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JACC Journals › JACC: BTS › Archives › Vol. 2 No. 6
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Molecular Epidemiology of Heart Failure: Translational Challenges and OpportunitiesOpen Access

Translational Perspectives

J Am Coll Cardiol Basic Trans Science. 2017 Dec, 2 (6) 757–769
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Summary

Heart failure (HF) is the end-stage of all heart disease and arguably constitutes the greatest unmet therapeutic need in cardiovascular medicine today. Classic epidemiological studies have established clinical risk factors for HF, but the cause remains poorly understood in many cases. Biochemical analyses of small case-control series and animal models have described a plethora of molecular characteristics of HF, but a single unifying pathogenic theory is lacking. Heart failure appears to result not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, metabolic, inflammatory, and other biochemical factors acting on the heart. Recent development of robust, high-throughput tools in molecular biology provides opportunity for deep molecular characterization of population-representative cohorts and HF cases (molecular epidemiology), including genome sequencing, profiling of myocardial gene expression and chromatin modifications, plasma composition of proteins and metabolites, and microbiomes. The integration of such detailed information holds promise for improving understanding of HF pathophysiology in humans, identification of therapeutic targets, and definition of disease subgroups beyond the current classification based on ejection fraction which may benefit from improved individual tailoring of therapy. Challenges include: 1) the need for large cohorts with deep, uniform phenotyping; 2) access to the relevant tissues, ideally with repeated sampling to capture dynamic processes; and 3) analytical issues related to integration and analysis of complex datasets. International research consortia have formed to address these challenges and combine datasets, and cohorts with up to 1 million participants are being collected. This paper describes the molecular epidemiology of HF and provides an overview of methods and tissue types and examples of published and ongoing efforts to systematically evaluate molecular determinants of HF in human populations.

References

  • 1. Jessup M., Brozena S. "Heart failure". N Engl J Med 2003;348:2007-2018.

    CrossrefMedlineGoogle Scholar

  • 2. Shafazand M., Schaufelberger M., Lappas G., Swedberg K., Rosengren A. "Survival trends in men and women with heart failure of ischaemic and non-ischaemic origin: data for the period 1987-2003 from the Swedish Hospital Discharge Registry". Eur Heart J 2009;30:671-678.

    CrossrefMedlineGoogle Scholar

  • 3. Roger V.L. "Epidemiology of heart failure". Circ Res 2013;113:646-659.

    CrossrefMedlineGoogle Scholar

  • 4. Lozano R., Naghavi M., Foreman K., et al. "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 2012;380:2095-2128.

    CrossrefMedlineGoogle Scholar

  • 5. Christiansen M.N., Kober L., Weeke P., et al. "Age-specific trends in incidence, mortality, and comorbidities of heart failure in Denmark, 1995 to 2012". Circulation 2017;135:1214-1223.

    CrossrefMedlineGoogle Scholar

  • 6. Mahmood S.S., Levy D., Vasan R.S., Wang T.J. "The Framingham heart study and the epidemiology of cardiovascular disease: a historical perspective". Lancet 2014;383:999-1008.

    CrossrefMedlineGoogle Scholar

  • 7. Kannel W.B., D'Agostino R.B., Silbershatz H., Belanger A.J., Wilson P.W., Levy D. "Profile for estimating risk of heart failure". Arch Intern Med 1999;159:1197-1204.

    CrossrefMedlineGoogle Scholar

  • 8. Smith J.G., Newton-Cheh C., Almgren P., et al. "Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation". J Am Coll Cardiol 2010;56:1712-1719.

    View ArticleGoogle Scholar

  • 9. Braunwald E., Bristow M.R. "Congestive heart failure: fifty years of progress". Circulation 2000;102:IV14-IV23.

    CrossrefMedlineGoogle Scholar

  • 10. Psaty B.M., O'Donnell C.J., Gudnason V., et al. "Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts". Circ Cardiovasc Genet 2009;2:73-80.

    CrossrefMedlineGoogle Scholar

  • 11. Wacholder S. "Practical considerations in choosing between the case-cohort and nested case-control designs". Epidemiology 1991;2:155-158.

    CrossrefMedlineGoogle Scholar

  • 12. de Bakker P.I., Ferreira M.A., Jia X., Neale B.M., Raychaudhuri S., Voight B.F. "Practical aspects of imputation-driven meta-analysis of genome-wide association studies". Hum Mol Genet 2008;17:R122-R128.

    CrossrefMedlineGoogle Scholar

  • 13. Deo R.C. "Machine learning in medicine". Circulation 2015;132:1920-1930.

    CrossrefMedlineGoogle Scholar

  • 14. Shah S.J., Katz D.H., Selvaraj S., et al. "Phenomapping for novel classification of heart failure with preserved ejection fraction". Circulation 2015;131:269-279.

    CrossrefMedlineGoogle Scholar

  • 15. Lee D.S., Pencina M.J., Benjamin E.J., et al. "Association of parental heart failure with risk of heart failure in offspring". N Engl J Med 2006;355:138-147.

    CrossrefMedlineGoogle Scholar

  • 16. Lindgren M.P., Smith J.G., Li X., Sundquist J., Sundquist K., Zoller B. "Sibling risk of hospitalization for heart failure: a nationwide study". Int J Cardiol 2016;223:379-384.

    CrossrefMedlineGoogle Scholar

  • 17. Genomes Project C., Auton A., Brooks L.D., et al. "A global reference for human genetic variation". Nature 2015;526:68-74.

    CrossrefMedlineGoogle Scholar

  • 18. Burke M.A., Cook S.A., Seidman J.G., Seidman C.E. "Clinical and mechanistic insights into the genetics of cardiomyopathy". J Am Coll Cardiol 2016;68:2871-2886.

    View ArticleGoogle Scholar

  • 19. Herman D.S., Lam L., Taylor M.R., et al. "Truncations of titin causing dilated cardiomyopathy". N Engl J Med 2012;366:619-628.

    CrossrefMedlineGoogle Scholar

  • 20. Hershberger R.E., Hedges D.J., Morales A. "Dilated cardiomyopathy: the complexity of a diverse genetic architecture". Nat Rev Cardiol 2013;10:531-547.

    CrossrefMedlineGoogle Scholar

  • 21. Green E.M., Wakimoto H., Anderson R.L., et al. "A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice". Science 2016;351:617-621.

    CrossrefMedlineGoogle Scholar

  • 22. Bick A.G., Flannick J., Ito K., et al. "Burden of rare sarcomere gene variants in the Framingham and Jackson heart study cohorts". Am J Hum Genet 2012;91:513-519.

    CrossrefMedlineGoogle Scholar

  • 23. Roberts A.M., Ware J.S., Herman D.S., et al. "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease". Sci Transl Med 2015;7:270ra6.

    CrossrefMedlineGoogle Scholar

  • 24. Dhandapany P.S., Sadayappan S., Xue Y., et al. "A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia". Nat Genet 2009;41:187-191.

    CrossrefMedlineGoogle Scholar

  • 25. Adalsteinsdottir B., Teekakirikul P., Maron B.J., et al. "Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation". Circulation 2014;130:1158-1167.

    CrossrefMedlineGoogle Scholar

  • 26. Thanassoulis G., Campbell C.Y., Owens D.S., et al. "Genetic associations with valvular calcification and aortic stenosis". N Engl J Med 2013;368:503-512.

    CrossrefMedlineGoogle Scholar

  • 27. Howson J.M.M., Zhao W., Barnes D.R., et al. "Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms". Nat Genet 2017;49:1113-1119.

    CrossrefMedlineGoogle Scholar

  • 28. Christophersen I.E., Rienstra M., Roselli C., et al. "Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation". Nat Genet 2017;49:946-952.

    CrossrefMedlineGoogle Scholar

  • 29. Scott R.A., Scott L.J., Magi R., et al. "An expanded genome-wide association study of type 2 diabetes in Europeans". Diabetes 2017;66:2888-2902.

    CrossrefMedlineGoogle Scholar

  • 30. Hoffmann T.J., Ehret G.B., Nandakumar P., et al. "Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation". Nat Genet 2017;49:54-64.

    CrossrefMedlineGoogle Scholar

  • 31. Dina C., Bouatia-Naji N., Tucker N., et al. "Genetic association analyses highlight biological pathways underlying mitral valve prolapse". Nat Genet 2015;47:1206-1211.

    CrossrefMedlineGoogle Scholar

  • 32. Cappola T.P., Li M., He J., et al. "Common variants in HSPB7 and FRMD4B associated with advanced heart failure". Circ Cardiovasc Genet 2010;3:147-154.

    CrossrefMedlineGoogle Scholar

  • 33. Garnier S., Hengstenberg C., Lamblin N., et al. "Involvement of BAG3 and HSPB7 loci in various etiologies of systolic heart failure: Results of a European collaboration assembling more than 2000 patients". Int J Cardiol 2015;189:105-107.

    CrossrefMedlineGoogle Scholar

  • 34. Villard E., Perret C., Gary F., et al. "A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy". Eur Heart J 2011;32:1065-1076.

    CrossrefMedlineGoogle Scholar

  • 35. Cappola T.P., Matkovich S.J., Wang W., et al. "Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation". Proc Natl Acad Sci U S A 2011;108:2456-2461.

    CrossrefMedlineGoogle Scholar

  • 36. Smith N.L., Felix J.F., Morrison A.C., et al. "Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium". Circ Cardiovasc Genet 2010;3:256-266.

    CrossrefMedlineGoogle Scholar

  • 37. Meder B., Ruhle F., Weis T., et al. "A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy". Eur Heart J 2014;35:1069-1077.

    CrossrefMedlineGoogle Scholar

  • 38. Wooten E.C., Hebl V.B., Wolf M.J., et al. "Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy". Circ Cardiovasc Genet 2013;6:10-18.

    CrossrefMedlineGoogle Scholar

  • 39. Esslinger U., Garnier S., Korniat A., et al. "Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy". PLoS One 2017;12:e0172995.

    CrossrefMedlineGoogle Scholar

  • 40. Patel R.S., Asselbergs F.W., The GENIUS-CHD consortium. Eur Heart J 2015;36:2674-2676.

    MedlineGoogle Scholar

  • 41. Vasan R.S., Glazer N.L., Felix J.F., et al. "Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data". JAMA 2009;302:168-178.

    CrossrefMedlineGoogle Scholar

  • 42. Wild P.S., Felix J.F., Schillert A., et al. "Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function". J Clin Invest 2017;127:1798-1812.

    CrossrefMedlineGoogle Scholar

  • 43. Fox E.R., Musani S.K., Barbalic M., et al. "Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study". Circ Cardiovasc Genet 2013;6:37-46.

    CrossrefMedlineGoogle Scholar

  • 44. Arnett D.K., Meyers K.J., Devereux R.B., et al. "Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families". Circ Res 2011;108:279-283.

    CrossrefMedlineGoogle Scholar

  • 45. van der Harst P., van Setten J., Verweij N., et al. "52 Genetic loci influencing myocardial mass". J Am Coll Cardiol 2016;68:1435-1448.

    View ArticleGoogle Scholar

  • 46. Arking D.E., Pulit S.L., Crotti L., et al. "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization". Nat Genet 2014;46:826-836.

    CrossrefMedlineGoogle Scholar

  • 47. Eppinga R.N., Hagemeijer Y., Burgess S., et al. "Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality". Nat Genet 2016;48:1557-1563.

    CrossrefMedlineGoogle Scholar

  • 48. Yang J., Manolio T.A., Pasquale L.R., et al. "Genome partitioning of genetic variation for complex traits using common SNPs". Nat Genet 2011;43:519-525.

    CrossrefMedlineGoogle Scholar

  • 49. Smith J.G., Felix J.F., Morrison A.C., et al. "Discovery of Genetic Variation on Chromosome 5q22 associated with mortality in heart failure". PLoS Genet 2016;12:e1006034.

    CrossrefGoogle Scholar

  • 50. Liggett S.B., Cresci S., Kelly R.J., et al. "A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure". Nat Med 2008;14:510-517.

    CrossrefMedlineGoogle Scholar

  • 51. Cresci S., Kelly R.J., Cappola T.P., et al. "Clinical and genetic modifiers of long-term survival in heart failure". J Am Coll Cardiol 2009;54:432-444.

    View ArticleGoogle Scholar

  • 52. Perez M.V., Pavlovic A., Shang C., et al. "Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure". J Am Coll Cardiol 2015;66:2522-2533.

    View ArticleGoogle Scholar

  • 53. Smith J.G., Melander O., Sjogren M., et al. "Genetic polymorphisms confer risk of atrial fibrillation in patients with heart failure: a population-based study". Eur J Heart Fail 2013;15:250-257.

    CrossrefMedlineGoogle Scholar

  • 54. Newton-Cheh C., Smith J.G. "What can human genetics teach us about the causes of cardiovascular disease?"J Am Coll Cardiol 2010;55:2843-2845.

    View ArticleGoogle Scholar

  • 55. Fall T., Hagg S., Magi R., et al. "The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis". PLoS Med 2013;10:e1001474.

    CrossrefMedlineGoogle Scholar

  • 56. Basuray A., French B., Ky B., et al. "Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes". Circulation 2014;129:2380-2387.

    CrossrefMedlineGoogle Scholar

  • 57. Margulies K.B., Matiwala S., Cornejo C., Olsen H., Craven W.A., Bednarik D. "Mixed messages: transcription patterns in failing and recovering human myocardium". Circ Res 2005;96:592-599.

    CrossrefMedlineGoogle Scholar

  • 58. Liu Y., Morley M., Brandimarto J., et al. "RNA-Seq identifies novel myocardial gene expression signatures of heart failure". Genomics 2015;105:83-89.

    CrossrefMedlineGoogle Scholar

  • 59. GTEx Consortium. "Genetic effects on gene expression across human tissues". Nature 2017;550:204-213.

    CrossrefMedlineGoogle Scholar

  • 60. Mele M., Ferreira P.G., Reverter F., et al. "Human genomics. The human transcriptome across tissues and individuals". Science 2015;348:660-665.

    CrossrefMedlineGoogle Scholar

  • 61. Kong S.W., Hu Y.W., Ho J.W., et al. "Heart failure-associated changes in RNA splicing of sarcomere genes". Circ Cardiovasc Genet 2010;3:138-146.

    CrossrefMedlineGoogle Scholar

  • 62. Lowes B.D., Gilbert E.M., Abraham W.T., et al. "Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents". N Engl J Med 2002;346:1357-1365.

    CrossrefMedlineGoogle Scholar

  • 63. Neagoe C., Kulke M., del Monte F., et al. "Titin isoform switch in ischemic human heart disease". Circulation 2002;106:1333-1341.

    CrossrefMedlineGoogle Scholar

  • 64. Kao D.P., Lowes B.D., Gilbert E.M., et al. "Therapeutic molecular phenotype of beta-blocker-associated reverse-remodeling in nonischemic dilated cardiomyopathy". Circ Cardiovasc Genet 2015;8:270-283.

    CrossrefMedlineGoogle Scholar

  • 65. Bedi K.C., Snyder N.W., Brandimarto J., et al. "Evidence for Intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure". Circulation 2016;133:706-716.

    CrossrefMedlineGoogle Scholar

  • 66. Nanni L., Romualdi C., Maseri A., Lanfranchi G. "Differential gene expression profiling in genetic and multifactorial cardiovascular diseases". J Mol Cell Cardiol 2006;41:934-948.

    CrossrefMedlineGoogle Scholar

  • 67. Boudina S., Abel E.D. "Diabetic cardiomyopathy revisited". Circulation 2007;115:3213-3223.

    CrossrefMedlineGoogle Scholar

  • 68. van Rooij E., Sutherland L.B., Qi X., Richardson J.A., Hill J., Olson E.N. "Control of stress-dependent cardiac growth and gene expression by a microRNA". Science 2007;316:575-579.

    CrossrefMedlineGoogle Scholar

  • 69. Thum T., Gross C., Fiedler J., et al. "MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts". Nature 2008;456:980-984.

    CrossrefMedlineGoogle Scholar

  • 70. Arora P., Wu C., Khan A.M., et al. "Atrial natriuretic peptide is negatively regulated by microRNA-425". J Clin Invest 2013;123:3378-3382.

    CrossrefMedlineGoogle Scholar

  • 71. Care A., Catalucci D., Felicetti F., et al. "MicroRNA-133 controls cardiac hypertrophy". Nat Med 2007;13:613-618.

    CrossrefMedlineGoogle Scholar

  • 72. Devaux Y., Zangrando J., Schroen B., et al. "Long noncoding RNAs in cardiac development and ageing". Nat Rev Cardiol 2015;12:415-425.

    CrossrefMedlineGoogle Scholar

  • 73. Liu S.J., Horlbeck M.A., Cho S.W., et al. "CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells". Science 2017;355:

    CrossrefGoogle Scholar

  • 74. Li J.J., Biggin M.D. "Gene expression. Statistics requantitates the central dogma". Science 2015;347:1066-1067.

    CrossrefMedlineGoogle Scholar

  • 75. Kooij V., Venkatraman V., Tra J., et al. "Sizing up models of heart failure: Proteomics from flies to humans". Proteomics Clin Appl 2014;8:653-664.

    CrossrefMedlineGoogle Scholar

  • 76. Di Salvo T.G., Haldar S.M. "Epigenetic mechanisms in heart failure pathogenesis". Circ Heart Fail 2014;7:850-863.

    CrossrefMedlineGoogle Scholar

  • 77. Das A., Morley M., Moravec C.S., et al. "Bayesian integration of genetics and epigenetics detects causal regulatory SNPs underlying expression variability". Nat Commun 2015;6:8555.

    CrossrefMedlineGoogle Scholar

  • 78. Wang X., Tucker N.R., Rizki G., et al. "Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures". eLife 2016;5:e10557.

    CrossrefMedlineGoogle Scholar

  • 79. Taegtmeyer H. "Failing heart and starving brain: ketone bodies to the rescue". Circulation 2016;134:265-266.

    CrossrefMedlineGoogle Scholar

  • 80. Bing R.J. "Myocardial metabolism". Circulation 1955;12:635-647.

    CrossrefMedlineGoogle Scholar

  • 81. Neubauer S. "The failing heart: an engine out of fuel". N Engl J Med 2007;356:1140-1151.

    CrossrefMedlineGoogle Scholar

  • 82. Diakos N.A., Navankasattusas S., Abel E.D., et al. "Evidence of glycolysis up-regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart. Implications for cardiac reloading and conditioning". J Am Coll Cardiol Basic Trans Science 2016;1:432-444.

    View ArticleGoogle Scholar

  • 83. Heggermont W.A., Papageorgiou A.P., Heymans S., van Bilsen M. "Metabolic support for the heart: complementary therapy for heart failure?"Eur J Heart Fail 2016;18:1420-1429.

    CrossrefMedlineGoogle Scholar

  • 84. Margulies K.B., Hernandez A.F., Redfield M.M., et al. "Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial". JAMA 2016;316:500-508.

    CrossrefMedlineGoogle Scholar

  • 85. Swedberg K., Eneroth P., Kjekshus J., Wilhelmsen L. "Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group". Circulation 1990;82:1730-1736.

    CrossrefMedlineGoogle Scholar

  • 86. Braunwald E. "Biomarkers in heart failure". N Engl J Med 2008;358:2148-2159.

    CrossrefMedlineGoogle Scholar

  • 87. Cohn J.N., Levine T.B., Olivari M.T., et al. "Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure". N Engl J Med 1984;311:819-823.

    CrossrefMedlineGoogle Scholar

  • 88. Smith J.G., Gerszten R.E. "Emerging affinity-based proteomic technologies for large-scale plasma profiling in cardiovascular disease". Circulation 2017;135:1651-1664.

    CrossrefMedlineGoogle Scholar

  • 89. Ngo D., Sinha S., Shen D., et al. "Aptamer-based proteomic profiling reveals novel candidate biomarkers and pathways in cardiovascular disease". Circulation 2016;134:270-285.

    CrossrefMedlineGoogle Scholar

  • 90. Mann D.L. "Inflammatory mediators and the failing heart: past, present, and the foreseeable future". Circ Res 2002;91:988-998.

    CrossrefMedlineGoogle Scholar

  • 91. Handoko M.L., de Man F.S., Vonk-Noordegraaf A. "The rise and fall of endothelin receptor antagonists in congestive heart failure". Eur Respir J 2011;37:484-485.

    CrossrefMedlineGoogle Scholar

  • 92. Jacobs L., Thijs L., Jin Y., et al. "Heart “omics” in AGEing (HOMAGE): design, research objectives and characteristics of the common database". J Biomed Res 2014;28:349-359.

    MedlineGoogle Scholar

  • 93. Wang T.J., Larson M.G., Vasan R.S., et al. "Metabolite profiles and the risk of developing diabetes". Nat Med 2011;17:448-453.

    CrossrefMedlineGoogle Scholar

  • 94. Sun H., Olson K.C., Gao C., et al. "Catabolic defect of branched-chain amino acids promotes heart failure". Circulation 2016;133:2038-2049.

    CrossrefMedlineGoogle Scholar

  • 95. Kitai T., Kirsop J., Tang W.H. "Exploring the microbiome in heart failure". Curr Heart Fail Rep 2016;13:103-109.

    CrossrefMedlineGoogle Scholar

  • 96. Lommi J., Kupari M., Koskinen P., et al. "Blood ketone bodies in congestive heart failure". J Am Coll Cardiol 1996;28:665-672.

    View ArticleGoogle Scholar

  • 97. Matsushita K., Williams E.K., Mongraw-Chaffin M.L., et al. "The association of plasma lactate with incident cardiovascular outcomes: the ARIC study". Am J Epidemiol 2013;178:401-409.

    CrossrefMedlineGoogle Scholar

  • 98. Wang T.J., Gupta D.K. "Metabolite profiles in heart failure: looking for unique signatures in a heterogeneous syndrome". J Am Coll Cardiol 2015;65:1521-1524.

    View ArticleGoogle Scholar

  • 99. Sender R., Fuchs S., Milo R. "Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans". Cell 2016;164:337-340.

    CrossrefMedlineGoogle Scholar

  • 100. Pedersen H.K., Gudmundsdottir V., Nielsen H.B., et al. "Human gut microbes impact host serum metabolome and insulin sensitivity". Nature 2016;535:376-381.

    CrossrefMedlineGoogle Scholar