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Diabetic Cardiomyopathy – to Take a Long Story Serious

Diabetische Kardiomyopathie – eine lang währende und ernstzunehmende Erkrankung

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Abstract

Being independent of coronary artery disease and hypertension, diabetic cardiomyopathy is a distinct primary disease process, which precedes the development of congestive heart failure. Epidemiologic as well as clinical studies confirmed the close link between diabetes mellitus and heart failure. Altered cardiac structure and function are common diagnoses in patients with type 2 diabetes mellitus. Hyperglycemia leading to the formation of advanced glycation end products and hyperlipidemia resulting in lipotoxicity are of structural and functional impact on cardiac muscle and cardiomyocytes. New and more sensitive methods of diagnosis identify early diastolic dysfunction as a precursor of the development of congestive heart failure. This review focuses on the mechanistic approach to understand the molecular basis of diabetic cardiomyopathy in patients with type 2 diabetes mellitus.

Zusammenfassung

Als von koronarer Herzkrankheit und Bluthochdruck unabhängige Krankheitsentität wird die diabetische Kardiomyopathie als Vorstufe der terminalen Herzinsuffizienz verstanden. Sowohl epidemiologische als auch klinische Studien bestätigen den engen Zusammenhang zwischen Diabetes mellitus und terminaler Herzinsuffizienz. Veränderte kardiale Struktur und Funktion sind häufige Diagnosen bei Patienten mit Diabetes mellitus. Hyperglykämie, die mit der Bildung von „advanced glycation end products“ einhergeht, und die in Lipotoxizität mündende Hyperlipidämie beeinflussen Funktion und Struktur des Herzmuskels und der Kardiomyozyten. Die frühe diastolische Dysfunktion wird durch neue und sensitivere Diagnosemethoden als Vorläufer der terminalen Herzinsuffizienz identifiziert. Dieser Übersichtsartikel stellt die wesentlichen Gesichtspunkte der molekularen Zusammenhänge, die zur Entstehung einer diabetischen Kardiomyopathie bei Patienten mit Diabetes mellitus beitragen, zusammen.

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References

  1. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006;291:H1489–506.

    Article  CAS  PubMed  Google Scholar 

  2. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation 2007;116:434–48.

    Article  CAS  PubMed  Google Scholar 

  3. Atkinson LL, Fischer MA, Lopaschuk GD. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol Chem 2002;277:29424–30.

    Article  CAS  PubMed  Google Scholar 

  4. Bell DS. Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 2003;26:2433–41.

    Article  PubMed  Google Scholar 

  5. Berry C, Brett M, Stevenson K, et al. Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure. Heart 2008;94:296–304.

    Article  CAS  PubMed  Google Scholar 

  6. Bing RJ, Hammond MM, Handelsman JC, et al. The measurement of coronary blood flow, oxygen consumption, and efficiency of the left ventricle in man. Am Heart J 1949;38:1–24.

    Article  CAS  PubMed  Google Scholar 

  7. Boner G, Cooper ME, McCarroll K, et al. Adverse effects of left ventricular hypertrophy in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Diabetologia 2005;48:1980–7.

    Article  CAS  PubMed  Google Scholar 

  8. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213–23.

    Article  PubMed  Google Scholar 

  9. Boyer JK, Thanigaraj S, Schechtman KB, et al. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 2004;93:870–5.

    Article  PubMed  Google Scholar 

  10. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000;355:773–8.

    Article  CAS  PubMed  Google Scholar 

  11. Carroll R, Carley AN, Dyck JR, et al. Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts. Am J Physiol Endocrinol Metab 2005;288:E900–6.

    Article  CAS  PubMed  Google Scholar 

  12. Chiu HC, Kovacs A, Blanton RM, et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 2005;96:225–33.

    Article  CAS  PubMed  Google Scholar 

  13. Chiu HC, Kovacs A, Ford DA, et al. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:813–22.

    Article  CAS  PubMed  Google Scholar 

  14. Conway MA, Allis J, Ouwerkerk R, et al. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet 1991;338:973–6.

    Article  CAS  PubMed  Google Scholar 

  15. Coort SL, Hasselbaink DM, Koonen DP, et al. Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes 2004;53:1655–63.

    Article  CAS  PubMed  Google Scholar 

  16. de Simone G, Devereux RB, Chinali M, et al. Metabolic syndrome and left ventricular hypertrophy in the prediction of cardiovascular events: the Strong Heart Study. Nutr Metab Cardiovasc Dis 2009;19:98–104.

    Article  PubMed  Google Scholar 

  17. de Simone G, Gottdiener JS, Chinali M, et al. Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study. Eur Heart J 2008;29:741–7.

    Article  PubMed  Google Scholar 

  18. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation 2000;101:2271–6.

    CAS  PubMed  Google Scholar 

  19. Eguchi K, Ishikawa J, Hoshide S, et al. Differential impact of left ventricular mass and relative wall thickness on cardiovascular prognosis in diabetic and nondiabetic hypertensive subjects. Am Heart J 2007;154:79 e9–15.

    Article  Google Scholar 

  20. Finck BN, Han X, Courtois M, et al. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A 2003;100:1226–31.

    Article  CAS  PubMed  Google Scholar 

  21. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002;109:121–30.

    CAS  PubMed  Google Scholar 

  22. Gawlowski T, Stratmann B, Stork I, et al. Heat shock protein 27 modification is increased in the human diabetic failing heart. Horm Metab Res 2009;41:594–9.

    Article  CAS  PubMed  Google Scholar 

  23. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59.

    Article  CAS  PubMed  Google Scholar 

  24. Giles TD, Sander GE. Diabetes mellitus and heart failure: basic mechanisms, clinical features, and therapeutic considerations. Cardiol Clin 2004;22:553–68.

    Article  PubMed  Google Scholar 

  25. Golfman LS, Wilson CR, Sharma S, et al. Activation of PPAR-gamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats. Am J Physiol Endocrinol Metab 2005;289:E328–36.

    Article  CAS  PubMed  Google Scholar 

  26. Guimbal C, Kilimann MW. A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J Biol Chem 1993;268:8418–21.

    CAS  PubMed  Google Scholar 

  27. Hardy CJ, Weiss RG, Bottomley PA, et al. Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 1991;122:795–801.

    Article  CAS  PubMed  Google Scholar 

  28. Held C, Gerstein HC, Yusuf S, et al. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation 2007;115:1371–5.

    Article  CAS  PubMed  Google Scholar 

  29. Horio T, Suzuki M, Takamisawa I, et al. Pioglitazone-induced insulin sensitization improves vascular endothelial function in nondiabetic patients with essential hypertension. Am J Hypertens 2005;18:1626–30.

    Article  CAS  PubMed  Google Scholar 

  30. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440:944–8.

    Article  CAS  PubMed  Google Scholar 

  31. How OJ, Aasum E, Severson DL, et al. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006;55:466–73.

    Article  CAS  PubMed  Google Scholar 

  32. Ingwall JS. Is creatine kinase a target for AMP-activated protein kinase in the heart? J Mol Cell Cardiol 2002;34:1111–20.

    Article  CAS  PubMed  Google Scholar 

  33. Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 2004;95:135–45.

    Article  CAS  PubMed  Google Scholar 

  34. Iozzo P, Chareonthaitawee P, Dutka D, et al. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes 2002;51:3020–4.

    Article  CAS  PubMed  Google Scholar 

  35. Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001;103:2668–73.

    CAS  PubMed  Google Scholar 

  36. Kalousova M, Skrha J, Zima T. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiol Res 2002;51:597–604.

    CAS  PubMed  Google Scholar 

  37. Kannel WB. Incidence and epidemiology of heart failure. Heart Fail Rev 2000;5:167–73.

    Article  CAS  PubMed  Google Scholar 

  38. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34:29–34.

    Article  CAS  PubMed  Google Scholar 

  39. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035–8.

    Article  CAS  PubMed  Google Scholar 

  40. Karamitsos TD, Karvounis HI, Dalamanga EG, et al. Early diastolic impairment of diabetic heart: the significance of right ventricle. Int J Cardiol 2007;114:218–23.

    Article  PubMed  Google Scholar 

  41. King KL, Okere IC, Sharma N, et al. Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power. Am J Physiol Heart Circ Physiol 2005;289:H1033–7.

    Article  CAS  PubMed  Google Scholar 

  42. Lamb HJ, Beyerbacht HP, van der Laarse A, et al. Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999;99:2261–7.

    CAS  PubMed  Google Scholar 

  43. Leyden E. Asthma und Diabetes mellitus. Z Klin Med 1881;3:358–64.

    Google Scholar 

  44. Lopez-Gomez JM, Verde E, Perez-Garcia R. Blood pressure, left ventricular hypertrophy and long-term prognosis in hemodialysis patients. Kidney Int Suppl 1998;68:S92–8.

    Article  CAS  PubMed  Google Scholar 

  45. Mayer J. Über den Zusammenhang des Diabetes mellitus mit Erkrankungen des Herzens. Z Klin Med 1888;14:212–39.

    Google Scholar 

  46. Montagnani M. Diabetic cardiomyopathy: how much does it depend on AGE? Br J Pharmacol 2008;154:725–6.

    Article  CAS  PubMed  Google Scholar 

  47. Monti LD, Landoni C, Setola E, et al. Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in type 2 diabetic patients. Am J Physiol Heart Circ Physiol 2004;287:H1225–31.

    Article  CAS  PubMed  Google Scholar 

  48. Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet 2004;364:1786–8.

    Article  CAS  PubMed  Google Scholar 

  49. Neubauer S. The failing heart — an engine out of fuel. N Engl J Med 2007;356:1140–51.

    Article  PubMed  Google Scholar 

  50. Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997;96:2190–6.

    CAS  PubMed  Google Scholar 

  51. Neubauer S, Horn M, Pabst T, et al. Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur Heart J 1995;16:Suppl O:115–8.

    CAS  PubMed  Google Scholar 

  52. Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992;86:1810–8.

    CAS  PubMed  Google Scholar 

  53. Norton GR, Candy G, Woodiwiss AJ. Aminoguanidine prevents the decreased myocardial compliance produced by streptozotocin-induced diabetes mellitus in rats. Circulation 1996;93:1905–12.

    CAS  PubMed  Google Scholar 

  54. O’Keefe JH, Bell DS. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol 2007;100:899–904.

    Article  PubMed  Google Scholar 

  55. Opie LH. Effect of fatty acids on contractility and rhythm of the heart. Nature 1970;227:1055–6.

    Article  CAS  PubMed  Google Scholar 

  56. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72.

    Article  CAS  PubMed  Google Scholar 

  57. Quinones MA, Greenberg BH, Kopelen HA, et al. Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 2000;35:1237–44.

    Article  CAS  PubMed  Google Scholar 

  58. Randell EW, Vasdev S, Gill V. Measurement of methylglyoxal in rat tissues by electrospray ionization mass spectrometry and liquid chromatography. J Pharmacol Toxicol Methods 2005;51:153–7.

    Article  CAS  PubMed  Google Scholar 

  59. Rijzewijk LJ, van der Meer RW, Lamb HJ, et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol 2009;54:1524–32.

    Article  CAS  PubMed  Google Scholar 

  60. Rosen P, Du X, Tschope D. Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by alpha-tocopherol? Mol Cell Biochem 1998;188:103–11.

    Article  CAS  PubMed  Google Scholar 

  61. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595–602.

    Article  CAS  PubMed  Google Scholar 

  62. Rui L, Aguirre V, Kim JK, et al. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 2001;107:181–9.

    Article  CAS  PubMed  Google Scholar 

  63. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000;5:415–8.

    Article  CAS  PubMed  Google Scholar 

  64. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 1997;34:25–33.

    Article  CAS  PubMed  Google Scholar 

  65. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–12.

    Article  CAS  PubMed  Google Scholar 

  66. Suga H. Ventricular energetics. Physiol Rev 1990;70:247–77.

    CAS  PubMed  Google Scholar 

  67. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes. Part I: General concepts. Circulation 2002;105:1727–33.

    Article  CAS  PubMed  Google Scholar 

  68. Uribarri J, Peppa M, Cai W, et al. Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients. Am J Kidney Dis 2003;42:532–8.

    Article  CAS  PubMed  Google Scholar 

  69. van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 2008;117:43–51.

    Article  PubMed  Google Scholar 

  70. Vlassara H, Palace MR. Glycoxidation: the menace of diabetes and aging. Mt Sinai J Med 2003;70:232–41.

    PubMed  Google Scholar 

  71. Wold LE, Ceylan-Isik AF, Ren J. Oxidative stress and stress signaling: menace of diabetic cardiomyopathy. Acta Pharmacol Sin 2005;26:908–17.

    Article  CAS  PubMed  Google Scholar 

  72. Wyss M, Wallimann T. Creatine metabolism and the consequences of creatine depletion in muscle. Mol Cell Biochem 1994;133–134:51–66.

    Article  PubMed  Google Scholar 

  73. Yagyu H, Chen G, Yokoyama M, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 2003;111:419–26.

    PubMed  Google Scholar 

  74. Yotsukura M, Suzuki J, Yamaguchi T, et al. Prognosis following acute myocardial infarction in patients with ECG evidence of left ventricular hypertrophy prior to infarction. J Electrocardiol 1998;31:91–9.

    Article  CAS  PubMed  Google Scholar 

  75. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes. Part II: Potential mechanisms. Circulation 2002;105:1861–70.

    Article  CAS  PubMed  Google Scholar 

  76. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesityand diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673–7.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Heart and Diabetes Center NRW, Ruhr, University of Bochum, Bochum, Germany

    Bernd Stratmann, Thomas Gawlowski &  Diethelm Tschoepe

  2. Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Georgstraße 11, 32545, Bad Oeynhausen, Germany

    Diethelm Tschoepe

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  1. Bernd Stratmann
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Correspondence to Diethelm Tschoepe.

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Stratmann, B., Gawlowski, T. & Tschoepe, D. Diabetic Cardiomyopathy – to Take a Long Story Serious. Herz 35, 161–168 (2010). https://doi.org/10.1007/s00059-010-3336-0

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