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Genomics and the pathophysiology of heart failure

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Abstract

Heart failure is not a single disease entity, but a syndrome with various causes, including hypertension, ischemic and congenital heart disease, cardiomyopathy, and myocarditis. Because of the multiple etiologies and secondary adaptations contributing to heart failure, the study of the cellular and molecular mechanisms underlying the development and progression of this syndrome has been rather challenging. Much has been learned about the remodeling processes in heart failure, which involve complex interactions among numerous mediators in signaling and regulatory pathways. The Human Genome Project and related projects have provided a preliminary database for a genome-wide analysis of complex polygenic disorders such as heart failure. With the aid of expressed sequence tag technology and microarray applications, both known and previously uncharacterized genes involved in the induction and regression of cardiac hypertrophy and its progression to heart failure can be analyzed simultaneously. Deciphering the complexity of sequence-structure-function relationships in heart failure is a goal for the future, and will require advances in structural biology, proteomics, and computational technology. In this review, we summarize the cellular and molecular aspects of heart failure, and how recent applications of genomic technologies have been successful in achieving a more complete portrait of gene expression in this pathologic state.

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References and Recommended Reading

  1. Givertz MM, Colucci WS: New targets for heart-failure therapy: endothelin, inflammatory cytokines, and oxidative stress. Lancet 1998, 352(Suppl I):34–38. Elegant review of the role of endothelin, cytokines and oxidative stress in the pathogenesis of heart failure and give the readers quick catch of the up-to-date knowledge.

    Google Scholar 

  2. Hunter JJ, Chien KR: Signaling pathway for cardiac hypertrophy and failure. N Eng J Med 1999, 341:1276–1283.

    Article  CAS  Google Scholar 

  3. Bowles NE, Bowles KR, Towbin JA: The ‘final common pathway’ hypothesis and inherited cardiovascular disease: the role of cytoskeletal proteins in dilated cardiomyopathy. Herz 2000, 25:168–175.

    Article  PubMed  CAS  Google Scholar 

  4. Satoh M, Takahashi M, Sakamoto T, et al.: Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun 1999, 262:411–417.

    Article  PubMed  CAS  Google Scholar 

  5. Chen J, Chien KR: Complexity in simplicity: monogenic disorders and complex cardiomyopathies. J Clin Invest 1999, 103:1483–1485.

    PubMed  CAS  Google Scholar 

  6. Epstein ND, Cohn GM, Cyran F, Fananapazir L: Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the b-myosin heavy chain gene: a 908LeuÆVal mutation and a 403ArgÆGln mutation. Circulation 1992, 86:345–352.

    PubMed  CAS  Google Scholar 

  7. Clerk A, Sugden PH: Activation of protein kinase cascades in the heart by hypertrophic G protein-coupled receptor agonists. Am J Cardiol 1999, 83:64H-69H.

    Article  PubMed  CAS  Google Scholar 

  8. Ruwhof C, van der Laarse A: Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res 2000, 47:23–37.

    Article  PubMed  CAS  Google Scholar 

  9. Yamazaki T, Komuro I, Kudoh S, et al.: Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy. Circ Res 1998, 82:430–437.

    PubMed  CAS  Google Scholar 

  10. Hemler ME: Dystroglycan versatility. Cell 1999, 97:543–546.

    Article  PubMed  CAS  Google Scholar 

  11. Badorff C, Lee GH, Lamphear BJ, et al.: Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 1999, 5:320–326.

    Article  PubMed  CAS  Google Scholar 

  12. Arber S, Hunter JJ, Ross J Jr, et al.: MLP-deficient mice exhibit a disruption of cardiac myofibrillar organization, dilated cardiomyopathy, and heart failure. Cell 1997, 88:393–404.

    Article  PubMed  CAS  Google Scholar 

  13. Zolk O, Caroni P, Bohm M: Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure. Circulation 2000, 101:2674–2677.

    PubMed  CAS  Google Scholar 

  14. McCoy G, Protonotarios N, Crosby A, et al.: Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000, 355:2119–2124.

    Article  Google Scholar 

  15. Bonne G, Di Barletta MR, Varnous S, et al.: Mutations in the gene encoding lamin A/C cause autosomal dominant Emery- Dreifuss muscular dystrophy. Nature Genet 1999, 21:285–288.

    Article  PubMed  CAS  Google Scholar 

  16. Mogensen J, Klausen IC, Pedersen AK, et al.: a-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest 1999, 103:R39-R43.

    PubMed  CAS  Google Scholar 

  17. Kamisago M, Sharma SD, DePalma SR, et al.: Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000, 343:1688–1696.

    Article  PubMed  CAS  Google Scholar 

  18. Sussman MA, Welch S, Walker A, et al.: Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. J Clin Invest 2000, 105:875–886.

    PubMed  CAS  Google Scholar 

  19. Molkentin JD, Lu JR, Antos CL, et al.: A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998, 93:215–228. This is the first report to link the increased intracellular calcium and cardiac hypertrophy in heart failure, and demonstrate the blocking effect of immunosuppressive drugs cyclosporin A or FK506 on cardiac hypertrophy in vivo and in vitro through the inhibition of calcineurin activity.

    Article  PubMed  CAS  Google Scholar 

  20. Taigen T, De Windt LJ, Lim HW, Molkentin JD: Targeted inhibition of calcineurin prevents aginist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 2000, 97:1196–1201.

    Article  PubMed  CAS  Google Scholar 

  21. Shimoyama M, Hayashi D, Zou Y, et al.: Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension. Circulation 2000, 102:1996–2004.

    PubMed  CAS  Google Scholar 

  22. Luo Z, Shyu KG, Gualberto A, Walsh K: Calcineurin inhibitors and cardiac hypertrophy. Nat Med 1998, 4:1092–1093.

    Article  PubMed  CAS  Google Scholar 

  23. Olson EN, Williams RS: Remodeling muscles with calcineurin. BioEssays 2000, 22:510–519.

    Article  PubMed  CAS  Google Scholar 

  24. Minamisawa S, Hoshijima M, Chu G, et al.: Chronic phospholamban- sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 1999, 99:313–322.

    Article  PubMed  CAS  Google Scholar 

  25. Miyamoto MI, Del Monte F, Schmidt U, et al.: Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A 2000, 97:793–798.

    Article  PubMed  CAS  Google Scholar 

  26. Ito K, Yan X, Tajima M, et al.: Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts. Circ Res 2000, 87:588–595.

    PubMed  CAS  Google Scholar 

  27. Marx SO, Reiken S, Hisamatsu Y, et al.: PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000, 101:365–376.

    Article  PubMed  CAS  Google Scholar 

  28. Sato Y, Ferguson DG, Sako H, et al.: Cardiac-specific overexpression of mouse cardiac calsequestrin is associated with depressed cardiovascular function and hypertrophy in transgenic mice. J Biol Chem 1998, 273:28470–28477.

    Article  PubMed  CAS  Google Scholar 

  29. Hasenfuss G: Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 1998, 37:279–289.

    Article  PubMed  CAS  Google Scholar 

  30. Gaughan JP, Furukawa S, Jeevanandam V, et al.: Sodium/ calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. Am J Physiol 1999, 277:H714-H724.

    PubMed  CAS  Google Scholar 

  31. Schillinger W, Janssen PML, Emami S, et al.: Impaired contractile performance of cultured rabbit ventricular myocytes after adenoviral gene transfer of Na+-Ca2+ exchanger. Circ Res 2000, 87:581–587.

    PubMed  CAS  Google Scholar 

  32. Hasenfuss G, Schillinger W, Lehnart SE, et al.: Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation 1999, 99:641–648.

    PubMed  CAS  Google Scholar 

  33. Lee JK, Nishiyama A, Kambe F, et al.: Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy. Am J Physiol 1999, 277:H1725-H1731.

    PubMed  CAS  Google Scholar 

  34. Huang B, Qin D, El-Sherif N: Early down-regulation of K+ channel genes and currents in the postinfarction heart. J Cardiovas Electrophysiol 2000, 11:1252–1261.

    Article  CAS  Google Scholar 

  35. Wickenden AD, Lee P, Sah R, et al.: Targeted expression of a dominant-negative KV4.2 K+ channel subunit in the mouse heart. Circ Res 1999, 85:1067–1076.

    PubMed  CAS  Google Scholar 

  36. Fernandez-Cobo M, Gingalewski C, Drujan D, de Maio A: Downregulation of connexin 43 gene expression in rat heart during inflammation: the role of tumour necrosis factor. Cytokine 1999, 11:216–224.

    Article  PubMed  CAS  Google Scholar 

  37. Hirota H, Chen J, Betz UA, et al.: Loss of a gp 130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 1999, 97:189–198.

    Article  PubMed  CAS  Google Scholar 

  38. Zhao YY, Sawyer DR, Baliga RR, et al.: Neuregulins promote survival and growth of cardiac myocytes: persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 1998, 273:10261–10269.

    Article  PubMed  CAS  Google Scholar 

  39. Akishita M, Horiuchi M, Yamada H, et al.: Inflammation influences vascular remodeling through AT2 receptor expression and signaling. Physiol Genomics 2000, 2:13–20.

    PubMed  CAS  Google Scholar 

  40. Rezvani M, Barrans JD, Dai KS, Liew CC: Apoptosis-related genes expressed in cardiovascular development and disease: an EST approach. Cardiovasc Res 2000, 45:621–629. Apoptosis is involved in various disease processes, and this review discusses the apoptosis-related genes in cardiovascular development and disease that broaden our current understanding of its role in heart failure. This article also offers important information about the potential genes.

    Article  PubMed  CAS  Google Scholar 

  41. Thomas CV, Coker ML, Zellner JL, et al.: Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998, 97:1708–1715.

    PubMed  CAS  Google Scholar 

  42. Coker ML, Thomas CV, Clair MJ, et al.: Myocardial matrix metalloproteinase activity and abundance with congestive heart failure. Am J Physiol 1998, 274:H1516-H1523.

    PubMed  CAS  Google Scholar 

  43. Spinale FG, Coker ML, Heung LJ, et al.: A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000, 102:1944–1949.

    PubMed  CAS  Google Scholar 

  44. Ducharme A, Frantz S, Aikawa M, et al.: Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000, 106:55–62.

    PubMed  CAS  Google Scholar 

  45. Kim HE, Dalal SS, Young E, et al.: Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 2000, 106:857–866. The transgenic animal model demonstrates the role of matrix metalloproteinase in heart failure by providing direct evidence that disruption of extracellular matrix by MMP-1 reproduces the changes observed in the progression of human heart failure.

    Article  PubMed  CAS  Google Scholar 

  46. Dieterich S, Bieligk U, Beulich K, et al.: Gene expression of antioxidative enzymes in the human heart: increased expression of catalase in the end-stage failing heart. Circulation 2000, 101:33–39.

    PubMed  CAS  Google Scholar 

  47. Siwik DA, Tzortzis JD, Pimental DR, et al.: Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circ Res 1999, 85:147–153.

    PubMed  CAS  Google Scholar 

  48. de Jong JW, Schoemaker RG, de Jonge R, et al.: Enhanced expression and activity of xanthine oxidoreductase in the failing heart. J Mol Cell Cardiol 2000, 32:2083–2089.

    Article  PubMed  CAS  Google Scholar 

  49. Sack MN, Kelly DP: The energy substrate switch during development of heart failure: gene regulatory mechanisms. Int J Mol Med 1998, 1:17–24.

    PubMed  CAS  Google Scholar 

  50. Pratt RE, Dzau VJ: Genomics and hypertension: concepts, potentials, and opportunities. Hypertension 1999, 33[Part II]:238–247.

    PubMed  CAS  Google Scholar 

  51. Dempsey AA, Ton C, Liew CC: A cardiovascular EST repertoire: progress and promise for understanding cardiovascular disease. Mol Med Today 2000, 6:231–237.

    Article  PubMed  CAS  Google Scholar 

  52. Chien KR: Genomic circuits and the integrative biology of cardiac diseases. Nature 2000, 407:227–232. The genes involved in various forms of heart diseases are highlighted, and the potential role of genomics approach in this complex field is also emphasized. This is a must-read article in the understanding of molecular events in the pathophysiology of cardiac diseases.

    Article  PubMed  CAS  Google Scholar 

  53. Collins FS, Patrinos A, Jordan E, et al., and the members of the DOE and NIH planning groups: New goals for the US Human Genome Project: 1998-2003. Science 1998, 282:682–689.

    Article  PubMed  CAS  Google Scholar 

  54. Liew CC: A human heart cDNA library-the development of an efficient and simple method for automated DNA sequencing. J Mol Cell Cardiol 1993, 25:891–894.

    Article  PubMed  CAS  Google Scholar 

  55. Ton C, Hwang DM, Dempsey AA, et al.: Identification, characterization, and mapping of expressed sequence tags from an embryonic zebrafish heart cDNA library. Genome Research 2001, in press.

  56. Hwang DM, Dempsey AA, Lee CY, Liew CC: Identification of differentially expressed genes in cardiac hypertrophy by analysis of expressed sequence tags. Genomics 2000, 66:1–14. This work offers the example of genomics approach to identification of genes involved in cardiac hypertrophy, and the result shows a proportional increase in transcripts related to cell/organism defense and a decrease in transcripts related to cell structure and motility in hypertrophic hearts.

    Article  PubMed  CAS  Google Scholar 

  57. Friddle CJ, Koga T, Rubin EM, Bristow J: Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci USA 2000, 97:6745–6750. A well-designed study on the genes involved in the induction and regression of cardiac hypertrophy using a pharmacologic mouse model and differential expression profiling of a more than 4000-gene database.

    Article  PubMed  CAS  Google Scholar 

  58. Barrans JD, Lu X, Francisco-Pabalan OL, et al.: Discovery of novel cardiac-enriched regulators of hypertrophy using cDNA microarrays and expressed sequence tags (ESTs). Circulation 2000, 102:II142.

    Google Scholar 

  59. Taylor LA, Carthy CM, Yang D, et al.: Host gene regulation during coxsackievirus B3 infection in mice: assessment by microarrays. Circ Res 2000, 87:328–334.

    PubMed  CAS  Google Scholar 

  60. Adams LD, Geary RL, McManus B, Schwartz SM: A comparison of aorta and vena cava medial message expression by cDNA array analysis identifies a set of 68 consistently differentially expressed genes, all in aortic media. Circ Res 2000, 87:623–631. A study of the differential display of genes between the medial layer of artery and vein using cDNA array analysis, starting a genome-wide approach to the vascular system.

    PubMed  CAS  Google Scholar 

  61. Attwood TK: The babble of bioinformatics. Science 2000, 290:471–473.

    Article  PubMed  CAS  Google Scholar 

  62. Massie BM: 15 years of heart-failure trials: what have we learned? Lancet 1998, 352(Suppl I):29–33.

    Google Scholar 

  63. Pitt B, Poole-Wilson PA, Segal R, et al.: Effects of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial — the Losartan Heart Failure Survival Study ELITE II. Lancet 2000, 355(9215):1582–1587. The beneficial effect of angiotensin II antagonist in the management of heart failure still awaits the results of clinical trials.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiovascular Genome Unit, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Thorn 1326, 02115, Boston, MA, USA

    Juey-Jen Hwang MD, PhD, Victor J. Dzau MD & Choong-Chin Liew PhD

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  1. Juey-Jen Hwang MD, PhD
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  2. Victor J. Dzau MD
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  3. Choong-Chin Liew PhD
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Hwang, JJ., Dzau, V.J. & Liew, CC. Genomics and the pathophysiology of heart failure. Curr Cardiol Rep 3, 198–207 (2001). https://doi.org/10.1007/s11886-001-0023-z

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