A comparative study of discriminating human heart failure etiology using gene expression profiles

BACKGROUND: Human heart failure is a complex disease that manifests from multiple genetic and environmental factors. Although ischemic and non-ischemic heart disease present clinically with many similar decreases in ventricular function, emerging work suggests that they are distinct diseases with different responses to therapy. The ability to distinguish between ischemic and non-ischemic heart failure may be essential to guide appropriate therapy and determine prognosis for successful treatment. In this paper we consider discriminating the etiologies of heart failure using gene expression libraries from two separate institutions. RESULTS: We apply five new statistical methods, including partial least squares, penalized partial least squares, LASSO, nearest shrunken centroids and random forest, to two real datasets and compare their performance for multiclass classification. It is found that the five statistical methods perform similarly on each of the two datasets: it is difficult to correctly distinguish the etiologies of heart failure in one dataset whereas it is easy for the other one. In a simulation study, it is confirmed that the five methods tend to have close performance, though the random forest seems to have a slight edge. CONCLUSIONS: For some gene expression data, several recently developed discriminant methods may perform similarly. More importantly, one must remain cautious when assessing the discriminating performance using gene expression profiles based on a small dataset; our analysis suggests the importance of utilizing multiple or larger datasets

Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection.

To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score >37%  = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection

Blood Signature of Pre-Heart Failure: A Microarrays Study

International audienceBACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF

Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure

<p>Abstract</p> <p>Background</p> <p>Isoproterenol-induced cardiac hypertrophy in mice has been used in a number of studies to model human cardiac disease. In this study, we compared the transcriptional response of the heart in this model to other animal models of heart failure, as well as to the transcriptional response of human hearts suffering heart failure.</p> <p>Results</p> <p>We performed microarray analyses on RNA from mice with isoproterenol-induced cardiac hypertrophy and mice with exercise-induced physiological hypertrophy and identified 865 and 2,534 genes that were significantly altered in pathological and physiological cardiac hypertrophy models, respectively. We compared our results to 18 different microarray data sets (318 individual arrays) representing various other animal models and four human cardiac diseases and identified a canonical set of 64 genes that are generally altered in failing hearts. We also produced a pairwise similarity matrix to illustrate relatedness of animal models with human heart disease and identified ischemia as the human condition that most resembles isoproterenol treatment.</p> <p>Conclusion</p> <p>The overall patterns of gene expression are consistent with observed structural and molecular differences between normal and maladaptive cardiac hypertrophy and support a role for the immune system (or immune cell infiltration) in the pathology of stress-induced hypertrophy. Cross-study comparisons such as the results presented here provide targets for further research of cardiac disease that might generally apply to maladaptive cardiac stresses and are also a means of identifying which animal models best recapitulate human disease at the transcriptional level.</p

Changes in gut microbiota in the acute phase after spinal cord injury correlate with severity of the lesion

open26noFunding: Non-profit study funded by each clinical centre with its own financial resources, also to cover the costs of the molecular tests, with a financial grant by SIMS, the Italian Society for Spinal Cord.After spinal cord injury (SCI), patients face many physical and psychological issues including intestinal dysfunction and comorbidities, strongly affecting quality of life. The gut microbiota has recently been suggested to influence the course of the disease in these patients. However, to date only two studies have profiled the gut microbiota in SCI patients, months after a traumatic injury. Here we characterized the gut microbiota in a large Italian SCI population, within a short time from a not only traumatic injury. Feces were collected within the first week at the rehabilitation center (no later than 60&nbsp;days after SCI), and profiled by 16S rRNA gene-based next-generation sequencing. Microbial profiles were compared to those publicly available of healthy age- and gender-matched Italians, and correlated to patient metadata, including type of SCI, spinal unit location, nutrition and concomitant antibiotic therapies. The gut microbiota of SCI patients shows distinct dysbiotic signatures, i.e. increase in potentially pathogenic, pro-inflammatory and mucus-degrading bacteria, and depletion of short-chain fatty acid producers. While robust to most host variables, such dysbiosis varies by lesion level and completeness, with the most neurologically impaired patients showing an even more unbalanced microbial profile. The SCI-related gut microbiome dysbiosis is very likely secondary to injury and closely related to the degree of completeness and severity of the lesion, regardless of etiology and time interval. This microbial layout could variously contribute to increased gut permeability and inflammation, potentially predisposing patients to the onset of severe comorbidities.openBazzocchi G.; Turroni S.; Bulzamini M.C.; D'Amico F.; Bava A.; Castiglioni M.; Cagnetta V.; Losavio E.; Cazzaniga M.; Terenghi L.; De Palma L.; Frasca G.; Aiachini B.; Cremascoli S.; Massone A.; Oggerino C.; Onesta M.P.; Rapisarda L.; Pagliacci M.C.; Biscotto S.; Scarazzato M.; Giovannini T.; Balloni M.; Candela M.; Brigidi P.; Kiekens C.Bazzocchi G.; Turroni S.; Bulzamini M.C.; D'Amico F.; Bava A.; Castiglioni M.; Cagnetta V.; Losavio E.; Cazzaniga M.; Terenghi L.; De Palma L.; Frasca G.; Aiachini B.; Cremascoli S.; Massone A.; Oggerino C.; Onesta M.P.; Rapisarda L.; Pagliacci M.C.; Biscotto S.; Scarazzato M.; Giovannini T.; Balloni M.; Candela M.; Brigidi P.; Kiekens C

Nutrition and biomarkers in psychiatry : research on micronutrient deficiencies in schizophrenia, the role of the intestine in the hyperserotonemia of autism, and a method for non-hypothesis driven discovery of biomarkers in urine

This thesis describes the study of markers of nutrition and intestinal motility in mental disorders with a focus on schizophrenia and autism, and the development, evaluation and application of a biomarker discovery method for urine. The aim of the thesis is to investigate the role of long-chain polyunsaturated fatty acids (LCPUFA), B-vitamins and platelet (PLT) serotonin (5-HT) in schizophrenia and autism. The thesis proposes also that biomarker research in psychiatric disease is of great relevance and describes a biomarker discovery method in urine using a non-hypothesis driven ‘-omics’-like approach. The thesis ends by summarizing its contents and putting biomarker research in psychiatric disease and its implications in a broader perspective. In the Introduction the complex etiology and potential role of non-hypothesis driven biomarker research in psychiatric disease is reviewed, with an accent on schizophrenia and autism. The enormous economic and psychosocial global burden of mental disorders is described as well as their epidemiology, clinical presentation and classification/diagnosis. Hypothesized etiological factors are discussed to create a framework in which biomarkers and the research thereof can be positioned. Furthermore, advances in the field of biomarker research in psychiatry are discussed in the context of epigenetics, proteomics and metabolomics. The first part (Part I) of this thesis describes a study of LCPUFA and B-vitamins in schizophrenia, of PLT 5-HT and intestinal permeability in autism, and of the value of PLT 5-HT as marker of intestinal motility in newborns. The chapters, in which these studies are described, are preceded by a review (Chapter 1), which gives an overview of the role of LCPUFA and folate in the etiology and severity of psychiatric diseases such as depression, bipolar disorders, schizophrenia and autism. Pregnancy complications and folate-substrated carbon-1 metabolism are considered and their possible epigenetic effect on the etiology of mental disorders is described. Other nutritional factors, such as LCPUFA, that are important for brain development, physico-chemical properties of membranes, signal transduction and DNA-transcription, and that have been used in supplementation trials, are suggested to be important factors in the origin and severity of schizophrenia. In Chapter 2 we describe the results from a study concerning the essential fatty acid (EFA) and functional B-vitamin status in patients with schizophrenia. Aberrant EFA-status and increased homocysteine (Hcy; a marker of functional B-vitamin deficiency), have been reported before in subgroups of patients with schizophrenia. We describe the characteristics of large subgroups with marginal to severe deficiencies of LCPUFA and B-vitamins, notably folate and vitamin B12. Deficiencies proved easily correctable in the most severely deficient patients upon supplementation with ω3 fatty acids and B-vitamins. Chapter 3 attempts to integrate and link previously reported findings of increased intestinal permeability and increased PLT 5-HT levels in subgroups of children with pervasive developmental disorders (PDD). Platelet 5-HT and intestinal permeability were assessed in children with PDD in Curaçao. Differential urinary excretion of inert sugars after ingestion of a sugar solution was used as marker of intestinal permeability. In Chapter 4 we examined the potential of PLT 5-HT as marker of intestinal motility. For this we studied whole blood and PLT 5-HT in mothers (normal motility) and their newborns (developing intestinal motility) at birth. The course of PLT 5-HT in relation to changes in feeding mode (i.e. parenteral/enteral) was investigated in a small group of preterm born infants to see whether PLT 5-HT was responsive to changes in intestinal motility. Chapters 2, 3 and 4 describe hypothesis-driven research in mental disorders. However, the advance of knowledge about mental disorders is slow and it is likely to benefit from complementation by information that is generated through non-hypothesis driven research with state-of-the art techniques that profile proteins (i.e. proteomics) and metabolites (i.e. metabolomics). These ‘-omics’ techniques are likely to deliver a multitude of candidate diagnostic and prognostic markers as well as therapeutic targets, compared to hypothesis driven research. Part II is thus devoted to the development, evaluation and application of such a non-hypothesis driven method. In Chapter 5 we describe the comparative analysis of low molecular weight urinary components using LC-MS and subsequent multivariate statistical analysis of the processed LC-MS data. This chapter deals with the development, evaluation and preliminary application of the method to proteinuria in humans. The potential and pitfalls of the method are contemplated upon. Chapter 6 describes an advanced proof-of-principle of the method through the comparison of urinary profiles from pregnant and non-pregnant females using the improved methodology described in Chapter 5. The methodology is significantly optimized with respect to data processing and multivariate statistical analysis. More focus is put on the selection of discriminatory peaks. --------------------------------------------------------------- Éénderde van de patiënten met schizofrenie blijkt matige tot ernstige tekorten aan bepaalde B-vitaminen en ω3- en ω6-vetzuren te hebben. Deze tekorten zijn eenvoudig op te heffen met voedingsupplementen (o.a. foliumzuur en visolie). Een lage status van deze micronutriënten speelt waarschijnlijk een rol in het ontstaan en de ernst van diverse psychiatrische ziekten en het ontstaan van hart- en vaatziekten. De behandelende artsen vermoedden het bestaan van deze tekorten niet. Ongeveer een kwart van de patiënten met autisme heeft een verhoogd serotoninegehalte in bloedplaatjes (hyperserotonemie: “biomarker”). Serotonine is een neurotransmitter in onze hersenen en darmen. Autisten zouden ook vaker maagdarmstoornissen hebben. We vonden geen relatie tussen hyperserotonemie (26%) en de darmdoorlaatbaarheid (in 0% verhoogd) in kinderen met autisme. Het idee dat een verhoogde darmmotiliteit hyperserotonemie veroorzaakt, werd ondersteund door een twee maal hoger bloedplaatjesserotonine van moeders (actieve darm) t.o.v. hun pasgeboren baby’s (inactieve darm). Tevens bleek starten en staken van enterale voeding in pasgeborenen gecorreleerd aan respectievelijk stijgingen en dalingen van hun bloedplaatjesserotonine. Meer onderzoek naar het maagdarmstelsel (onze “second brain”) bij autisme is gewenst. Niet-hypothesegedreven onderzoek als aanvulling op het veelal hypothesegedreven onderzoek kan helpen bij het vinden van diagnostische en therapeutische biomarkers voor psychiatrische stoornissen. De hiertoe opgezette methode onderzoekt urinemonsters met vloeistofchromatografie-massaspectrometrie, waarna de 3D-data multivariaat geanalyseerd worden om biomarkers te ontdekken. Experimenten met urinemonsters van patiënten met eiwit in hun urine (vanwege een nierziekte) en controles, en van zwangere en niet-zwangere vrouwen, lieten duidelijke groepsverschillen zien (“proof-of-principle”). Dit geeft hoop dat de ontwikkelde methode in de toekomst gebruikt kan worden voor het opsporen van biomarkers bij psychiatrische stoornissen en andere ziektes.

Proteomics in cardiovascular disease: recent progress and clinical implication and implementation

Introduction: Although multiple efforts have been initiated to shed light into the molecular mechanisms underlying cardiovascular disease, it still remains one of the major causes of death worldwide. Proteomic approaches are unequivocally powerful tools that may provide deeper understanding into the molecular mechanisms associated with cardiovascular disease and improve its management. Areas covered: Cardiovascular proteomics is an emerging field and significant progress has been made during the past few years with the aim of defining novel candidate biomarkers and obtaining insight into molecular pathophysiology. To summarize the recent progress in the field, a literature search was conducted in PubMed and Web of Science. As a result, 704 studies from PubMed and 320 studies from Web of Science were retrieved. Findings from original research articles using proteomics technologies for the discovery of biomarkers for cardiovascular disease in human are summarized in this review. Expert commentary: Proteins associated with cardiovascular disease represent pathways in inflammation, wound healing and coagulation, proteolysis and extracellular matrix organization, handling of cholesterol and LDL. Future research in the field should target to increase proteome coverage as well as integrate proteomics with other omics data to facilitate both drug development as well as clinical implementation of findings

High-mobility group box 1 as a surrogate prognostic marker in dogs with systemic inflammatory response syndrome

To evaluate various surrogate markers associated with the inflammatory and counter-inflammatory responses with respect to mortality in dogs with systemic inflammatory response syndrome (SIRS).Prospective observational study.Veterinary Teaching Hospital.Twenty-eight dogs with naturally occurring diseases and SIRS from January 2007 to May 2009.Upon admission to the veterinary hospital, history and baseline data from the physical examination, including parameters previously defined for meeting SIRS criteria, were documented. Heparinized blood samples were collected and plasma cytokines interleukin-6 (IL-6), IL-10, and high-mobility group box 1 (HMGB1) were measured by sandwich ELISA.In nonsurvivors, median plasma HMGB1 concentrations (0.718 μg/L, interquartile range [IQR]; 0.300–1.626 μg/L) and the ratio of HMGB1 to IL-10 (2.236, IQR; 0.972–5.367) were significantly increased as compared with those found in survivors (0.300 μg/L, IQR; 0.300–0.312 μg/L for HMGB1; 1.017, IQR; 0.862–1.126 for the ratio of HMGB1 to IL-10, P =0.007 and 0.024, respectively). Plasma IL-6, IL-10, and the ratio of IL-6 to IL-10 were not significantly different between groups. Among the parameters studied, HMGB1 and the ratio of HMGB1 to IL-10 performed the best in discriminating outcome in dogs with SIRS according to receiver operator characteristic curve analysis.Increases in plasma HMGB1 concentration and the ratio of HMGB1 to IL-10 may predict poorer outcomes in dogs with SIRS. The approach described may lead to reliable prognostic biomarkers and new therapeutic concepts in the study of SIRS in dogs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79125/1/j.1476-4431.2010.00539.x.pd