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Heart failure: advances through genomics

Nature Reviews Genetics volume 12, pages 357–362 (2011)Cite this article

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Abstract

Heart failure is an increasingly prevalent and highly lethal disease that is most often caused by underlying pathologies, such as myocardial infarction or hypertension, but it can also be the result of a single gene mutation. Comprehensive genetic and genomic approaches are starting to disentangle the diverse molecular underpinnings of both forms of the disease and promise to yield much-needed novel diagnostic and therapeutic options for specific subtypes of heart failure.

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Figure 1: Genetic and acquired forms of heart failure induce a common cardiac response.

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References

  1. Hunt, S. A. et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119, e391–e479 (2009).

    PubMed  Google Scholar 

  2. Creemers, E. E. & Pinto, Y. M. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc. Res. 89, 265–272 (2010).

    Article  PubMed  Google Scholar 

  3. Swynghedauw, B. Molecular mechanisms of myocardial remodeling. Physiol. Rev. 79, 215–262 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Benjamin, I. J. & Schneider, M. D. Learning from failure: congestive heart failure in the postgenomic age. J. Clin. Invest. 115, 495–499 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mudd, J. O. & Kass, D. A. Tackling heart failure in the twenty-first century. Nature 451, 919–928 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Lee, D. S. et al. Association of parental heart failure with risk of heart failure in offspring. N. Engl. J. Med. 355, 138–147 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Smith, N. L. 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. 3, 256–266 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Morrison, A. C. et al. Genomic variation associated with mortality among adults of European and african ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. Circ. Cardiovasc. Genet. 3, 248–255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vasan, R. S. et al. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JAMA 302, 168–178 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cappola, T. P. 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. USA 108, 2456–2461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hershberger, R. E. et al. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J. Card. Fail. 15, 83–97 (2009).

    Article  PubMed  Google Scholar 

  12. van der Zwaag, P. A. et al. One mutation fits all: phospolamban R14del causes both dilated cardiomypathy and arrhytmogenic right ventricular cardiomyopathy/dysplasia. Circulation 122, A17663 (2010).

    Google Scholar 

  13. van Spaendonck-Zwarts, K. Y. et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 121, 2169–2175 (2010).

    Article  PubMed  Google Scholar 

  14. Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genet. 42, 790–793 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Movassagh, M. et al. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS ONE 5, e8564 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yi, P., Han, Z., Li, X. & Olson, E. N. The mevalonate pathway controls heart formation in Drosophila by isoprenylation of Gγ1. Science 313, 1301–1303 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Milan, D. J. et al. Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization. Circulation 120, 553–559 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lowes, B. D. et al. Myocardial gene expression in dilated cardiomyopathy treated with β-blocking agents. N. Engl. J. Med. 346, 1357–1365 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Knollmann, B. C. & Roden, D. M. A genetic framework for improving arrhythmia therapy. Nature 451, 929–936 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Nanni, L., Romualdi, C., Maseri, A. & Lanfranchi, G. Differential gene expression profiling in genetic and multifactorial cardiovascular diseases. J. Mol. Cell. Cardiol. 41, 934–948 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Hwang, J. J. et al. Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure. Physiol. Genomics 10, 31–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Schroen, B. et al. Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. Circ. Res. 95, 515–522 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Schroen, B. et al. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy. J. Exp. Med. 204, 1227–1235 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Kimmenade, R. R. et al. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J. Am. Coll. Cardiol. 48, 1217–1224 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Matkovich, S. J., Zhang, Y., Van Booven, D. J. & Dorn, G. W. Deep mRNA sequencing for in vivo functional analysis of cardiac transcriptional regulators: application to Gαq. Circ. Res. 106, 1459–1467 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Creemers, E. E., Sutherland, L. B., Oh, J., Barbosa, A. C. & Olson, E. N. Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR. Mol. Cell 23, 83–96 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Kong, S. W. et al. Heart failure-associated changes in RNA splicing of sarcomere genes. Circ. Cardiovasc. Genet. 3, 138–146 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Neagoe, C. et al. Titin isoform switch in ischemic human heart disease. Circulation 106, 1333–1341 (2002).

    Article  PubMed  Google Scholar 

  30. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotech. 28, 511–515 (2010).

    Article  CAS  Google Scholar 

  31. Kleinjan, D. A. & van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76, 8–32 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Blow, M. J. et al. ChIP-Seq identification of weakly conserved heart enhancers. Nature Genet. 42, 806–810 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Rev. Genet. 10, 32–42 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Rakyan, V. K. & Beck, S. Epigenetic variation and inheritance in mammals. Curr. Opin. Genet. Dev. 16, 573–577 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Small, E. M., Frost, R. J. & Olson, E. N. MicroRNAs add a new dimension to cardiovascular disease. Circulation 121, 1022–1032 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  39. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Tijsen, A. J. et al. MiR423–425p as a circulating biomarker for heart failure. Circ. Res. 106, 1035–1039 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Clop, A. et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nature Genet. 38, 813–818 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Kasowski, M. et al. Variation in transcription factor binding among humans. Science 328, 232–235 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dorn, G. W. Pharmacogenetic profiling in the treatment of heart disease. Transl. Res. 154, 295–302 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Johnson, J. A. & Liggett, S. B. Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin. Pharmacol. Ther. 89, 366–378 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Brugts, J. J. et al. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease. Eur. Heart J. 31, 1854–1864 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Sakuntabhai, A. et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nature Genet. 21, 271–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Mayosi, B. M. et al. Heterozygous disruption of SERCA2a is not associated with impairment of cardiac performance in humans: implications for SERCA2a as a therapeutic target in heart failure. Heart 92, 105–109 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Shull, G. E. et al. Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants. Ann. N. Y. Acad. Sci. 986, 453–460 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to M. van den Hoogenhof for his help in preparing this manuscript and B. Knollmann for critical reading of this manuscript. The authors acknowledge grant support from the Center of Translational Molecular Medicine (CTMM), the European Commission project INHERITANCE, The InterUniversity Cardiology Institute Netherlands (ICIN) and the Netherlands Heart Foundation (NHS).

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Authors and Affiliations

  1. Esther E. Creemers, Arthur A. Wilde and Yigal M. Pinto are at The Heart Failure Research Center, Room K2-120, Academic Medical Center (AMC), Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.,

    Esther E. Creemers, Arthur A. Wilde & Yigal M. Pinto

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  1. Esther E. Creemers
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  3. Yigal M. Pinto
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Correspondence to Yigal M. Pinto.

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Competing interests

Y.M.P. has a minor interest in a spin-off company that has rights relating to the biomarker galectin 3, which is mentioned in this article.

Supplementary information

Supplementary information S1 (table)

Genes linked to Mendelian forms of heart failure. (PDF 265 kb)

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Glossary

Interstitial fibrosis

Excessive deposition and accumulation of extracellular matrix proteins in the cardiac interstitium.

Kabuki syndrome

A rare congenital disorder, named after the facial resemblance of affected individuals to white Kabuki makeup, a Japanese traditional theatrical form. There is a wide range of congenital problems associated with Kabuki syndrome, including heart defects, urinary tract anomalies, hearing loss and postnatal growth deficiency.

Odds ratio

The ratio of the odds of disease between two groups, in which the odds describe the probability of being affected divided by the probability of not being affected.

Peri-partum cardiomyopathy

A rare but often fatal form of dilated cardiomyopathy that is defined as heart failure occurring in the mother in the last months of pregnancy or in the first 6 months after delivery. It occurs in the absence of an identifiable cause, and without demonstrable pre-existing or concurrent heart disease.

Sarcomere

The basic contractile unit of a muscle cell.

Tachyarrhythmias or bradyarrhythmias

An excessively rapid or excessively slow heartbeat of more than 120 or less than 50 beats per minute, respectively.

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Creemers, E., Wilde, A. & Pinto, Y. Heart failure: advances through genomics. Nat Rev Genet 12, 357–362 (2011). https://doi.org/10.1038/nrg2983

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