Irish Journal of Medical Science

, Volume 171, Issue 2, pp 99–104 | Cite as

New molecular insights into heart failure and cardiomyopathy: potential strategies and therapies




In the most severely affected patients the mortality for congestive heart failure exceeds that of many cancers. While therapies are largely aimed at attenuating neurohumoral responses recent molecular insights reveal other potential targets for therapy.


To summarise some of the recent developments in the management of heart failure and provide the clinician who treats heart failure with new insights into emerging approaches.


A literature review was conducted of the recent literature together with personal research data.


Large randomised trials will provide a more comprehensive understanding of the interaction of β-blockers and other heart failure therapies with gene polymorphisms. Cytokines are important in the progression of heart failure, yet therapy aimed at blocking cytokine effects has not been successful. More selective use of anti-cytokine therapy may have beneficial effects. Gene therapy to improve heart failure has not yet reached clinical trials. The molecular genetics of hypertrophic and dilated cardiomyopathy is rapidly improving our understanding so that genetic diagnostics and counselling may soon be performed for patients and families.


The emergence of a molecular based understanding of heart failure will hopefully improve therapy of this common condition.


Heart Failure Angiotensin Converting Enzyme Dilate Cardiomyopathy Hypertrophic Cardiomyopathy Negative Inotropic Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cleland JGF, Khand A, Clark A. The heart failure epidemic: exactly how big is it.Eur Heart J 2001; 22: 623–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Kannel WB, Belanger AJ. Epidemiology of heart failure.Am Heart J 1991; 211: 951–7.CrossRefGoogle Scholar
  3. 3.
    Pfeffer MA, Braunwald E, Move LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction — Results of the survival and ventricular enlargement trial.N Engl J Med 1992; 327: 669–77.PubMedGoogle Scholar
  4. 4.
    Yusuf S, Nicklas JM, Timmis G et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med 1992; 327: 685–91.Google Scholar
  5. 5.
    Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.N Engl J Med 1996; 334: 1349–55.CrossRefPubMedGoogle Scholar
  6. 6.
    Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure.Lancet 1999; 353: 2001–7.CrossRefGoogle Scholar
  7. 7.
    Parmley WW. How many medicines do patients with heart failure need?Circulation 2001; 103: 1611–2.PubMedGoogle Scholar
  8. 8.
    Deng MC, De Meester JMJ, Smits JMA, Heinecke J, Scheid HH. Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity.BMJ 2000; 321: 540–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Oz MC, Argenziano M, Catanese KA et al. Bridge experience with long term implantable left ventricular assist devices. Are they an alternative to transplantation?Circulation 1997; 95: 1844–52.PubMedGoogle Scholar
  10. 10.
    Rose EA, Gelijns AC, Moskowitz AJ et al. Long-term use of a left ventricular assist device for end-stage heart failure.N Engl J Med 2001; 345: 1435–43.CrossRefPubMedGoogle Scholar
  11. 11.
    Alhenc-Gelas F, Richard J, Courbon D, Warnet JM, Corvol P. Distribution of plasma angiotensin 1-converting enzyme levels in healthy men: relationship to environmental and hormonal parameters.J Lab Clin Med 1991; 117: 33–9.PubMedGoogle Scholar
  12. 12.
    Soubrier F, Alhenc-Gelas F, Hubert C et al. Two putative active centers in human angiotensin 1-converting enzyme revealed by molecular cloning.Proc Natl Acad Sci USA 1988; 85: 9386–90.CrossRefPubMedGoogle Scholar
  13. 13.
    Tiret L, Rigat B, Visvikis S et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACF2 levels.Am J Hum Genet 1992; 51: 197–205.PubMedGoogle Scholar
  14. 14.
    Rigat B, Hubert C, Alhenc-Gelas F et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.J Clin Invest 1990; 86: 1343–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Cody RJ, Franklin KW, Kulger J et al. Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril.Am J Med 1982; 72: 791–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Danser AH, Derkx FH, Hense HW et al. Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels.J Hypertens 1998; 16: 1879–83.CrossRefPubMedGoogle Scholar
  17. 17.
    Byrne J, Murdoch DR, Robb SD et al. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene, and indices of left ventricular function following myocardial infarction.J Am Coll Cardiol 1998; 31(suppl 2): 491A.CrossRefGoogle Scholar
  18. 18.
    Andersson B, Sylven C. The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure.J Am Coll Cardiol 1996; 28: 162–7.CrossRefPubMedGoogle Scholar
  19. 19.
    McNamara DM, Holubkov R, Janosko K et al. Pharmacogenetic interactions between β-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.Circulation 2001; 103: 1644–8.PubMedGoogle Scholar
  20. 20.
    Roden DM. Prescription genotyping: Not yet ready for prime time.Circulation 2001; 103: 1608–10.PubMedGoogle Scholar
  21. 21.
    Ghosh S, Collins FS. The geneticist’s approach to complex disease.Annu Rev Med 1996; 47: 333–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.N Engl J Med 1990; 323: 236–41.PubMedGoogle Scholar
  23. 23.
    Balkwill F, Osborne R, Burke F et al: Evidence of tumor necrosis factor/cachectin production in cancer.Lancet 1987; 2: 1229–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease.Lancet 1987; 1: 355–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Maury CP, Teppo A-M. Tumour necrosis factor in the serum of patients with systemic lupus erythematosis.Arthritis Rheum 1989; 32: 146–50.CrossRefPubMedGoogle Scholar
  26. 26.
    Oliff A. The role of tumor necrosis factor (cachectin) in cachexia.Cell 1998; 54: 141–2.CrossRefGoogle Scholar
  27. 27.
    MacGowan GA, Mann DL, Kormos RL, Feldman AM, Murali S. Circulating interleukin-6 in severe heart failure.Am J Cardiol 1997; 79: 1128–31.CrossRefPubMedGoogle Scholar
  28. 28.
    MacGowan GA, Kormos RL, McNamara DM et al. Predicting short term outcome in severely ill heart failure patients: Implications regarding listing for urgent cardiac transplantation and patient selection for temporary ventricular assist device support.J Card Fail 1998; 4 (3): 169–75.CrossRefPubMedGoogle Scholar
  29. 29.
    Finkel MS, Oddis CV, Jacob TD et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide.Science 1992; 257 (5068): 387–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Yokoyama T, Vaca L, Rossen RD et al. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart.J Clin Invest 1993; 92: 2303–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Oral H, Dorn GW, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte.J Biol Chem 1997; 272: 4836–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Kubota T, McTiernan CF, Frye CS et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha.Circ Res 1997; 81 (4): 627–35.PubMedGoogle Scholar
  33. 33.
    Deswal A, Bozkurt B, Seta Y et al. A phase I trial of tumor necrosis factor receptor (p75) fusion protein (TNFR:Fc) in patients with advanced heart failure.Circulation 1999; 99: 3224–6.PubMedGoogle Scholar
  34. 34.
    Mohler KM, Murray KM, Mann DL, Francis DL. Use of targeted anticytokine treatments in heart failure.Circulation 2000; 102: 65.Google Scholar
  35. 35.
    Bozkurt B, Torre-Amione G, Smith Warren M et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure.Circulation 2001; 103: 1044.PubMedGoogle Scholar
  36. 36.
    Wada H, Saito K, Kanda T et al. Tumor necrosis factor-α (TNF-α) plays a protective role in acute viral myocarditis in mice: A study using mice lacking TNF-α.Circulation 2001; 103: 743–9.PubMedGoogle Scholar
  37. 37.
    McNamara DM, Starling R, Dec GW et al. Plasma cytokines in acute cardiomyopathy: Evolution over time, correlation with functional studies, and potential role in recovery.Circulation 2000; 102: 11–415 (abstract).Google Scholar
  38. 38.
    Gwathmey JK, Copelas L, MacKinnon R et al. Abnormal intracellular calcium handling from patients with end-stage heart failure.Circ Res 1987; 61: 70–6.PubMedGoogle Scholar
  39. 39.
    Houser SR, Piacentino Valentino III, Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart.J Mol Cell Cardiol 2000; 32: 1595–607.CrossRefPubMedGoogle Scholar
  40. 40.
    Schmidt U, del Monte F, Miyamoto MI et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase.Circulation 2000; 101: 790–6.PubMedGoogle Scholar
  41. 41.
    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 USA 2000; 97: 793–8.CrossRefPubMedGoogle Scholar
  42. 42.
    del Monte F, Harding SE, Schmidt U et al. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a.Circulation 1999; 100: 2308–11.Google Scholar
  43. 43.
    Bristow MR, Ginsburg R, Minobe W et al. Decreased catecholamine sensitivity and b-adrenergic receptor density in failing human hearts.N Engl J Med 1982; 307: 205–11.PubMedCrossRefGoogle Scholar
  44. 44.
    Brodde OE. Beta-adrenoreceptors in cardiac disease.Pharmacol Ther 1993; 60: 405–30.CrossRefPubMedGoogle Scholar
  45. 45.
    Ungerer M, Bohm Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta l-adrenergic receptors in the failing human heart.Circulation 1993; 87: 454–63.PubMedGoogle Scholar
  46. 46.
    Akhter SA, Skaer CA, Kypson AP et al. Restoration of beta-adrenergic signaling in failing cardiac myocytes via adenoviral-mediated gene transfer.Proc Natl Acad Sci USA 1997; 94: 12100–105.CrossRefPubMedGoogle Scholar
  47. 47.
    Rockman HA, Chien KR, Choi DJ et al. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.Proc Natl Acad Sci USA 1998; 95: 7000–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Shah AS, White DC, Emani S et al. In vivo delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.Circulation 2001; 103: 1311–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Hajjar RJ, del Monte F, Matsui T, Rosenzweig A. Prospects for gene therapy for heart failure.Circ Res 2000; 86: 616–21.PubMedGoogle Scholar
  50. 50.
    Packer M, Carver JR, Rodeheffer RJ et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.N Engl J Med 1991; 325: 1468–75.PubMedCrossRefGoogle Scholar
  51. 51.
    Francis SC, Raizada MK, Angi AA et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?Physiol Genomics 2001; 7: 79–94.PubMedGoogle Scholar
  52. 52.
    Esakof DD, Maysky M, Losordo DW et al. Intraoperative multiplane transesophageal echocardiography for guiding direct myocardial gene transfer of vascular endothelial growth factor in patients with refractory angina pectoris.Hum Gene Ther 1999; 10: 2315–23.CrossRefGoogle Scholar
  53. 53.
    Kypson AP, Peppel K, Akhter SA. Ex-vivo adenoviral-mediated gene transfer to the transplanted adult rat heart heart.J Thorac Cardiovasc Surg 1998; 115: 623–30.CrossRefPubMedGoogle Scholar
  54. 54.
    Kypson A, Hendrickson S, Akhter S et al. Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function.Gene Ther 1999; 6: 1298–04.CrossRefPubMedGoogle Scholar
  55. 55.
    Maurice JP, Hata JA, Shah AS et al. Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery.J Clin Invest 1999; 104: 21–9.CrossRefPubMedGoogle Scholar
  56. 56.
    White DC, Hata JA, Shah AS et al. Preservation of myocardial β-adrenergic receptor signaling delays development of heart failure after myocardial infarction.Proc Natl Acad Sci USA 2000; 97: 5428–33.CrossRefPubMedGoogle Scholar
  57. 57.
    Shah AS, Lilly RE, Kypson AP et al. Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart. Prospects for molecular ventricular assistance.Circulation 2000; 101: 408–14.PubMedGoogle Scholar
  58. 58.
    Maron BJ, Bonow RO, Cannon RO III, Leon MB, Epstein SE. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (1).N Engl J Med 1987; 316: 780–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Maron BJ, Bonow RO, Cannon RO III, Leon MB, Epstein SE. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2).N Engl J Med 1987; 316: 844–52.PubMedCrossRefGoogle Scholar
  60. 60.
    Redwood CS, Moolman-Smook JC, Watkins H. Properties of mutant contractile proteins that cause hypertrophie cardiomyopathy.Cardiovasc Res 1999; 44: 20–36.CrossRefPubMedGoogle Scholar
  61. 61.
    Moolman JC, Corfield VA, Posen B et al. Sudden death due to troponin T mutations:J Am Coll Cardiol 1997; 29: 549–55.CrossRefPubMedGoogle Scholar
  62. 62.
    Niimura H, Bachinski LL, Sangwatanaroj S et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.N Engl J Med 1998; 338: 1303–4.CrossRefGoogle Scholar
  63. 63.
    Lankford EB, Epstein ND, Fananapazir L, Sweeney HL. Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.J Clin Invest 1995; 95: 1409–14.CrossRefPubMedGoogle Scholar
  64. 64.
    Bottinelli R, Coviello DA, Redwood CS, et al. A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity.Circ Res 1998; 82: 106–15.PubMedGoogle Scholar
  65. 65.
    Elliott K, Watkins H, Redwood CS. Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy.J Biol Chem 2000; 275: 22069–74.CrossRefPubMedGoogle Scholar
  66. 66.
    Blair E, Redwood C, Ashrafian H et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.Hum Mol Genet 2001; 10: 1215–20.CrossRefPubMedGoogle Scholar
  67. 67.
    MacGowan GA, Koretsky AP. Inotropic and energetic effects of altering the force-calcium relationship: mechanisms, experimental results, and potential molecular targets.J Card Fail 2000; 6: 144–56.PubMedGoogle Scholar
  68. 68.
    Gao WD, Perez NG, Seidman CE, Seidman JG, Marban E. Altered cardiac excitation-contraction coupling in mutant mice with familial hypertrophic cardiomyopathy.J Clin Invest 1999; 103: 661–6.CrossRefPubMedGoogle Scholar
  69. 69.
    MacGowan GA, Du C, Cowan DB et al. Ischaemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites.Am J Physiol (Heart Circ Physiol) 2001; 280: H835–43.Google Scholar
  70. 70.
    Michels W, Moll PP, Miller FA et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy.N Engl J Med 1992; 326: 77–82.PubMedCrossRefGoogle Scholar
  71. 71.
    Hoffman EP, Brown RH, Kunkel LM. Dystrophin; the protein product of the Duchenne muscular dystrophy locus.Cell 1987; 24: 919–28.CrossRefGoogle Scholar
  72. 72.
    Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure.N Engl J Med 1999; 341: 1276–83.CrossRefPubMedGoogle Scholar
  73. 73.
    Li D, Tapscoft T, Gonzalez O et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy.Circulation 1999; 100: 461–4.PubMedGoogle Scholar
  74. 74.
    Olson TM, Michels W, Thibodeau SN, Tai YS, Keating MT. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure.Science 1998; 280: 750–2.CrossRefPubMedGoogle Scholar
  75. 75.
    Mogensen J, Klausen IC, Pedersen AK et al. Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.J Clin Invest 1999; 103: R39–43.CrossRefPubMedGoogle Scholar
  76. 76.
    Minamisawa S, Hoshijima M, Chu G et al. Chronic phospholambansarcoplasmic calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy.Cell 1999; 99: 313–22.CrossRefPubMedGoogle Scholar
  77. 77.
    McDonald K, Ledwidge M, Cahill J et al. Elimination of early rehospitalisation in a randomised, controlled trial of multidisciplinary care in a high risk, elderly heart failure population: the potential contributions of specialist care, clinical stability and optimal angiotensin-converting enzyme inhibitor dose at discharge.Eur J Heart Fail. 2001; 3: 209–15.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2002

Authors and Affiliations

  1. 1.Cardiovascular institute of the University of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations