The American Journal of Medicine
Volume 121, Issue 9 , Pages 748-757 , September 2008

Diabetic Cardiomyopathy: Insights into Pathogenesis, Diagnostic Challenges, and Therapeutic Options

  • Ashish Aneja, MD

      Affiliations

    • The Mount Sinai Cardiovascular Institute, New York, NY
    • ,
  • W.H. Wilson Tang, MD

      Affiliations

    • Section of Heart Failure, Department of Cardiology, Cleveland Clinic, Ohio
    • ,
  • Sameer Bansilal, MD

      Affiliations

    • The Mount Sinai Cardiovascular Institute, New York, NY
    • ,
  • Mario J. Garcia, MD

      Affiliations

    • The Mount Sinai Cardiovascular Institute, New York, NY
    • ,
  • Michael E. Farkouh, MD, MSc

      Affiliations

    • The Mount Sinai Cardiovascular Institute, New York, NY
    • Corresponding Author InformationRequests for reprints should be addressed to Michael E. Farkouh, MD, MSc, 1 Gustave Levy Place, Box 1074, Mount Sinai Cardiovascular Institute, New York, NY 10029

References 

  1. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic Glomerulosclerosis. Am J Cardiol. 1972;595–602
  2. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;26:3213–3223
  3. Tang WH. Glycemic control and treatment patterns in patients with heart failure. Curr Cardiol Rep. 2007;9:242–247
  4. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34:29–34
  5. Stratton IM, Adler AI, Neil HA, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (United Kingdom Prospective Diabetes Study 35): prospective observational study. BMJ. 2000;321:405–412
  6. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol. 2000;35:1628–1637
  7. Follath F. University Hospital Zürich, Switzerland: ESC Congress 2007 Press Release. September 2, 2007.
  8. Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27:699–703
  9. Galderisi M, Anderson KM, Wilson PW, Levy D. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol. 1991;68:85–89
  10. Lee M, Gardin JM, Lynch JC, et al. Diabetes mellitus and echocardiographic left ventricular function in free-living elderly men and women (The Cardiovascular Health Study). Am Heart J. 1997;133:36–43
  11. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation. 2000;101:2271–2276
  12. Palmieri V, Bella JN, Arnett DK, et al. Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects (Hypertension Genetic Epidemioloy Network (Hyper-GEN) study). Circulation. 2001;103:102–107
  13. Ilercil A, Devereux RB, Roman MJ, et al. Relationships of impaired glucose tolerance to left ventricular structure and function: the Strong Heart Study. Am Heart J. 2001;14:992–998
  14. Bella JN, Devereux RB, Roman MJ, et al. Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study). Am J Cardiol. 2001;87:1260–1265
  15. Liu JE, Palmieri V, Roman MJ, et al. The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study. J Am Coll Cardiol. 2001;37:1943–1949
  16. Rutter MK, Parise H, Benjamin EJ, et al. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation. 2003;107:448–454
  17. Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem. 1998;180:53–57
  18. Eckel J, Reinauer H. Insulin action on glucose transport in isolated cardiac myocytes: signalling pathways and diabetes-induced alterations. Biochem Soc Trans. 1990;18:1125–1127
  19. Liedtke AJ, DeMaison L, Eggleston AM, et al. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res. 1988;62:535–542
  20. Yazaki Y, Isobe M, Takahashi W, et al. Assessment of myocardial fatty acid abnormalities in patients with idiopathic dilated cardiomyopathy using I123 BMIPP SPECT: correlation with clinicopathological findings and clinical course. Heart. 1999;81:153–159
  21. Malhotra A, Sanghi V. Regulation of contractile proteins in diabetic heart. Cardiovasc Res. 1997;34:34–40
  22. Takeda N, Nakamura I, Hatanaka T, et al. Myocardial mechanical and myosin isoenzyme alterations in streptozotocin-diabetic rats. Jpn Heart J. 1988;29:455–463
  23. Abe T, Ohga Y, Tabayashi N, et al. Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol. 2002;282:H138–H148
  24. Fiordaliso F, Leri A, Cesselli D, et al. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 2001;50:2363–2375
  25. Frustaci A, Kajstura J, Chimenti C, et al. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123–1132
  26. Chen S, Evans T, Mukherjee K, et al. Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors. J Mol Cell Cardiol. 2000;32:1621–1629
  27. Fischer VW, Barner HB, Larose LS. Pathomorphologic aspects of muscular tissue in diabetes mellitus. Hum Pathol. 1984;15:1127–1136
  28. Shimizu M, Umeda K, Sugihara N, et al. Collagen remodelling in myocardia of diabetic patients. J Clin Pathol. 1993;46:32–36
  29. Berg TJ, Snorgaard O, Faber J, et al. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care. 1999;22:118–1190
  30. Zieman SJ, Kass DA. Advanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease. Drugs. 2004;64:459–470
  31. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21:3–12
  32. Uusitupa MI, Mustonen JN, Airaksinen KE. Diabetic heart muscle disease. Ann Med. 1990;22:377–386
  33. Kajstura J, Fiordaliso F, Andreoli AM, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes. 2001;50:1414–1424
  34. Mizushige K, Yao L, Noma T, et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation. 2000;101:899–907
  35. Walter RM, Uriu-Hare JY, Olin KL, et al. Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care. 1991;14:1050–1056
  36. Islam KN, Takahashi M, Higashiyama S, et al. Fragmentation of ceruloplasmin following nonenzymatic glycation reaction. J Biochem. 1995;118:1054–1060
  37. Argirova MD, Ortwerth BJ. Activation of protein-bound copper ions during early glycation: study on two proteins. Arch Biochem Biophys. 2003;420:176–184
  38. Eaton JW, Qian M. Interactions of copper with glycated proteins: possible involvement in the etiology of diabetic neuropathy. Mol Cell Biochem. 2002;234-235:135–142
  39. Qian M, Eaton JW. Glycochelates and the etiology of diabetic peripheral neuropathy. Free Radic Biol Med. 2000;28:652–656
  40. Yim MB, Yim HS, Lee C, et al. Protein glycation: creation of catalytic sites for free radical generation. Ann N Y Acad Sci. 2001;928:48–53
  41. Bisognano JD, Weinberger HD, Bohlmeyer TJ, et al. Myocardial-directed overexpression of the human β(1)-adrenergic receptor in transgenic mice. J Mol Cell Cardiol. 2000;32:817–830
  42. Rota M, LeCapitaine N, Hosoda T, et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res. 2006;99:44–52
  43. Park JY, Takahara N, Gabriele A, et al. Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation. Diabetes. 2000;49:1239–1248
  44. Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol. 1991;261:H1086–H1094
  45. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium dependent vasodilatation in experimental diabetes. J Clin Invest. 1991;87:432–438
  46. Tesfamariam B, Jakubowski JA, Cohen RA. Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. Am J Physiol. 1989;257:H1327–H1333
  47. Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991;87:1643–1648
  48. Chung J, Abraszewski P, Yu X, et al. Paradoxical increase in ventricular torsion and systolic torsion rate in type I diabetic patients under tight glycemic control. J Am Coll Cardiol. 2006;47:384–390
  49. Fonseca CG, Dissanayake AM, Doughty RN, et al. Three-dimensional assessment of left ventricular systolic strain in patients with type 2 diabetes mellitus, diastolic dysfunction, and normal ejection fraction. Am J Cardiol. 2004;94:1391–1395
  50. Zabalgoitia M, Ismaeil MF, Anderson L, Maklady FA. Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. Am J Cardiol. 2001;87:320–323
  51. Poirier P, Bogaty P, Garneau C, et al. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes (Importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy). Diabetes Care. 2001;24:5–10
  52. Regan TJ, Wu CF, Yeh CK, et al. Myocardial composition and function in diabetes (The effects of chronic insulin use). Circ Res. 1981;49:1268–1277
  53. Airaksinen J, Ikäheimo M, Kaila J, et al. Impaired left ventricular filling in young female diabetics (An echocardiographic study). Acta Med Scand. 1984;216:509–516
  54. Bertoni PD, Morandi G, Di Michele R, Canziani R. Altered diastolic function of the left ventricle in juvenile diabetes (Computerized echocardiographic study). G Ital Cardiol. 1984;14:839–846
  55. Venco A, Grandi A, Barzizza F, Finardi G. Echocardiographic features of hypertensive-diabetic heart muscle disease. Cardiology. 1987;74:28–34
  56. Attali JR, Sachs RN, Valensi P, et al. Asymptomatic diabetic cardiomyopathy: a noninvasive study. Diabetes Res Clin Pract. 1988;4:183–190
  57. Zarich SW, Arbuckle BE, Cohen LR, et al. Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography. J Am Coll Cardiol. 1988;12:114–120
  58. Bouchard A, Sanz N, Botvinick EH, et al. Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old. Am J Med. 1989;87:160–166
  59. Robillon JF, Sadoul JL, Jullien D, et al. Abnormalities suggestive of cardiomyopathy in patients with type 2 diabetes of relatively short duration. Diabetes Metab. 1994;20:473–480
  60. Raev DC. Left ventricular function and specific diabetic complications in other target organs in young insulin-dependent diabetics: an echocardiographic study. Heart Vessels. 1994;9:121–128
  61. Von Bibra H, Hansen A, Dounis V, et al. Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart. 2004;90:1483–1484
  62. Von Bibra H, Siegmund T, Hansen A, et al. Augmentation of myocardial function by improved glycemic control in patients with type 2 diabetes mellitus. Dtsch Med Wochenschr. 2007;132:729–734
  63. Hordern MD, Smith LM, Short L, et al. Use of diastolic tissue velocity and standard parameters to assess treatment response in subclinical myocardial disease. A randomized trial of lifestyle intervention in type 2 diabetes. Poster abstract presented at the proceedings of the Annual American Heart Association Meeting at Orlando, Florida, November 4-7, 2007.
  64. Boyer JK, Thanigaraj S, Schechtman KB, Perez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive diabetic mellitus. Am J Cardiol. 2004;93:870–875
  65. Di Bonito P, Moio N, Cavuto L, et al. Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging. Diabet Med. 2005;22:1720–1725
  66. Fang ZY, Yuda S, Anderson V, et al. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol. 2003;41:611–617
  67. Fang ZY, Schull-Meade R, Downey M, et al. Determinants of subclinical diabetic heart disease. Diabetologia. 2005;48:394–402
  68. Von Bibra H, Thrainsdottir IS, Hansen A, et al. Tissue Doppler imaging for the detection and quantitation of myocardial dysfunction in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2005;2:24–30
  69. Ha JW, Lee HC, Kang ES, et al. Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiography. Heart. 2007;93:1571–1576
  70. Konduracka E, Gackowski A, Rostoff P, et al. Diabetes-specific cardiomyopathy in type 1 diabetes mellitus: no evidence for its occurrence in the era of intensive insulin therapy. Eur Heart J. 2007;28:2465–2471
  71. Thrainsdottir I, Malmberg K, Olsson A, et al. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diab Vasc Dis Res. 2004;1:40–43
  72. Rösen R, Rump AF, Rösen P. The ACE-inhibitor captopril improves myocardial perfusion in spontaneously diabetic (BB) rats. Diabetologia. 1995;38:509–517
  73. Al-Shafei AI, Wise RG, Gresham GA, et al. Magnetic resonance imaging analysis of cardiac cycle events in diabetic rats: the effect of angiotensin-converting enzyme inhibition. J Physiol. 2002;538(Pt 2):555–572
  74. Al-Shafei AI, Wise RG, Gresham GA, et al. Non-invasive magnetic resonance imaging assessment of myocardial changes and the effects of angiotensin-converting enzyme inhibition in diabetic rats. J Physiol. 2002;538(Pt 2):541–553
  75. Zaman AK, Fujii S, Goto D, et al. Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. J Mol Cell Cardiol. 2004;37:525–535
  76. Kawasaki D, Kosugi K, Waki H, et al. Role of activated renin-angiotensin system in myocardial fibrosis and left ventricular diastolic dysfunction in diabetic patients-reversal by chronic angiotensin II type 1A receptor blockade. Circ J. 2007;71:524–529
  77. Orea-Tejeda A, Colín-Ramírez E, Castillo-Martínez L, et al. Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Rev Invest Clin. 2007;59:103–107
  78. Tang WH, Parameswaran AC, Maroo AP, Francis GS. Aldosterone receptor antagonists in the medical management of chronic heart failure. Mayo Clin Proc. 2005;80:1623–1630

PII: S0002-9343(08)00471-3

doi: 10.1016/j.amjmed.2008.03.046

The American Journal of Medicine
Volume 121, Issue 9 , Pages 748-757 , September 2008

Article Tools

* Image Usage & Resolution