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      Omics phenotyping in heart failure: the next frontier

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          Abstract

          This state-of-the-art review aims to provide an up-to-date look at breakthrough omic technologies that are helping to unravel heart failure (HF) disease mechanisms and heterogeneity. Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and physiology involved in HF than achieved by either one alone and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible and can be validated across multiple independent populations to ensure confidence in clinical decision-making.

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          Most cited references89

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          Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations

          A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. 1 Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, 2–5 it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0%, 6.1%, 3.5%, 3.2% and 1.5% of the population at greater than three-fold increased risk for coronary artery disease (CAD), atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For CAD, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. 6 We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care and discuss relevant issues.
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            Global Public Health Burden of Heart Failure.

            Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide and is increasing in prevalence. HF health expenditures are considerable and will increase dramatically with an ageing population. Despite the significant advances in therapies and prevention, mortality and morbidity are still high and quality of life poor. The prevalence, incidence, mortality and morbidity rates reported show geographic variations, depending on the different aetiologies and clinical characteristics observed among patients with HF. In this review we focus on the global epidemiology of HF, providing data about prevalence, incidence, mortality and morbidity worldwide.
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              Nitrosative stress drives heart failure with preserved ejection fraction

              Heart failure with preserved ejection fraction (HFpEF) is a common, morbid, and mortal syndrome for which there are no evidence-based therapies. Here, we report that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide (NO) synthase inhibition by N [w] -nitro-l-arginine methyl ester (L-NAME) recapitulates the numerous systemic and cardiovascular features of human HFpEF. One of the unfolded protein response (UPR) effectors, the spliced form of X-box binding protein 1 (Xbp1s), was reduced in the myocardium of both experimental and human HFpEF. Mechanistically, the decrease in Xbp1s resulted from increased inducible NO synthase (iNOS) activity and S-nitrosylation of endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective Xbp1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of Xbp1s, each ameliorated the HFpEF phenotype. We have unveiled iNOS-driven dysregulation of IRE1α-Xbp1s as a crucial mechanism of cardiomyocyte dysfunction in HFpEF.
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                Author and article information

                Contributors
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                Journal
                European Heart Journal
                Oxford University Press (OUP)
                0195-668X
                1522-9645
                September 21 2020
                September 21 2020
                April 26 2020
                September 21 2020
                September 21 2020
                April 26 2020
                : 41
                : 36
                : 3477-3484
                Affiliations
                [1 ]Heart Institute (iCor), University Hospital Germans Trias i Pujol, Badalona, Spain
                [2 ]CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
                [3 ]Department of Medicine, Universitat Autònoma Barcelona
                [4 ]University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
                [5 ]Henry Ford Heart and Vascular Institute, Center for Individualized and Genomic Medicine Research, Henry Ford Hospital, Detroit, MI, USA
                [6 ]Department of Cardiology, University of Groningen, University Medical Center, Groningen, The Netherlands
                [7 ]Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA, Pamplona, Spain
                [8 ]Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
                [9 ]Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
                [10 ]Fondazione Toscana G. Monasterio, Pisa, Italy
                [11 ]Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                Article
                10.1093/eurheartj/ehaa270
                32337540
                f2296e61-9183-4bf7-bcd3-12ce12e9bf78
                © 2020

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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