagnostic tool for MS.
Ageing is considered as a major risk factor for the development of chronic diseases. Among these, heart failure seems to be particularly important for both triggering and accelerating pathological ageing. In the present review, we give a general overview of the most relevant results concerning the mechanism of normal and premature senescence of cardiomyocytes and cardiac stromal cells. In particular, we will address the role of telomere dysfunction, DNA damage response, impairment of mitochondrial function, miRNAs and secretome of senescent cells in cardiac ageing and failure.
© 2015 médecine/sciences – Inserm.
Physical exercise or hypertension requires that the heart increases its hemodynamic work. However, this adaptation is based on distinct cardiac remodelling according to the physiological or pathological origin of the stress. As shown here with two examples, understanding the molecular events leading to cardiac remodeling may offer new opportunities for the development of therapies for heart failure. The recently described Epac1 protein is an effector of the second messenger cAMP. Following a pathological stress, the cAMP-binding protein Epac1 induces cardiac hypertrophy and fibrosis as well as alteration of calcium cycling suggesting that Epac1 pharmacological inhibition may be of therapeutic value. Furthermore, the protein carabin is an important regulator of several effectors of pathological cardiac remodelling. Experimental manipulation of carabin expression profoundly alters the development of heart failure.
Risk stratification of patients with systolic chronic heart failure (HF) is critical to better identify those who may benefit from invasive therapeutic strategies such as cardiac transplantation. Proteomics has been used to provide prognostic information in various diseases. Our aim was to investigate the potential value of plasma proteomic profiling for risk stratification in HF. A proteomic profiling using surface enhanced laser desorption ionization - time of flight - mass spectrometry was performed in a case/control discovery population of 198 patients with systolic HF (left ventricular ejection fraction <45%): 99 patients who died from cardiovascular cause within 3 years and 99 patients alive at 3 years. Proteomic scores predicting cardiovascular death were developed using 3 regression methods: support vector machine, sparse partial least square discriminant analysis, and lasso logistic regression. Forty two ion m/z peaks were differentially intense between cases and controls in the discovery population and were used to develop proteomic scores. In the validation population, score levels were higher in patients who subsequently died within 3 years. Similar areas under the curves (0.66 - 0.68) were observed for the 3 methods. After adjustment on confounders, proteomic scores remained significantly associated with cardiovascular mortality. Use of the proteomic scores allowed a significant improvement in discrimination of HF patients as determined by integrated discrimination improvement and net reclassification improvement indexes. In conclusion, proteomic analysis of plasma proteins may help to improve risk prediction in HF patients.
Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between thousands of genes. High-throughput techniques (omics) allow identification of such genes and their products, but functional understanding is a formidable challenge. Network-based analyses of omics data have identified modules of disease-associated genes that have been used to obtain both a systems level and a molecular understanding of disease mechanisms. For example, in allergy a module was used to find a novel candidate gene that was validated by functional and clinical studies. Such analyses play important roles in systems medicine. This is an emerging discipline that aims to gain a translational understanding of the complex mechanisms underlying common diseases. In this review, we will explain and provide examples of how network-based analyses of omics data, in combination with functional and clinical studies, are aiding our understanding of disease, as well as helping to prioritize diagnostic markers or therapeutic candidate genes. Such analyses involve significant problems and limitations, which will be discussed. We also highlight the steps needed for clinical implementation.
Heart failure is common in older people and its prevalence is increasing. The Heart 'omics' in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising 'omics'-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n = 7,124), patients with heart failure (n = 4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n = 31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.
The transcription of essentially the entire eukaryotic genome generates a myriad of non-coding RNA species that show complex overlapping patterns of expression and regulation. In the last decade, several large scale genomic analyses have shed light on the widespread existence of long non-coding RNAs (lncRNAs) in mammals. Although the function of most lncRNAs remains unknown, many of them have been suggested to play important roles in the regulation of gene expression during normal development and diseases, including cancers. Indeed, functional studies have demonstrated that lncRNAs participate in various biological processes, including reprogramming of pluripotent stem cells, oncogenic progression and cell cycle regulation. In this review, we summarize recent findings about the biology of lncRNAs and their functions in normal and pathological development in mammals.
© 2014 médecine/sciences – Inserm.
The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized-but not naked-DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.
Significance
The role of noncoding RNAs in mammalian biology is of great interest, especially since the Encyclopedia of DNA Elements results were published. We and others have studied microRNAs in the heart, but little is known about their larger cousins, long noncoding RNAs (lncRNAs). Here, we used genome-wide sequencing and improved bioinformatics to quantify lncRNA expression in mouse hearts, define a subset of cardiac-specific lncRNAs, and measure dynamic lncRNA regulation during the transition between embryo and adult, and in the adult heart after experimental pressure overload (a model resembling human hypertensive cardiomyopathy). We linked specific regulated lncRNAs to cardiac-expressed mRNAs that they target and, through network analyses, discovered a broader role of regulated cardiac lncRNAs as modulators of key cardiac transcriptional pathways.
Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis.
We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease.
These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic.
Search for new biomarkers able to improve patient diagnosis has become a real challenge in the era of personalized medicine. Considering that early detection of cancer greatly increases the chances for successful treatment, the identification of accurate biomarkers is essential. In addition, the possibility to optimize patients' care and follow-up using "companion" diagnostic tests is emerging under the term of theranostics and should become a key step in future therapeutics. Since their discovery in serum and their close associations with pathological conditions, miRNA found in biological fluids represent a new promising class of potential biomarkers. First identified in cancer patients, possible applications are very broad and address the vast majority of human diseases. This review focuses on recent advances in our knowledge of circulating miRNA. Their production in cells, export in extra-cellular environment and presumed physiological functions are addressed. The review also emphasizes their potential applications in clinics as biomarkers or therapeutic agents.
© 2014 médecine/sciences – Inserm.
microRNA are small non coding RNA, which negatively regulate the expression of their targets. Due to their various targets, miRNAs play a key role in number of physiological processes and in oncogenesis. The identification of specific miRNA signatures in various types of tumours, including hepatocellular carcinoma (HCC), highlights the dual role of miRNA, both oncogenes and tumour suppressors. Here, we review the current knowledge concerning the deregulation of miRNA expression in liver disease. All studies focusing on miRNAs argue for their possible use as diagnostic, prognostic and therapeutic markers. Here, we preferentially discuss the promising therapeutic strategies based on miRNAs that have been tested in HCC.
© 2013 médecine/sciences – Inserm.
The human genome contains many thousands of long noncoding RNAs (lncRNAs). While several studies have demonstrated compelling biological and disease roles for individual examples, analytical and experimental approaches to investigate these genes have been hampered by the lack of comprehensive lncRNA annotation. Here, we present and analyze the most complete human lncRNA annotation to date, produced by the GENCODE consortium within the framework of the ENCODE project and comprising 9277 manually annotated genes producing 14,880 transcripts. Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts, they are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Importantly, about one-third seem to have arisen within the primate lineage. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. This GENCODE annotation represents a valuable resource for future studies of lncRNAs.
AimsPrevious studies have demonstrated that the radionuclide right ventricular (RV) ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE), and tissue Doppler peak systolic tricuspid annular velocity (STr) were independent predictors of cardiac survival in stable patients with left ventricular systolic dysfunction (LVSD). No study has compared the prognostic value of these three RV parameters. The aim of this study was to compare the prognostic value of RVEF, TAPSE, and STr in a large group of patients with LVSD.Methods and resultsWe analysed 527 consecutive patients who underwent an extensive prognostic evaluation (clinical data, biological data, radionuclide angiography, echoDopplercardiography, cardiopulmonary exercise test). Tricuspid annular plane systolic excursion and STr were weakly correlated with RVEF (r 0.20). During a follow-up period of 1268 days (802-1830), there were 121 cardiovascular deaths. Best cut-off values were 37, 9.7 cm/s, and 18.5 mm for RVEF, STr, and TAPSE, respectively. Right ventricular ejection fraction was a powerful independent predictor of cardiac survival [relative risk (RR): 2.05 (1.29-3.26), P = 0.002]. Peak systolic tricuspid annular velocity added a modest prognostic information [RR: 1.56 (1.02-2.39), P = 0.04]. However, the combination of STr with RVEF was the most powerful predictor of cardiovascular death. Tricuspid annular plane systolic excursion was not an independent predictor of cardiac survival.Conclusions
Right ventricular systolic function remains a powerful independent predictor of the clinical outcome. Even in the context of a complete echocardiographic assessment, radionuclide RVEF continues to be the most powerful RV systolic parameter for cardiac survival prediction. However, the determination of STr, in addition to RVEF, could improve risk stratification.
Micro RNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Many studies show that they are implicated in essential physiological functions and particularly in tumors. Specific alterations of miRNA expression have been identified directly involved in carcinogenesis. Indeed, miRNAs could act as oncogenes or tumor suppressors. In addition, some miRNAs deregulations seem to be associated to specific tumors subtypes, suggesting that they could be used as tumor biomarkers. In this review, we summarize recent works about miRNAs and hepatocellular tumorigenesis in order to understand the role of these small non-coding RNAs in the carcino-genesis process and their possible use as diagnostic and prognostic markers of these tumors.
The aim of this paper is to review the clinical epidemiology of heart failure. The last paper comprehensively addressing the epidemiology of heart failure in Heart appeared in 2000. Despite an increase in manuscripts describing epidemiological aspects of heart failure since the 1990s, additional information is still needed, as indicated by various editorials.
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The idea of personalized medicine raises a series of questions. If one considers that the physician takes into account the uniqueness of his patient in the frame of the medical consultation, is the definition of medicine as "personalized" not a pleonasm? If not, why has this ambiguous denomination been adopted? In addition, is this form of medicine a novel discipline capable of revolutionizing therapeutic approaches as claimed in its accompanying discourses or is it in continuity with the molecular conception of biomedicine? Rather than attempting to directly answer these questions, we focused our attention on the organizing concepts, the technological breakthroughs and the transformations in medical practices that characterize this medicine. Following this brief analysis, it appears that the choice of a term as equivocal as personalized medicine and the emphasis on the antagonistic notions of revolution and continuity in medicine are the signs of reshuffling that is emerging between actors in the health care system, in academia and in pharmaceutical companies.
© 2015 médecine/sciences – Inserm.
The identification and characterization of long noncoding RNA in a variety of tissues represent major achievements that contribute to our understanding of the molecular mechanisms controlling gene expression. In particular, long noncoding RNA play crucial roles in the epigenetic regulation of the adaptive response to environmental cues via their capacity to target chromatin modifiers to specific locus. In addition, these transcripts have been implicated in controlling splicing, translation and degradation of messenger RNA. Long noncoding RNA have also been shown to act as decoy molecules for microRNA. In the heart, a few long noncoding RNA have been demonstrated to regulate cardiac commitment and differentiation during development. Furthermore, recent findings suggest their involvement as regulators of the pathophysiological response to injury in the adult heart. Their high cellular specificity makes them attractive target molecules for innovative therapies and ideal biomarkers.
© 2015 médecine/sciences – Inserm.
This article proposes a brief inquiry into the field of scientific and medical practices currently referred to as "personalized medicine". Our inquiry identifies four recurring themes in the literature: health care that is tailored to the individual patient, that is enabled by emerging technologies, in which genetics and genomics occupy a prominent place, and which requires the collection of a massive amount of data. Personalized medicine, thus characterized, turns out to be less interested in the uniqueness of each patient's case than in the differences among patients within the same category. The aim of personalized medicine, thus described, is to obtain, with the help of cutting edge technology, more objective biological data on patients, in an attempt to improve the tools it has at its disposal to establish diagnoses, make therapeutic decisions, and provide more effective preventive measures.
© 2014 médecine/sciences – Inserm.
Cardiac stress leads to remodelling of cardiac tissue, which often progresses to heart failure and death. Part of the remodelling process is the formation of fibrotic tissue, which is caused by exaggerated activity of cardiac fibroblasts leading to excessive extracellular matrix production within the myocardium. Noncoding RNAs (ncRNAs) are a diverse group of endogenous RNA-based molecules, which include short (∼22 nucleotides) microRNAs and long ncRNAs (of >200 nucleotides). These ncRNAs can regulate important functions in many cardiovascular cells types. This Review focuses on the role of ncRNAs in cardiac fibrosis; specifically, ncRNAs as therapeutic targets, factors for direct fibroblast transdifferentation, their use as diagnostic and prognostic markers, and their potential to function as paracrine modulators of cardiac fibrosis and remodelling.
Rationale:
Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia.
Objective:
To measure lncRNAs in patients with myocardial infarction (MI).
Methods and results:
We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative polymerase chain reaction: hypoxia inducible factor 1A antisense RNA 2, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL), potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1), myocardial infarction-associated transcript, and metastasis-associated lung adenocarcinoma transcript 1. Levels of hypoxia inducible factor 1A antisense RNA 2, KCNQ1OT1, and metastasis-associated lung adenocarcinoma transcript 1 were higher in patients with MI than in healthy volunteers (P<0.01), and levels of ANRIL were lower in patients with MI (P=0.003). Patients with ST-segment-elevation MI had lower levels of ANRIL (P<0.001), KCNQ1OT1 (P<0.001), myocardial infarction-associated transcript (P<0.001), and metastasis-associated lung adenocarcinoma transcript 1 (P=0.005) when compared with patients with non-ST-segment-elevation MI. Levels of ANRIL were associated with age, diabetes mellitus, and hypertension. Patients presenting within 3 hours of chest pain onset had elevated levels of hypoxia inducible factor 1A antisense RNA 2 when compared with patients presenting later on. ANRIL, KCNQ1OT1, myocardial infarction-associated transcript, and metastasis-associated lung adenocarcinoma transcript 1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction ≤40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model, including demographic features, clinical parameters, and cardiac biomarkers.
Conclusions:
Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI.
All proteins are translated from RNA, but only a fraction of RNAs seem to be translated into proteins. Advanced genomics technologies have uncovered noncoding regulatory RNAs exhibiting extraordinary diversity in size, structure, and molecular function. We know a great deal about small (≈20 nucleotides) microRNAs that post-transcriptionally regulate translation of protein from target mRNAs having complementary 3′ sequences. These linear single-stranded nucleotides are transcribed either as independent gene products or as passengers within so-called miRtrons (microRNA-containing introns) of protein-coding genes and then processed and exported from the nucleus where they incorporate into RNA-induced silencing complexes. 1 Because some microRNAs exhibit altered expression or differing circulating levels, they are being assessed as diagnostic biomarkers in cardiac disease. As yet, we know far less about the larger (>200 nucleotides) long noncoding RNAs (lncRNAs). lncRNAs are generated as antisense transcripts of protein-coding genes, as sense transcripts from within protein-coding gene introns, or as independent transcripts originating from intergenic regions. 2 Unlike short microRNAs, lncRNAs are sufficiently long to develop multiple intramolecular RNA–RNA interactions conferring on them complex 3-dimensional structures. The unique physical configurations of different lncRNAs enable many of them to bind specific sets of proteins. Likewise, openly configured single-strand RNA sequences within lncRNA structures permit them to bind to complementary sequences in the genome. The combination of these 2 characteristics, protein binding and recognition of specific DNA sequences, evokes a characteristic lncRNA functionality: chaperoning transcriptional modulators or chromatin modifiers to specific genomic locations. In this manner, lncRNAs can epigenetically regulate gene expression. 3
Long non-coding RNAs (lncRNAs) represent a novel class of molecules regulating gene expression. LncRNAs are present in body fluids, but their potential as biomarkers was never investigated in cardiovascular disease.
Role of lncRNAs as potential biomarkers in heart disease.
Global transcriptomic analyses were done in plasma RNA from patients with/without left ventricular (LV)-remodeling after myocardial infarction. Regulated candidates were validated in three independent patient cohorts developing cardiac remodeling and heart failure (788 patients). The mitochondrial lncRNA uc022bqs.1 (LIPCAR) was down-regulated early after MI but up-regulated during later stages. LIPCAR levels identified patients developing cardiac remodeling and were independently to other risk markers associated with future cardiovascular deaths.
LIPCAR is a novel biomarker of cardiac remodeling and predicts future death in heart failure patients.
Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. microRNAs and Long non-coding RNAs (LncRNAs) have various biological functions, and have been extensively investigated throughout the past years.
We identified miR-489 and LncRNAs (CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro.
A microarray was performed to analyze miRNAs in response to angiotensin II (Ang-II) treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response upon Ang-II treatment. We identified myeloid differentiation primary response gene 88 (Myd88) as a miR-489 target to mediate the function of miR-489 in cardiac hypertrophy. Knockdown of Myd88 in cardiomyocytes and Myd88 knockout mice both showed attenuated hypertrophic responses. Further, we explored the molecular mechanism by which miR-489 expression is regulated, and found that a long non-coding RNA that we named cardiac hypertrophy related factor (CHRF) acts as an endogenous 'sponge' of miR-489, which downregulates miR-489 expression levels. CHRF is able to directly bind to miR-489, and regulates Myd88 expression and hypertrophy.
Our present study reveals a novel cardiac hypertrophy regulating model which is composed of CHRF, miR-489 and Myd88. Modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA) and long non-coding RNA (lncRNA) expression in failing human heart, before and after mechanical support with a left ventricular assisted device (LVAD) METHODS AND RESULTS: Deep sequencing of RNA isolated from paired non-ischemic (NICM,n=8) and ischemic (ICM,n=8) human failing LV samples collected pre- and post-LVAD, as well as from non-failing human LV (n=8), was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with non-failing LV. Among these only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ~10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes cardiomyopathy of ischemic and non-ischemic origins. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs.
The myocardial transcriptome is dynamically regulated in advanced heart failure and following LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different etiologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.
Heart failure is a leading cause of death in industrialized nations especially in an aging population. The recent improvements in cardiac revascularization therapy reduced death rates because of myocardial infarction but steadily increased the number of individuals developing cardiac remodeling and heart failure in the future. Conceptual novel approaches entering the clinics to treat cardiac remodeling and heart failure remain scarce. MicroRNAs emerged as powerful and dynamic modifiers of cardiovascular diseases. In this review, the current approaches using microRNAs as novel diagnostic and therapeutic strategies for cardiac remodeling and heart failure are highlighted. Other gene regulatory mechanisms presented include long (>200 bp) noncoding RNAs that function as an additional regulatory machinery of the genome controlling both transcriptional and post-transcriptional events also in the cardiovascular system.
Without question, the last half century has witnessed spectacular advances in cardiovascular medicine and surgery. In the United States, a full two-thirds of the six-year prolongation of life that has occurred has been a direct consequence of these advances which did not spring forth simply from the heads of brilliant, insightful clinicians. Instead, most were based on preclinical research which was then translated into improvements in clinical care.For instance, the microbiologists who connected streptococcal infection to acute rheumatic fever, and subsequently the discovery of penicillin by a microbiologist, an experimental pathologist, and a biochemist led to the virtual elimination of acute rheumatic fever which in turn was responsible for the marked reduction of chronic rheumatic valvular heart disease in large portions of the world. Almost all residual cases of the latter can now be corrected by open heart surgery or catheter-based techniques which were made possible by the efforts of bioengineers, pharmacologists, and physiologists collaborating with surgeons and cardiologists. The striking reduction in mortality of acute myocardial infarction that has occurred since 1960 would not have been possible had physicists not previously developed the cathode ray oscilloscope which enabled the continuous monitoring of the electrocardiogram, and if engineers had not developed the capacitors that store the electrical charge required for ventricular defibrillation. Without pharmacologists and cell biologists, statins, which are enormously useful in preventing the development and progression of atherosclerosis, would not have been developed. These are just a few examples of the seminal scientific efforts that have provided the underpinnings of modern cardiology. [Extract][Note: The full Compendium on Heart Failure will be published in the August 30, 2013 issue of Circulation Research.].
Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology's longstanding concern with the evolution and function of genomes.
Background:
Recent studies have suggested that the microRNAs miR-133a and miR-423-5p may serve as useful biomarkers in patients with left ventricular (LV) heart failure or with LV remodeling after myocardial infarction (MI). These results were however obtained in small series of patients and control subjects were used as reference groups. Whether these microRNAs may be indicators of the degree of LV remodeling after MI is unknown.
Methods:
246 patients with a first anterior Q-wave MI were included. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI and analyzed at a core laboratory. We investigated the temporal profile (baseline, 1, 3 and 12 months) of circulating miR-133a and miR-423-5p and their relations with cardiac biomarkers (B-type natriuretic peptide, C-reactive protein, and cardiac troponin I) and LV remodeling during the 1 year follow-up.
Results:
There were time-dependent changes in the levels of circulating miR-133a and miR-423-5p with significant increase of miR-133a at 12 months compared to 3 months and significant increase of miR-423-5p at 1, 3, and 12 months compared to baseline. However, miR-133a and miR-423-5p were not associated with indices of LV function and LV remodeling serially assessed during a 1 year period after an acute anterior MI, nor with B-type natriuretic peptide.
Conclusions:
Circulating levels of miR-133a and miR-423-5p are not useful biomarkers of LV remodeling after MI.
Left ventricular (LV) remodeling after myocardial infarction (MI) indicates a high risk of heart failure and death, but LV remodeling remains difficult to predict. Biomarkers may help to refine risk stratification for a more personalized medical approach. They may also shed light on the pathophysiologic processes involved. We performed a systematic review of the published evidence about the association of circulating biomarkers with LV remodeling after MI. We selected 59 publications. Overall, these studies examined 112 relations between 52 different biomarkers and LV remodeling. The biomarkers most consistently associated with LV remodeling were involved in extracellular matrix turnover or neurohormonal activation: matrix metalloproteinase-9, collagen peptides, and B-type natriuretic peptide. This review underscores the vitality of the research on LV remodeling but concludes that the ideal biomarker has not yet been identified. To reach this goal, future studies will have to be larger, have standardized imaging end points, and include replication populations to define optimal cutoffs for LV remodeling prediction. Cardiovascular magnetic resonance appears to be the best technique for LV remodeling assessment but its current availability may be a concern for recruitment for multicenter studies. Recent technologic advances will probably yield new candidate biomarkers of LV remodeling. Tests are necessary to determine whether a multimarker approach would significantly improve risk prediction.
Heart failure (HF) remains a severe disease with a poor prognosis. HF biomarkers may include demographic features, cardiac imaging, or genetic polymorphisms but this term is commonly applied to circulating serum or plasma analytes. Biomarkers may have at least three clinical uses in the context of HF: diagnosis, risk stratification, and guidance in the selection of therapy. Proteomic studies on HF biomarkers can be designed as case/control using clinical endpoints; alternatively, left ventricular remodeling can be used as a surrogate endpoint. The type of samples (tissue, cells, serum or plasma) used for proteomic analysis is a key factor in the research of biomarkers. Since the final aim is the discovery of circulating biomarkers, and since plasma and serum samples are easily accessible, proteomic analysis is frequently used for blood samples. However, standardization of sampling and access to low-abundance proteins remains problematic. Although, proteomics is playing a major role in the discovery phase of biomarkers, validation in independent populations is necessary by using more specific methods. The knowledge of new HF biomarkers may allow a more personalized medicine in the future.
Left ventricular (LV) remodeling after myocardial infarction (MI) indicates a high risk of heart failure and death. However, LV remodeling is difficult to predict, and limited information is available on the association of cardiac biomarkers with LV remodeling. Our aim was to study the association of B-type natriuretic peptide (BNP), cardiac troponin I (cTnI), and C-reactive protein with LV remodeling after MI. We designed a prospective multicenter study including 246 patients with a first anterior Q-wave MI. Serial echocardiographic studies were performed at hospital discharge and 3 months and 1 year after MI; quantitative analysis was performed at a core echocardiographic laboratory. Blood samples for determination of BNP, cTnI, and C-reactive protein levels were obtained at hospital discharge and the 1-month, 3-month, and 1-year follow up visits. One-year echocardiographic follow-up was obtained in 226 patients. End-diastolic volume increased from 52.3 ± 13.8 ml/m(2) at baseline to 62.3 ± 18.4 ml/m(2) at 1 year (p <0.0001); LV remodeling (>20% increase in end-diastolic volume) was observed in 87 patients (38%). At baseline, we found significant univariate relations between LV remodeling and the 3 biomarkers. During follow-up, high BNP levels and persistently detectable levels of cTnI were associated with LV remodeling. In multivariate analysis, none of the 3 biomarkers at baseline was independently predictive of LV remodeling. In contrast, during follow-up, high BNP and positive cTnI were independently associated with LV remodeling. In conclusion, circulating cardiac biomarkers may reflect pathophysiologic processes implicated in LV remodeling after MI. Determination of BNP and cTnI during follow-up can help refine risk stratification.
We examined whether population-level hospitalization rates for heart failure (HF) and subsequent survival have continued to improve since the turn of the century. We also examined trends in the prescribing of evidence-based pharmacological treatment for HF.
All patients in Scotland hospitalized with a first episode of HF between 1986 and 2003 were followed up until death or the end of 2004. Prescriptions of evidence-based treatments issued from 1997 to 2003 by a sample of primary care practices were also examined. A total of 116 556 individuals (52.6% women) had a first hospital discharge for HF. Age-adjusted first hospitalization rates for HF (per 100 000; 95% CI in parentheses) rose from 124 (119 to 129) in 1986 to 162 (157 to 168) in 1994 and then fell to 105 (101 to 109) in 2003 in men; in women, they rose from 128 (123 to 132) in 1986 to 160 (155 to 165) in 1993, falling to 101 (97 to 105) in 2003. Case-fatality rates fell steadily over the period. Adjusted 30-day case-fatality rates fell after discharge (adjusted odds [2003 versus 1986] 0.59 [95% CI 0.45 to 0.63] in men and 0.77 [95% CI 0.67 to 0.88] in women). Adjusted 1- and 5-year survival improved similarly. Median survival increased from 1.33 to 2.34 years in men and from 1.32 to 1.79 years in women. Age-adjusted prescribing rates for angiotensin-converting enzyme inhibitors, beta-blockers, and spironolactone increased from 1997 to 2003 (all P<0.0001 for trend).
After rising between 1986 and 1994, rates of first hospitalization for HF declined. Case-fatality rates also fell. Prescribing rates for HF therapies increased from 1997 to 2003. These findings suggest that improvements in the prevention and treatment of HF may have had progressive, sustained effects on outcomes at the population level; however, prognosis remains poor in HF.
We sought to study the relationship between survival and right ventricular ejection fraction (RVEF) in a subgroup of patients with moderate congestive heart failure (CHF).
It has been demonstrated that RVEF is an independent predictor of survival in patients with advanced CHF.
Cardiopulmonary exercise testing and radionuclide angiography (to determine right and left ventricular ejection fraction) were prospectively performed in 205 consecutive patients with moderate CHF (140 patients in New York Heart Association [NYHA] class II, 65 in class III).
Left ventricular ejection fraction was 29.3%+/-10.1%, RVEF was 37.5%+/-14.6% and peak oxygen consumption (VO2) was 16.2+/-5.4 ml/min/kg (60.2%+/-19% of maximal predicted VO2). After a median follow-up period of 755 days, there were 44 cardiac-related deaths, 3 deaths from noncardiac causes and 15 transplantations of whom 2 were urgent; 1 patient was lost to follow-up. Multivariate analysis showed that three variables-NYHA classification, percent of maximal predicted VO2 and RVEF-were independent predictors of both survival and event-free cardiac survival. Left ventricular ejection fraction and peak VO2 normalized to body weight had no predictive value. The event-free survival rates from cardiovascular mortality and urgent transplantation at 1 year were 80%, 90% and 95% in patients with an RVEF <25%, with a RVEF > or =25% and <35% and with a RVEF > or =35%, respectively. At 2 years, survival rates were 59%, 77% and 93% in the same subgroups, respectively.
In addition to the NYHA classification and to the percent of maximal predicted VO2, RVEF is an independent predictor of survival in patients with moderate CHF.
The aim of this study was to compare the prognostic value of peak oxygen consumption (VO(2)) and B-type natriuretic peptide (BNP) in patients with stable congestive heart failure (CHF).
Previous studies have demonstrated that both peak VO(2) and BNP are useful for risk stratification in patients with CHF. No study has compared the respective prognostic value of these two parameters in a large series of patients receiving a combination of angiotensin-converting enzyme inhibitors and of beta-blockers.
Patients with stable CHF underwent radionuclide angiography, echocardiography, 24-h Holter monitoring, and a cardiopulmonary exercise test. Blood samples were drawn for standard measurements and for hormonal determinations.
After a median follow-up period of 787 days, there were 75 cardiac-related deaths and three urgent transplantations. Independent predictors of cardiac survival were percent of maximal predicted VO(2) (%VO(2), relative risk [RR] = 2.84 [95% confidence interval, CI = 1.73 to 4.65], p < 0.00001), BNP (RR = 3.17 [95% CI 1.68 to 5.96], p = 0.0004), left atrial diameter (LAD) (RR = 2.04 [95% CI 1.25 to 3.34], p = 0.004), age (RR = 1.93 [95% CI 1.22 to 3.05], p = 0.005), and aldosterone (RR = 1.84 [95% CI 1.12 to 3.00], p = 0.015). In patients with infra-median levels of BNP (<109 pg/ml), age was the only independent predictor of cardiac survival. However, in patients with supra-median levels of BNP, independent predictors of cardiac survival were %VO(2) (RR = 3.76 [95% CI 2.19 to 6.45], p < 0.00001) and LAD (RR = 1.90 [95% CI 1.10 to 3.28], p = 0.02).
B-type natriuretic peptide, in combination with %VO(2), improves risk stratification of patients with stable CHF.
This paper reviews recent advances in heart failure biomarkers for identification of disease precursors, subclinical disease, and onset or progression of overt disease.
Heart failure biomarkers can be categorized empirically as neurohormonal mediators, markers of myocyte injury and remodeling, and indicators of systemic inflammation. Brain natriuretic peptide is the most widely studied, with a potentially important but evolving role for determining prognosis and as a surrogate endpoint in clinical trials. Strong evidence exists for use of brain natriuretic peptide in the diagnosis of acute heart failure and for improved clinical outcomes with a brain natriuretic peptide-guided approach to heart failure care. The use of brain natriuretic peptide as a screening tool for asymptomatic left ventricular systolic dysfunction, or to distinguish systolic from diastolic heart failure, is not supported by current data. Markers of myocyte injury, including troponins, heart-type fatty acid binding protein, and myosin light chain-1, may further improve heart failure prognostication in conjunction with plasma brain natriuretic peptide. Biomarkers of matrix remodeling and inflammation have emerged as potential preclinical indicators to identify individuals at risk of developing clinical heart failure. A role for cellular adhesion molecules may also emerge in identifying those at risk for cardiovascular thrombotic complications, such as stroke.
The spectrum of heart failure biomarkers and their potential clinical applications continues to grow. Ongoing research on multimarker strategies will likely identify biomarker combinations that are optimal at various stages during the evolution of heart failure, ranging from their use for screening, diagnosis, determining prognosis, and guiding management.
The detection of circulating nucleic acids has long been explored for the non-invasive diagnosis of a variety of clinical conditions. In earlier studies, detection of circulating DNA has been investigated for the detection of various forms of cancer. Metastasis and recurrence in certain cancer types have been associated with the presence of high levels of tumor-derived DNA in the circulation. In the case of pregnancies, detection of fetal DNA in maternal plasma is a useful tool for detecting and monitoring certain fetal diseases and pregnancy-associated complications. Similarly, levels of circulating DNA have been reported to be elevated in acute medical emergencies, including trauma and stroke, and have been explored as indicators of clinical severity. Apart from circulating DNA, much attention and effort have been put into the study of circulating RNA over the last few years. This area started from the detection of tumor-derived RNA in the plasma of cancer patients. Soon after that, detection of circulating fetal RNA in maternal plasma was described. Plasma RNA detection appears to be a promising approach for the development of gender- and polymorphism-independent fetal markers for prenatal diagnosis and monitoring. This development also opens up the possibility of non-invasive prenatal gene expression profiling by maternal blood analysis. Besides circulating DNA and RNA in plasma and serum, cell-free DNA in other body fluids, such as urine, has been detected in patients with different clinical conditions. Regardless of the sources of cell-free DNA for clinical use, the amount is frequently scarce.
Technical advancements in detecting free DNA have been made over the years.
It is likely that further developments in the field of circulating nucleic acids will provide us with new diagnostic and monitoring possibilities over the next few years.
Left ventricular (LV) remodeling after acute myocardial infarction (AMI) has been well described in previous studies. However, there is a paucity of data on the incidence of and risk factors for LV remodeling in modern clinical practice that incorporates widespread use of acute reperfusion strategies and almost systematic use of "antiremodeling" medications, such as angiotensin-converting enzyme inhibitors and beta blockers. We enrolled 266 patients with anterior wall Q-wave AMI who had >or=3 segments of the infarct zone that were akinetic on echocardiography before discharge. Echocardiographic follow-up was performed 3 months and 1 year after AMI. LV volumes, ejection fraction, wall motion score index, and mitral flow velocities were determined in a blinded analysis at a core echocardiographic laboratory. Acute reperfusion was attempted in 220 patients (83%; primary angioplasty in 29% and thrombolysis in 54%). During hospitalization, 99% of patients underwent coronary angiography and 87% underwent coronary stenting of the infarct-related lesion. At 1 year, 95% of patients received an antiplatelet agent, 89% a beta blocker, 93% an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and 93% a statin. Echocardiographic follow-up was obtained in 215 patients. There was recovery in LV systolic function as shown by a decrease in wall motion score index and an increase in ejection fraction. There was a significant increase in end-diastolic volume (EDV; 56.4 +/- 14.7 ml/m2 at baseline, 59.3 +/- 15.7 ml/m2 at 3 months, 62.8 +/- 18.7 ml/m2 at 1 year, p <0.0001). LV remodeling (>20% increase in EDV) was observed in 67 patients (31%). Peak creatine kinase level, systolic blood pressure, and wall motion score index were independently associated with changes in EDV. In conclusion, recent improvements in AMI management do not abolish LV remodeling, which remains a relatively frequent event after an initial anterior wall AMI.
Of all persons aged over 40 years, approximately 1% have heart failure. The prevalence of heart failure doubles with each decade of life, and is around 10% in persons over 70 years of age. In Spain, heart failure causes nearly 80,000 hospital admissions every year. As in other developed countries, heart failure is the most frequent cause of hospitalization among persons 65 years of age and over, and is responsible for 5% of all hospitalizations. The incidence of heart failure increases with age, and reaches 1% per year in those over 65. Heart failure is a progressive, lethal disorder, even with adequate treatment. Five-year survival is around 50%, which is no better than that for many cancers. In Spain, heart failure is the third leading cause of cardiovascular mortality, after coronary disease and stroke. In 2000, heart failure caused 4% of all deaths and 10% of cardiovascular deaths in men; the corresponding figures for women were 8% and 18%. In recent decades the prevalence and number of hospitalizations due to heart failure have increased steadily in developed countries. Heart failure will probably continue to increase in coming years: although its incidence has not materially decreased, survival is increasing due to better treatment. The control of risk factors for hypertension and ischemic heart disease, the main causes of heart failure in Spain, is the only method to halt the foreseeable increase in heart failure in the near future.
Heart failure results not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, inflammatory, and biochemical changes acting on cardiac myocytes, the cardiac interstitium, or both. This review focuses on biomarkers for heart failure other than routinely determined laboratory values and discusses how these might be used in assessing and managing heart failure.
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