Obesity and Cardiac Dysfunction

  • Gary Sweeney
  • Sheldon E. Litwin
  • Evan Dale Abel


The dramatic increase in the prevalence of obesity and its strong association with cardiovascular disease has resulted in unprecedented interest in understanding the effects of obesity on the cardiovascular system. A consistent but puzzling clinical observation is that obesity confers an increased susceptibility to the development of cardiac disease, while at the same time affording protection against subsequent mortality (termed the obesity paradox). This chapter will review the current state of knowledge concerning cardiac dysfunction in humans with obesity, review studies that have been performed in animal models, shed some insight into molecular mechanisms that lead to cardiac dysfunction in obesity, and discuss potential mechanisms that can contribute to cardiac dysfunction in obesity that represent attractive testable hypotheses.


Sleep Apnea Right Ventricular Left Ventricular Hypertrophy Obese Subject Leave Atrial 


  1. 1.
    Gelber, R. P., Gaziano, J. M., Orav, E. J., Manson, J. E., Buring, J. E., & Kurth, T. (2008). Measures of obesity and cardiovascular risk among men and women. Journal of the American College of Cardiology, 52(8), 605–615.PubMedCrossRefGoogle Scholar
  2. 2.
    Litwin, S. E. (2008). Which measures of obesity best predict cardiovascular risk? Journal of the American College of Cardiology, 52(8), 616–619.PubMedCrossRefGoogle Scholar
  3. 3.
    Alpert, M. A., Lambert, C. R., Panayiotou, H., et al. (1995). Relation of duration of morbid obesity to left ventricular mass, systolic function, and diastolic filling, and effect of weight loss. The American Journal of Cardiology, 76(16), 1194–1197.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilhelmsen, L., Rosengren, A., Eriksson, H., & Lappas, G. (2001). Heart failure in the general population of men–morbidity, risk factors and prognosis. Journal of Internal Medicine, 249(3), 253–261.PubMedCrossRefGoogle Scholar
  5. 5.
    He, J., Ogden, L. G., Bazzano, L. A., Vupputuri, S., Loria, C., & Whelton, P. K. (2001). Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Archives of Internal Medicine, 161(7), 996–1002.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen, Y. T., Vaccarino, V., Williams, C. S., Butler, J., Berkman, L. F., & Krumholz, H. M. (1999). Risk factors for heart failure in the elderly: A prospective community-based study. The American Journal of Medicine, 106(6), 605–612.PubMedCrossRefGoogle Scholar
  7. 7.
    Caruana, L., Petrie, M. C., Davie, A. P., & McMurray, J. J. (2000). Do patients with suspected heart failure and preserved left ventricular systolic function suffer from “diastolic heart failure” or from misdiagnosis? A prospective descriptive study. BMJ (Clinical Research Ed.), 321(7255), 215–218.CrossRefGoogle Scholar
  8. 8.
    Kenchaiah, S., Evans, J. C., Levy, D., et al. (2002). Obesity and the risk of heart failure. The New England Journal of Medicine, 347(5), 305–313.PubMedCrossRefGoogle Scholar
  9. 9.
    Abel, E. D., Litwin, S. E., & Sweeney, G. (2008). Cardiac remodeling in obesity. Physiological Reviews, 88(2), 389–419.PubMedCrossRefGoogle Scholar
  10. 10.
    Aurigemma, G. P., Silver, K. H., Priest, M. A., & Gaasch, W. H. (1995). Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. Journal of the American College of Cardiology, 26(1), 195–202.PubMedCrossRefGoogle Scholar
  11. 11.
    de Simone, G., Devereux, R. B., Koren, M. J., Mensah, G. A., Casale, P. N., & Laragh, J. H. (1996). Midwall left ventricular mechanics. An independent predictor of cardiovascular risk in arterial hypertension. Circulation, 93(2), 259–265.PubMedGoogle Scholar
  12. 12.
    Garavaglia, G. E., Messerli, F. H., Nunez, B. D., Schmieder, R. E., & Grossman, E. (1988). Myocardial contractility and left ventricular function in obese patients with essential hypertension. The American Journal of Cardiology, 62(9), 594–597.PubMedCrossRefGoogle Scholar
  13. 13.
    Chinali, M., de Simone, G., Roman, M. J., et al. (2006). Impact of obesity on cardiac geometry and function in a population of adolescents: The Strong Heart Study. Journal of the American College of Cardiology, 47(11), 2267–2273.PubMedCrossRefGoogle Scholar
  14. 14.
    von Haehling, S., Doehner, W., & Anker, S. D. (2006). Obesity and the heart a weighty issue. Journal of the American College of Cardiology, 47(11), 2274–2276.PubMedCrossRefGoogle Scholar
  15. 15.
    Wong, C. Y., O’Moore-Sullivan, T., Leano, R., Byrne, N., Beller, E., & Marwick, T. H. (2004). Alterations of left ventricular myocardial characteristics associated with obesity. Circulation, 110(19), 3081–3087.PubMedCrossRefGoogle Scholar
  16. 16.
    Pascual, M., Pascual, D. A., Soria, F., et al. (2003). Effects of isolated obesity on systolic and diastolic left ventricular function. Heart (British Cardiac Society), 89(10), 1152–1156.CrossRefGoogle Scholar
  17. 17.
    Peterson, L. R., Waggoner, A. D., Schechtman, K. B., et al. (2004). Alterations in left ventricular structure and function in young healthy obese women: Assessment by echocardiography and tissue Doppler imaging. Journal of the American College of Cardiology, 43(8), 1399–1404.PubMedCrossRefGoogle Scholar
  18. 18.
    Morricone, L., Malavazos, A. E., Coman, C., Donati, C., Hassan, T., & Caviezel, F. (2002). Echocardiographic abnormalities in normotensive obese patients: Relationship with visceral fat. Obesity Research, 10(6), 489–498.PubMedCrossRefGoogle Scholar
  19. 19.
    Berkalp, B., Cesur, V., Corapcioglu, D., Erol, C., & Baskal, N. (1995). Obesity and left ventricular diastolic dysfunction. International Journal of Cardiology, 52(1), 23–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Wikstrand, J., Pettersson, P., & Bjorntorp, P. (1993). Body fat distribution and left ventricular morphology and function in obese females. Journal of Hypertension, 11(11), 1259–1266.PubMedCrossRefGoogle Scholar
  21. 21.
    Mottram, P. M., & Marwick, T. H. (2005). Assessment of diastolic function: What the general cardiologist needs to know. Heart (British Cardiac Society), 91(5), 681–695.CrossRefGoogle Scholar
  22. 22.
    Ho, C. Y., & Solomon, S. D. (2006). A clinician’s guide to tissue Doppler imaging. Circulation, 113(10), e396–e398.PubMedCrossRefGoogle Scholar
  23. 23.
    Kaltman, A. J., & Goldring, R. M. (1976). Role of circulatory congestion in the cardiorespiratory failure of obesity. The American Journal of Medicine, 60(5), 645–653.PubMedCrossRefGoogle Scholar
  24. 24.
    Dokainish, H., Zoghbi, W. A., Lakkis, N. M., et al. (2004). Optimal noninvasive assessment of left ventricular filling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation, 109(20), 2432–2439.PubMedCrossRefGoogle Scholar
  25. 25.
    Ommen, S. R., Nishimura, R. A., Appleton, C. P., et al. (2000). Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation, 102(15), 1788–1794.PubMedGoogle Scholar
  26. 26.
    Mehra, M. R., Uber, P. A., Park, M. H., et al. (2004). Obesity and suppressed B-type natriuretic peptide levels in heart failure. Journal of the American College of Cardiology, 43(9), 1590–1595.PubMedCrossRefGoogle Scholar
  27. 27.
    Das, S. R., Drazner, M. H., Dries, D. L., et al. (2005). Impact of body mass and body composition on circulating levels of natriuretic peptides: Results from the Dallas Heart Study. Circulation, 112(14), 2163–2168.PubMedCrossRefGoogle Scholar
  28. 28.
    Wong, C. Y., O’Moore-Sullivan, T., Leano, R., Hukins, C., Jenkins, C., & Marwick, T. H. (2006). Association of subclinical right ventricular dysfunction with obesity. Journal of the American College of Cardiology, 47(3), 611–616.PubMedCrossRefGoogle Scholar
  29. 29.
    Her, C., Cerabona, T., Bairamian, M., & McGoldrick, K. E. (2006). Right ventricular systolic function is not depressed in morbid obesity. Obesity Surgery, 16(10), 1287–1293.PubMedCrossRefGoogle Scholar
  30. 30.
    Otto, M. E., Belohlavek, M., Khandheria, B., Gilman, G., Svatikova, A., & Somers, V. (2004). Comparison of right and left ventricular function in obese and nonobese men. The American Journal of Cardiology, 93(12), 1569–1572.PubMedCrossRefGoogle Scholar
  31. 31.
    Kortelainen, M. L., & Sarkioja, T. (2001). Visceral fat and coronary pathology in male adolescents. International Journal of Obesity and Related Metabolic Disorders, 25(2), 228–232.PubMedCrossRefGoogle Scholar
  32. 32.
    Morricone, L., Donati, C., Hassan, T., Cioffi, P., & Caviezel, F. (2002). Relationship of visceral fat distribution to angiographically assessed coronary artery disease: Results in subjects with or without diabetes or impaired glucose tolerance. Nutrition, Metabolism, and Cardiovascular Diseases, 12(5), 275–283.PubMedGoogle Scholar
  33. 33.
    Allison, M. A., & Michael Wright, C. (2004). Body morphology differentially predicts coronary calcium. International Journal of Obesity and Related Metabolic Disorders, 28(3), 396–401.PubMedCrossRefGoogle Scholar
  34. 34.
    Van Gaal, L. F., Mertens, I. L., & De Block, C. E. (2006). Mechanisms linking obesity with cardiovascular disease. Nature, 444(7121), 875–880.PubMedCrossRefGoogle Scholar
  35. 35.
    Diamant, M., & Tushuizen, M. E. (2006). The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD. Current Diabetes Reports, 6(4), 279–286.PubMedCrossRefGoogle Scholar
  36. 36.
    Skilton, M. R., & Celermajer, D. S. (2006). Endothelial dysfunction and arterial abnormalities in childhood obesity. International Journal of Obesity, 30(7), 1041–1049.PubMedCrossRefGoogle Scholar
  37. 37.
    Lauer, M. S., Anderson, K. M., Larson, M. G., & Levy, D. (1994). A new method for indexing left ventricular mass for differences in body size. The American Journal of Cardiology, 74(5), 487–491.PubMedCrossRefGoogle Scholar
  38. 38.
    de Simone, G., Devereux, R. B., Roman, M. J., Alderman, M. H., & Laragh, J. H. (1994). Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension, 23(5), 600–606.PubMedGoogle Scholar
  39. 39.
    de Simone, G., Kizer, J. R., Chinali, M., et al. (2005). Normalization for body size and population-attributable risk of left ventricular hypertrophy: The Strong Heart Study. American Journal of Hypertension, 18(2 pt 1), 191–196.PubMedCrossRefGoogle Scholar
  40. 40.
    Alpert, M. A., Terry, B. E., & Kelly, D. L. (1985). Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity. The American Journal of Cardiology, 55(6), 783–786.PubMedCrossRefGoogle Scholar
  41. 41.
    Alpert, M. A., Terry, B. E., Mulekar, M., et al. (1997). Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. The American Journal of Cardiology, 80(6), 736–740.PubMedCrossRefGoogle Scholar
  42. 42.
    Gerdts, E., Wachtell, K., Omvik, P., et al. (2007). Left atrial size and risk of major cardiovascular events during antihypertensive treatment: Losartan intervention for endpoint reduction in hypertension trial. Hypertension, 49(2), 311–316.PubMedCrossRefGoogle Scholar
  43. 43.
    Kizer, J. R., Bella, J. N., Palmieri, V., et al. (2006). Left atrial diameter as an independent predictor of first clinical cardiovascular events in middle-aged and elderly adults: The Strong Heart Study (SHS). American Heart Journal, 151(2), 412–418.PubMedCrossRefGoogle Scholar
  44. 44.
    Wang, T. J., Parise, H., Levy, D., et al. (2004). Obesity and the risk of new-onset atrial fibrillation. JAMA, 292(20), 2471–2477.PubMedCrossRefGoogle Scholar
  45. 45.
    Connolly, H. M., Crary, J. L., McGoon, M. D., et al. (1997). Valvular heart disease associated with fenfluramine-phentermine. The New England Journal of Medicine, 337(9), 581–588.PubMedCrossRefGoogle Scholar
  46. 46.
    Singh, J. P., Evans, J. C., Levy, D., et al. (1999). Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). The American Journal of Cardiology, 83(6), 897–902.PubMedCrossRefGoogle Scholar
  47. 47.
    Szczepaniak, L. S., Dobbins, R. L., Metzger, G. J., et al. (2003). Myocardial triglycerides and systolic function in humans: In vivo evaluation by localized proton spectroscopy and cardiac imaging. Magnetic Resonance in Medicine, 49(3), 417–423.PubMedCrossRefGoogle Scholar
  48. 48.
    McGavock, J. M., Lingvay, I., Zib, I., et al. (2007). Cardiac steatosis in diabetes mellitus: A 1H-magnetic resonance spectroscopy study. Circulation, 116(10), 1170–1175.PubMedCrossRefGoogle Scholar
  49. 49.
    Wende, A. R., & Abel, E. D. (2010). Lipotoxicity in the heart. Biochimica et Biophysica Acta, 1801(3), 311–319.PubMedGoogle Scholar
  50. 50.
    Rabkin, S. W. (2007). Epicardial fat: Properties, function and relationship to obesity. Obesity Reviews, 8(3), 253–261.PubMedCrossRefGoogle Scholar
  51. 51.
    Sarin, S., Wenger, C., Marwaha, A., et al. (2008). Clinical significance of epicardial fat measured using cardiac multislice computed tomography. The American Journal of Cardiology, 102(6), 767–771.PubMedCrossRefGoogle Scholar
  52. 52.
    Silaghi, A., Piercecchi-Marti, M. D., Grino, M., et al. (2008). Epicardial adipose tissue extent: Relationship with age, body fat distribution, and coronaropathy. Obesity (Silver Spring), 16(11), 2424–2430.CrossRefGoogle Scholar
  53. 53.
    Iacobellis, G., Ribaudo, M. C., Leto, G., et al. (2002). Influence of excess fat on cardiac morphology and function: Study in uncomplicated obesity. Obesity Research, 10(8), 767–773.PubMedCrossRefGoogle Scholar
  54. 54.
    Iacobellis, G., & Leonetti, F. (2005). Epicardial adipose tissue and insulin resistance in obese subjects. The Journal of Clinical Endocrinology and Metabolism, 90(11), 6300–6302.PubMedCrossRefGoogle Scholar
  55. 55.
    Iacobellis, G., Singh, N., Wharton, S., & Sharma, A. M. (2008). Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity (Silver Spring), 16(7), 1693–1697.CrossRefGoogle Scholar
  56. 56.
    Kim, M. K., Tomita, T., Kim, M. J., Sasai, H., Maeda, S., & Tanaka, K. (2009). Aerobic exercise training reduces epicardial fat in obese men. Journal of Applied Physiology, 106(1), 5–11.PubMedCrossRefGoogle Scholar
  57. 57.
    Willens, H. J., Byers, P., Chirinos, J. A., Labrador, E., Hare, J. M., & de Marchena, E. (2007). Effects of weight loss after bariatric surgery on epicardial fat measured using echocardiography. The American Journal of Cardiology, 99(9), 1242–1245.PubMedCrossRefGoogle Scholar
  58. 58.
    Uretsky, S., Messerli, F. H., Bangalore, S., et al. (2007). Obesity paradox in patients with hypertension and coronary artery disease. The American Journal of Medicine, 120(10), 863–870.PubMedCrossRefGoogle Scholar
  59. 59.
    Romero-Corral, A., Montori, V. M., Somers, V. K., et al. (2006). Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: A systematic review of cohort studies. Lancet, 368(9536), 666–678.PubMedCrossRefGoogle Scholar
  60. 60.
    Galal, W., van Gestel, Y. R., Hoeks, S. E., et al. (2008). The obesity paradox in patients with peripheral arterial disease. Chest, 134(5), 925–930.PubMedCrossRefGoogle Scholar
  61. 61.
    Mehta, R. H., Califf, R. M., Garg, J., et al. (2007). The impact of anthropomorphic indices on clinical outcomes in patients with acute ST-elevation myocardial infarction. European Heart Journal, 28(4), 415–424.PubMedCrossRefGoogle Scholar
  62. 62.
    Diercks, D. B., Roe, M. T., Mulgund, J., et al. (2006). The obesity paradox in non-ST-segment elevation acute coronary syndromes: Results from the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the American College of Cardiology/American Heart Association Guidelines Quality Improvement Initiative. American Heart Journal, 152(1), 140–148.PubMedCrossRefGoogle Scholar
  63. 63.
    Habbu, A., Lakkis, N. M., & Dokainish, H. (2006). The obesity paradox: Fact or fiction? The American Journal of Cardiology, 98(7), 944–948.PubMedCrossRefGoogle Scholar
  64. 64.
    Nigam, A., Wright, R. S., Allison, T. G., et al. (2006). Excess weight at time of presentation of myocardial infarction is associated with lower initial mortality risks but higher long-term risks including recurrent re-infarction and cardiac death. International Journal of Cardiology, 110(2), 153–159.PubMedCrossRefGoogle Scholar
  65. 65.
    Maggio, C. A., & Pi-Sunyer, F. X. (2003). Obesity and type 2 diabetes. Endocrinology and Metabolism Clinics of North America, 32(4), 805–822, viii.PubMedCrossRefGoogle Scholar
  66. 66.
    Kahn, B. B., & Flier, J. S. (2000). Obesity and insulin resistance. The Journal of Clinical Investigation, 106(4), 473–481.PubMedCrossRefGoogle Scholar
  67. 67.
    Mensah, G. A., Mokdad, A. H., Ford, E., et al. (2004). Obesity, metabolic syndrome, and type 2 diabetes: Emerging epidemics and their cardiovascular implications. Cardiology Clinics, 22(4), 485–504.PubMedCrossRefGoogle Scholar
  68. 68.
    Nilsson, P. M. (2005). Diabetes and obesity: New data on mechanisms and intervention trials. Expert Review of Cardiovascular Therapy, 3(2), 243–247.PubMedCrossRefGoogle Scholar
  69. 69.
    Tsujino, T., Kawasaki, D., & Masuyama, T. (2006). Left ventricular diastolic dysfunction in diabetic patients: Pathophysiology and therapeutic implications. American Journal of Cardiovascular Drugs, 6(4), 219–230.PubMedCrossRefGoogle Scholar
  70. 70.
    Boudina, S., & Abel, E. D. (2007). Diabetic cardiomyopathy revisited. Circulation, 115(25), 3213–3223.PubMedCrossRefGoogle Scholar
  71. 71.
    Avelar, E., Cloward, T. V., Walker, J. M., et al. (2007). Left ventricular hypertrophy in severe obesity: Interactions among blood pressure, nocturnal hypoxemia, and body mass. Hypertension, 49(1), 34–39.PubMedCrossRefGoogle Scholar
  72. 72.
    Rutter, M. K., Parise, H., Benjamin, E. J., et al. (2003). Impact of glucose intolerance and insulin resistance on cardiac structure and function: Sex-related differences in the Framingham Heart Study. Circulation, 107(3), 448–454.PubMedCrossRefGoogle Scholar
  73. 73.
    Palmieri, V., Bella, J. N., Arnett, D. K., et al. (2001). Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects: Hypertension Genetic Epidemiology Network (HyperGEN) study. Circulation, 103(1), 102–107.PubMedGoogle Scholar
  74. 74.
    Kilhovd, B. K., Juutilainen, A., Lehto, S., et al. (2005). High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic men: A population-based 18-year follow-up study. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(4), 815–820.PubMedCrossRefGoogle Scholar
  75. 75.
    Bucciarelli, L. G., Kaneko, M., Ananthakrishnan, R., et al. (2006). Receptor for advanced-glycation end products: Key modulator of myocardial ischemic injury. Circulation, 113(9), 1226–1234.PubMedCrossRefGoogle Scholar
  76. 76.
    Li, S. Y., Liu, Y., Sigmon, V. K., McCort, A., & Ren, J. (2005). High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogen-activated protein kinase activation and apoptosis. Diabetes, Obesity & Metabolism, 7(4), 448–454.CrossRefGoogle Scholar
  77. 77.
    Li, S. Y., Sigmon, V. K., Babcock, S. A., & Ren, J. (2007). Advanced glycation endproduct induces ROS accumulation, apoptosis, MAP kinase activation and nuclear O-GlcNAcylation in human cardiac myocytes. Life Sciences, 80(11), 1051–1056.PubMedCrossRefGoogle Scholar
  78. 78.
    Grossman, W., Jones, D., & McLaurin, L. P. (1975). Wall stress and patterns of hypertrophy in the human left ventricle. The Journal of Clinical Investigation, 56(1), 56–64.PubMedCrossRefGoogle Scholar
  79. 79.
    Kotsis, V., Stabouli, S., Bouldin, M., Low, A., Toumanidis, S., & Zakopoulos, N. (2005). Impact of obesity on 24-hour ambulatory blood pressure and hypertension. Hypertension, 45(4), 602–607.PubMedCrossRefGoogle Scholar
  80. 80.
    Alpert, M. A., & Hashimi, M. W. (1993). Obesity and the heart. The American Journal of the Medical Sciences, 306(2), 117–123.PubMedCrossRefGoogle Scholar
  81. 81.
    Lavie, C. J., & Messerli, F. H. (1986). Cardiovascular adaptation to obesity and hypertension. Chest, 90(2), 275–279.PubMedCrossRefGoogle Scholar
  82. 82.
    Contaldo, F., Pasanisi, F., Finelli, C., & de Simone, G. (2002). Obesity, heart failure and sudden death. Nutrition, Metabolism, and Cardiovascular Diseases, 12(4), 190–197.PubMedGoogle Scholar
  83. 83.
    Quan, S. F., & Gersh, B. J. (2004). Cardiovascular consequences of sleep-disordered breathing: Past, present and future: Report of a workshop from the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute. Circulation, 109(8), 951–957.PubMedCrossRefGoogle Scholar
  84. 84.
    de Simone, G. (2007). Morbid obesity and left ventricular geometry. Hypertension, 49(1), 7–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Cloward, T. V., Walker, J. M., Farney, R. J., & Anderson, J. L. (2003). Left ventricular hypertrophy is a common echocardiographic abnormality in severe obstructive sleep apnea and reverses with nasal continuous positive airway pressure. Chest, 124(2), 594–601.PubMedCrossRefGoogle Scholar
  86. 86.
    Bugger, H., & Abel, E. D. (2009). Rodent models of diabetic cardiomyopathy. Disease Model & Mechanisms, 2(9–10), 454–466.CrossRefGoogle Scholar
  87. 87.
    Hsueh, W., Abel, E. D., Breslow, J. L., et al. (2007). Recipes for creating animal models of diabetic cardiovascular disease. Circulation Research, 100(10), 1415–1427.PubMedCrossRefGoogle Scholar
  88. 88.
    Wright, J. J., Kim, J., Buchanan, J., et al. (2009). Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovascular Research, 82(2), 351–360.PubMedCrossRefGoogle Scholar
  89. 89.
    Buchanan, J., Mazumder, P. K., Hu, P., et al. (2005). Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology, 146(12), 5341–5349.PubMedCrossRefGoogle Scholar
  90. 90.
    Cook, S. A., Varela-Carver, A., Mongillo, M., et al. (2010). Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. European Heart Journal, 31(1), 100–111.PubMedCrossRefGoogle Scholar
  91. 91.
    Ko, H. J., Zhang, Z., Jung, D. Y., et al. (2009). Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart. Diabetes, 58(11), 2536–2546.PubMedCrossRefGoogle Scholar
  92. 92.
    Coort, S. L., Hasselbaink, D. M., Koonen, D. P., et al. (2004). Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes, 53(7), 1655–1663.PubMedCrossRefGoogle Scholar
  93. 93.
    Peterson, L. R., Herrero, P., Schechtman, K. B., et al. (2004). Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation, 109(18), 2191–2196.PubMedCrossRefGoogle Scholar
  94. 94.
    Sharma, S., Adrogue, J. V., Golfman, L., et al. (2004). Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. The FASEB Journal, 18(14), 1692–1700.PubMedCrossRefGoogle Scholar
  95. 95.
    Boudina, S., Abel, E. D. (2006). Mitochondrial uncoupling: A key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda), 21, 250–258.Google Scholar
  96. 96.
    Boudina, S., Sena, S., Theobald, H., et al. (2007). Mitochondrial energetics in the heart in obesity-related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes, 56(10), 2457–2466.PubMedCrossRefGoogle Scholar
  97. 97.
    Boudina, S., Sena, S., O’Neill, B. T., Tathireddy, P., Young, M. E., & Abel, E. D. (2005). Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation, 112(17), 2686–2695.PubMedCrossRefGoogle Scholar
  98. 98.
    Duncan, J. G., Fong, J. L., Medeiros, D. M., Finck, B. N., & Kelly, D. P. (2007). Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation, 115(7), 909–917.PubMedCrossRefGoogle Scholar
  99. 99.
    Scheuermann-Freestone, M., Madsen, P. L., Manners, D., et al. (2003). Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation, 107(24), 3040–3046.PubMedCrossRefGoogle Scholar
  100. 100.
    Rijzewijk, L. J., van der Meer, R. W., Lamb, H. J., et al. (2009). Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: Studies with cardiac positron emission tomography and magnetic resonance imaging. Journal of the American College of Cardiology, 54(16), 1524–1532.PubMedCrossRefGoogle Scholar
  101. 101.
    Anderson, E. J., Kypson, A. P., Rodriguez, E., Anderson, C. A., Lehr, E. J., & Neufer, P. D. (2009). Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. Journal of the American College of Cardiology, 54(20), 1891–1898.PubMedCrossRefGoogle Scholar
  102. 102.
    Boudina, S., Bugger, H., Sena, S., et al. (2009). Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation, 119(9), 1272–1283.PubMedCrossRefGoogle Scholar
  103. 103.
    Ouwens, D. M., Boer, C., Fodor, M., et al. (2005). Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia, 48(6), 1229–1237.PubMedCrossRefGoogle Scholar
  104. 104.
    Zhou, Y. T., Grayburn, P., Karim, A., et al. (2000). Lipotoxic heart disease in obese rats: Implications for human obesity. Proceedings of the National Academy of Sciences of the United States of America, 97(4), 1784–1789.PubMedCrossRefGoogle Scholar
  105. 105.
    Park, T. S., Hu, Y., Noh, H. L., et al. (2008). Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. Journal of Lipid Research, 49(10), 2101–2112.PubMedCrossRefGoogle Scholar
  106. 106.
    Chiu, H. C., Kovacs, A., Ford, D. A., et al. (2001). A novel mouse model of lipotoxic cardiomyopathy. The Journal of Clinical Investigation, 107(7), 813–822.PubMedCrossRefGoogle Scholar
  107. 107.
    Finck, B. N., Lehman, J. J., Leone, T. C., et al. (2002). The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. The Journal of Clinical Investigation, 109(1), 121–130.PubMedGoogle Scholar
  108. 108.
    Finck, B. N., Han, X., Courtois, M., et al. (2003). A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content. Proceedings of the National Academy of Sciences of the United States of America, 100(3), 1226–1231.PubMedCrossRefGoogle Scholar
  109. 109.
    Yang, J., Sambandam, N., Han, X., et al. (2007). CD36 deficiency rescues lipotoxic cardiomyopathy. Circulation Research, 100(8), 1208–1217.PubMedCrossRefGoogle Scholar
  110. 110.
    Schwenk, R. W., Luiken, J. J., Bonen, A., Glatz, J. F. (2008). Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovascular Research, 79(2), 249–258.PubMedCrossRefGoogle Scholar
  111. 111.
    Koonen, D. P., Febbraio, M., Bonnet, S., et al. (2007). CD36 expression contributes to age-induced cardiomyopathy in mice. Circulation, 116(19), 2139–2147.PubMedCrossRefGoogle Scholar
  112. 112.
    Chiu, H. C., Kovacs, A., Blanton, R. M., et al. (2005). Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circulation Research, 96(2), 225–233.PubMedCrossRefGoogle Scholar
  113. 113.
    Ruano, M., Silvestre, V., Castro, R., et al. (2005). Morbid obesity, hypertensive disease and the renin-angiotensin-aldosterone axis. Obesity Surgery, 15(5), 670–676.PubMedCrossRefGoogle Scholar
  114. 114.
    Engeli, S., Negrel, R., & Sharma, A. M. (2000). Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension, 35(6), 1270–1277.PubMedGoogle Scholar
  115. 115.
    Davy, K. P., & Hall, J. E. (2004). Obesity and hypertension: Two epidemics or one? American Journal of Physiology, 286(5), R803–R813.PubMedGoogle Scholar
  116. 116.
    van Harmelen, V., Elizalde, M., Ariapart, P., et al. (2000). The association of human adipose angiotensinogen gene expression with abdominal fat distribution in obesity. International Journal of Obesity and Related Metabolic Disorders, 24(6), 673–678.PubMedCrossRefGoogle Scholar
  117. 117.
    Goldstein, B. J., Scalia, R. G., & Ma, X. L. (2009). Protective vascular and myocardial effects of adiponectin. Nature Clinical Practice. Cardiovascular medicine, 6(1), 27–35.PubMedCrossRefGoogle Scholar
  118. 118.
    Sweeney, G. (2010). Cardiovascular effects of leptin. Nature Reviews. Cardiology, 7(1), 22–29.PubMedCrossRefGoogle Scholar
  119. 119.
    Ouchi, N., Shibata, R., & Walsh, K. (2006). Targeting adiponectin for cardioprotection. Expert Opinion on Therapeutic Targets, 10(4), 573–581.PubMedCrossRefGoogle Scholar
  120. 120.
    Ouchi, N., Shibata, R., & Walsh, K. (2006). Cardioprotection by adiponectin. Trends in Cardiovascular Medicine, 16(5), 141–146.PubMedCrossRefGoogle Scholar
  121. 121.
    Pineiro, R., Iglesias, M. J., Gallego, R., et al. (2005). Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Letters, 579(23), 5163–5169.PubMedCrossRefGoogle Scholar
  122. 122.
    Takahashi, T., Saegusa, S., Sumino, H., et al. (2005). Adiponectin, T-cadherin and tumour necrosis factor-alpha in damaged cardiomyocytes from autopsy specimens. The Journal of International Medical Research, 33(2), 236–244.PubMedGoogle Scholar
  123. 123.
    Fujita, K., Maeda, N., Sonoda, M., et al. (2008). Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(5), 863–870.PubMedCrossRefGoogle Scholar
  124. 124.
    Kadowaki, T., & Yamauchi, T. (2005). Adiponectin and adiponectin receptors. Endocrine Reviews, 26(3), 439–451.PubMedCrossRefGoogle Scholar
  125. 125.
    Liao, Y., Takashima, S., Maeda, N., et al. (2005). Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovascular Research, 67(4), 705–713.PubMedCrossRefGoogle Scholar
  126. 126.
    Shibata, R., Ouchi, N., Ito, M., et al. (2004). Adiponectin-mediated modulation of hypertrophic signals in the heart. Nature Medicine, 10(12), 1384–1389.PubMedCrossRefGoogle Scholar
  127. 127.
    Shibata, R., Sato, K., Pimentel, D. R., et al. (2005). Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nature Medicine, 11(10), 1096–1103.PubMedCrossRefGoogle Scholar
  128. 128.
    Shibata, R., Izumiya, Y., Sato, K., et al. (2007). Adiponectin protects against the development of systolic dysfunction following myocardial infarction. Journal of Molecular and Cellular Cardiology, 42(6), 1065–1074.PubMedCrossRefGoogle Scholar
  129. 129.
    Tao, L., Gao, E., Jiao, X., et al. (2007). Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation, 115(11), 1408–1416.PubMedCrossRefGoogle Scholar
  130. 130.
    Palanivel, R., Fang, X., Park, M., et al. (2007). Globular and full-length adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes. Cardiovascular Research, 75(1), 148–157.PubMedCrossRefGoogle Scholar
  131. 131.
    Kanda, T., Saegusa, S., Takahashi, T., et al. (2007). Reduced-energy diet improves survival of obese KKAy mice with viral myocarditis: Induction of cardiac adiponectin expression. International Journal of Cardiology, 119, 310–318.PubMedCrossRefGoogle Scholar
  132. 132.
    Takahashi, T., Yu, F., Saegusa, S., et al. (2006). Impaired expression of cardiac adiponectin in leptin-deficient mice with viral myocarditis. International Heart Journal, 47(1), 107–123.PubMedCrossRefGoogle Scholar
  133. 133.
    Takahashi, T., Saegusa, S., Sumino, H., et al. (2005). Adiponectin replacement therapy attenuates myocardial damage in leptin-deficient mice with viral myocarditis. The Journal of International Medical Research, 33(2), 207–214.PubMedGoogle Scholar
  134. 134.
    Celik, T., & Yaman, H. (2009). Elevated adiponectin levels in patients with chronic heart failure: An independent predictor of mortality or a marker of cardiac cachexia? International Journal of Cardiology in press.Google Scholar
  135. 135.
    Dieplinger, B., Gegenhuber, A., Poelz, W., Haltmayer, M., & Mueller, T. (2009). Prognostic value of increased adiponectin plasma concentrations in patients with acute destabilized heart failure. Clinical Biochemistry, 42(10–11), 1190–1193.PubMedCrossRefGoogle Scholar
  136. 136.
    Kimura, K., Miura, S., Iwata, A., et al. (2009). Association between cardiac function and metabolic factors including adiponectin in patients with acute myocardial infarction. Journal of Cardiology, 53(1), 65–71.PubMedCrossRefGoogle Scholar
  137. 137.
    Laoutaris, I. D., Vasiliadis, I. K., Dritsas, A., et al. (2009). High plasma adiponectin is related to low functional capacity in patients with chronic heart failure. International Journal of Cardiology in press.Google Scholar
  138. 138.
    Iacobellis, G., Petrone, A., Leonetti, F., & Buzzetti, R. (2006). Left ventricular mass and +276 G/G single nucleotide polymorphism of the adiponectin gene in uncomplicated obesity. Obesity (Silver Spring), 14(3), 368–372.CrossRefGoogle Scholar
  139. 139.
    Okamoto, H. (2009). Can adiponectin be a novel metabolic biomarker for heart failure? Circulation Journal, 73(6), 1012–1013.PubMedCrossRefGoogle Scholar
  140. 140.
    Fang, X., & Sweeney, G. (2006). Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes. Biochemical Society Transactions, 34(pt 5), 798–801.PubMedGoogle Scholar
  141. 141.
    Onay-Besikci, A., Altarejos, J. Y., & Lopaschuk, G. D. (2004). gAd-globular head domain of adiponectin increases fatty acid oxidation in newborn rabbit hearts. The Journal of Biological Chemistry, 279(43), 44320–44326.PubMedCrossRefGoogle Scholar
  142. 142.
    Yamauchi, T., Kamon, J., Ito, Y., et al. (2003). Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature, 423(6941), 762–769.PubMedCrossRefGoogle Scholar
  143. 143.
    Fang, X., Palanivel, R., Zhou, X., et al. (2005). Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts. Journal of Molecular Endocrinology, 35(3), 465–476.PubMedCrossRefGoogle Scholar
  144. 144.
    Ding, G., Qin, Q., He, N., et al. (2007). Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome ­proliferator-activated receptor gamma. Journal of Molecular and Cellular Cardiology, 43(1), 73–84.PubMedCrossRefGoogle Scholar
  145. 145.
    Guo, Z., Xia, Z., Yuen, V. G., & McNeill, J. H. (2007). Cardiac expression of adiponectin and its receptors in streptozotocin-induced diabetic rats. Metabolism, 56(10), 1363–1371.PubMedCrossRefGoogle Scholar
  146. 146.
    Saito, Y., Fujioka, D., Kawabata, K. I., et al. (2007). Statin reverses reduction of adiponectin receptor expression in infarcted heart and in TNF{alpha}-treated cardiomyocytes in association with improved glucose uptake. American Journal of Physiology. Heart and Circulatory Physiology, 293, H390–H397.CrossRefGoogle Scholar
  147. 147.
    Civitarese, A. E., Jenkinson, C. P., Richardson, D., et al. (2004). Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes. Diabetologia, 47(5), 816–820.PubMedCrossRefGoogle Scholar
  148. 148.
    Tsuchida, A., Yamauchi, T., Ito, Y., et al. (2004). Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. The Journal of Biological Chemistry, 279(29), 30817–30822.PubMedCrossRefGoogle Scholar
  149. 149.
    Inukai, K., Nakashima, Y., Watanabe, M., et al. (2004). Regulation of adiponectin receptor gene expression in diabetic mice. American Journal of Physiology. Endocrinology and Metabolism, 288, E876–E882.PubMedCrossRefGoogle Scholar
  150. 150.
    Mao, X., Kikani, C. K., Riojas, R. A., et al. (2006). APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nature Cell Biology, 8(5), 516–523.PubMedCrossRefGoogle Scholar
  151. 151.
    Cheng, K. K., Iglesias, M. A., Lam, K. S., et al. (2009). APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metabolism, 9(5), 417–427.PubMedCrossRefGoogle Scholar
  152. 152.
    Wang, C., Mao, X., Wang, L., et al. (2007). Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. The Journal of Biological Chemistry, 282(11), 7991–7996.PubMedCrossRefGoogle Scholar
  153. 153.
    Pajvani, U. B., Hawkins, M., Combs, T. P., et al. (2004). Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. The Journal of Biological Chemistry, 279(13), 12152–12162.PubMedCrossRefGoogle Scholar
  154. 154.
    Luo, J. D., Zhang, G. S., & Chen, M. S. (2005). Leptin and cardiovascular diseases. Timely Topics in Medicine. Cardiovascular Diseases, 9, E34.PubMedGoogle Scholar
  155. 155.
    Rahmouni, K., & Haynes, W. G. (2004). Leptin and the cardiovascular system. Recent Progress in Hormone Research, 59, 225–244.PubMedCrossRefGoogle Scholar
  156. 156.
    Barouch, L. A., Gao, D., Chen, L., et al. (2006). Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circulation Research, 98(1), 119–124.PubMedCrossRefGoogle Scholar
  157. 157.
    Xu, F. P., Chen, M. S., Wang, Y. Z., et al. (2004). Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation, 110(10), 1269–1275.PubMedCrossRefGoogle Scholar
  158. 158.
    Minhas, K. M., Khan, S. A., Raju, S. V., et al. (2005). Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. The Journal of Physiology, 565(pt 2), 463–474.PubMedCrossRefGoogle Scholar
  159. 159.
    Barouch, L. A., Berkowitz, D. E., Harrison, R. W., O’Donnell, C. P., & Hare, J. M. (2003). Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation, 108(6), 754–759.PubMedCrossRefGoogle Scholar
  160. 160.
    Ren, J. (2004). Leptin and hyperleptinemia – from friend to foe for cardiovascular function. The Journal of Endocrinology, 181(1), 1–10.PubMedCrossRefGoogle Scholar
  161. 161.
    Mark, A. L., Shaffer, R. A., Correia, M. L., Morgan, D. A., Sigmund, C. D., & Haynes, W. G. (1999). Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. Journal of Hypertension, 17(12 pt 2), 1949–1953.PubMedCrossRefGoogle Scholar
  162. 162.
    Correia, M. L., & Rahmouni, K. (2006). Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome. Diabetes, Obesity & Metabolism, 8(6), 603–610.CrossRefGoogle Scholar
  163. 163.
    Martin, S. S., Qasim, A., & Reilly, M. P. (2008). Leptin resistance: A possible interface of inflammation and metabolism in obesity-related cardiovascular disease. Journal of the American College of Cardiology, 52(15), 1201–1210.PubMedCrossRefGoogle Scholar
  164. 164.
    Hintz, K. K., Aberle, N. S., & Ren, J. (2003). Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes. International Journal of Obesity and Related Metabolic Disorders, 27(10), 1196–1203.PubMedCrossRefGoogle Scholar
  165. 165.
    Smith, C. C., Mocanu, M. M., Davidson, S. M., Wynne, A. M., Simpkin, J. C., & Yellon, D. M. (2006). Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. British Journal of Pharmacology, 149(1), 5–13.PubMedCrossRefGoogle Scholar
  166. 166.
    Abe, Y., Ono, K., Kawamura, T., et al. (2007). Leptin induces elongation of cardiac myocyte and causes eccentric left ventricular dilatation with compensation. American Journal of Physiology. Heart and Circulatory Physiology, 292, H2387–H2396.PubMedCrossRefGoogle Scholar
  167. 167.
    Sweeney, G. (2002). Leptin signaling. Cellular Signalling, 14(8), 655–663.PubMedCrossRefGoogle Scholar
  168. 168.
    Ahima, R. S., & Flier, J. S. (2000). Leptin. Annual Review of Physiology, 62, 413–437.PubMedCrossRefGoogle Scholar
  169. 169.
    Schulze, P. C., & Kratzsch, J. (2005). Leptin as a new diagnostic tool in chronic heart failure. Clinica Chimica Acta, 362(1–2), 1–11.CrossRefGoogle Scholar
  170. 170.
    Giganti, A., & Friederich, E. (2003). The actin cytoskeleton as a therapeutic target: State of the art and future directions. Progress in Cell Cycle Research, 5, 511–525.PubMedGoogle Scholar
  171. 171.
    Lin, G., Craig, G. P., Zhang, L., et al. (2007). Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats. Cardiovascular Research, 75(1), 51–58.PubMedCrossRefGoogle Scholar
  172. 172.
    Zeidan, A., Javadov, S., & Karmazyn, M. (2006). Essential role of Rho/ROCK-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovascular Research, 72(1), 101–111.PubMedCrossRefGoogle Scholar
  173. 173.
    Schram, K., Wong, M. M., Palanivel, R., No, E. K., Dixon, I. M., & Sweeney, G. (2008). Increased expression and cell surface localization of MT1-MMP plays a role in stimulation of MMP-2 activity by leptin in neonatal rat cardiac myofibroblasts. Journal of Molecular and Cellular Cardiology, 44(5), 874–881.PubMedCrossRefGoogle Scholar
  174. 174.
    Ren, J., & Ma, H. (2008). Impaired cardiac function in leptin-deficient mice. Current Hypertension Reports, 10(6), 448–453.PubMedCrossRefGoogle Scholar
  175. 175.
    Trivedi, P. S., & Barouch, L. A. (2008). Cardiomyocyte apoptosis in animal models of obesity. Current Hypertension Reports, 10(6), 454–460.PubMedCrossRefGoogle Scholar
  176. 176.
    Yang, R., & Barouch, L. A. (2007). Leptin signaling and obesity: Cardiovascular consequences. Circulation Research, 101(6), 545–559.PubMedCrossRefGoogle Scholar
  177. 177.
    Dong, F., Zhang, X., Yang, X., et al. (2006). Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice. The Journal of Endocrinology, 188(1), 25–36.PubMedCrossRefGoogle Scholar
  178. 178.
    Barouch, L., Gao, D., Chen, L., Miller, K. L., Xy, W., Phan, A. C., et al. (2006). Cardiac myocytes apopotosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circulation Research, 98(1), 119–124.PubMedCrossRefGoogle Scholar
  179. 179.
    Christoffersen, C., Bollano, E., Lindegaard, M. L., et al. (2003). Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology, 144(8), 3483–3490.PubMedCrossRefGoogle Scholar
  180. 180.
    Semeniuk, L. M., Kryski, A. J., & Severson, D. L. (2002). Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. American Journal of Physiology. Heart and Circulatory Physiology, 283(3), H976–H982.PubMedGoogle Scholar
  181. 181.
    Fedak, P. W., Verma, S., Weisel, R. D., & Li, R. K. (2005). Cardiac remodeling and failure from molecules to man (Part II). Cardiovascular Pathology, 14(2), 49–60.PubMedCrossRefGoogle Scholar
  182. 182.
    Miner, E. C., & Miller, W. L. (2006). A look between the cardiomyocytes: The extracellular matrix in heart failure. Mayo Clinic Proceedings, 81(1), 71–76.PubMedCrossRefGoogle Scholar
  183. 183.
    Felkin, L. E., Birks, E. J., George, R., et al. (2006). A quantitative gene expression profile of matrix metalloproteinases (MMPS) and their inhibitors (TIMPS) in the myocardium of patients with deteriorating heart failure requiring left ventricular assist device support. The Journal of Heart and Lung Transplantation, 25(12), 1413–1419.PubMedCrossRefGoogle Scholar
  184. 184.
    Deschamps, A. M., & Spinale, F. G. (2006). Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation. Cardiovascular Research, 69(3), 666–676.PubMedCrossRefGoogle Scholar
  185. 185.
    Fedak, P., Verma, S., Weisel, R. D., & Li, R. K. (2005). Cardiac remodeling and failure: From molecules to man (Part II). Cardiovascular Pathology, 14(2), 49–60.PubMedCrossRefGoogle Scholar
  186. 186.
    Fedak, P., Verma, S., Weisel, R. D., & Li, R. K. (2005). Cardiac remodeling and failure: From molecules to man (Part I). Cardiovascular Pathology, 14(1), 1–11.PubMedCrossRefGoogle Scholar
  187. 187.
    Graham, H. K., Horn, M., & Trafford, A. W. (2008). Extracellular matrix profiles in the progression to heart failure. European Young Physiologists Symposium Keynote Lecture-Bratislava 2007. Acta Physiology, 194(1), 3–21.CrossRefGoogle Scholar
  188. 188.
    Fazel, S., Chen, L., Weisel, R. D., et al. (2005). Cell transplantation preserves cardiac function after infarction by infarct stabilization: Augmentation by stem cell factor. The Journal of Thoracic and Cardiovascular Surgery, 130(5), 1310.PubMedCrossRefGoogle Scholar
  189. 189.
    Spinale, F. G. (2007). Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiological Reviews, 87(4), 1285–1342.PubMedCrossRefGoogle Scholar
  190. 190.
    Zaman, A. K., Fujii, S., Sawa, H., et al. (2001). Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice. Circulation, 103(25), 3123–3128.PubMedGoogle Scholar
  191. 191.
    Zaman, A. K., Fujii, S., Goto, D., et al. (2004). Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. Journal of Molecular and Cellular Cardiology, 37(2), 525–535.PubMedCrossRefGoogle Scholar
  192. 192.
    Toblli, J. E., Cao, G., DeRosa, G., & Forcada, P. (2005). Reduced cardiac expression of plasminogen activator inhibitor 1 and transforming growth factor beta1 in obese Zucker rats by perindopril. Heart (British Cardiac Society), 91(1), 80–86.CrossRefGoogle Scholar
  193. 193.
    Graham, H. K., & Trafford, A. W. (2007). Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure. American Journal of Physiology. Heart and Circulatory Physiology, 292(3), H1364–H1372.PubMedCrossRefGoogle Scholar
  194. 194.
    Mujumdar, V. S., & Tyagi, S. C. (1999). Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure. Journal of Hypertension, 17(2), 261–270.PubMedCrossRefGoogle Scholar
  195. 195.
    Iwanaga, Y., Aoyama, T., Kihara, Y., Onozawa, Y., Yoneda, T., & Sasayama, S. (2002). Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. Journal of the American College of Cardiology, 39(8), 1384–1391.PubMedCrossRefGoogle Scholar
  196. 196.
    Spinale, F. G., Coker, M. L., Thomas, C. V., Walker, J. D., Mukherjee, R., & Hebbar, L. (1998). Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: Relation to ventricular and myocyte function. Circulation Research, 82(4), 482–495.PubMedGoogle Scholar
  197. 197.
    Spinale, F. G., Zellner, J. L., Johnson, W. S., Eble, D. M., & Munyer, P. D. (1996). Cellular and extracellular remodeling with the development and recovery from tachycardia-induced cardiomyopathy: Changes in fibrillar collagen, myocyte adhesion capacity and proteoglycans. Journal of Molecular and Cellular Cardiology, 28(8), 1591–1608.PubMedCrossRefGoogle Scholar
  198. 198.
    Gilbert, S. J., Wotton, P. R., Tarlton, J. F., Duance, V. C., & Bailey, A. J. (1997). Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy. Cardiovascular Research, 34(2), 377–383.PubMedCrossRefGoogle Scholar
  199. 199.
    Moshal, K. S., Tyagi, N., Moss, V., et al. (2005). Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. Journal of Cellular and Molecular Medicine, 9(3), 704–713.PubMedCrossRefGoogle Scholar
  200. 200.
    Polyakova, V., Hein, S., Kostin, S., Ziegelhoeffer, T., & Schaper, J. (2004). Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression. Journal of the American College of Cardiology, 44(8), 1609–1618.PubMedCrossRefGoogle Scholar
  201. 201.
    Matsumura, S., Iwanaga, S., Mochizuki, S., Okamoto, H., Ogawa, S., & Okada, Y. (2005). Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. The Journal of Clinical Investigation, 115(3), 599–609.PubMedGoogle Scholar
  202. 202.
    Rohde, L. E., Ducharme, A., Arroyo, L. H., et al. (1999). Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation, 99(23), 3063–3070.PubMedGoogle Scholar
  203. 203.
    Troeberg, L., Tanaka, M., Wait, R., Shi, Y. E., Brew, K., & Nagase, H. (2002). E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: Insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A). Biochemistry, 41(50), 15025–15035.PubMedCrossRefGoogle Scholar
  204. 204.
    Schulz, R. (2007). Intracellular targets of matrix metalloproteinase-2 in cardiac disease: Rationale and therapeutic approaches. Annual Review of Pharmacology and Toxicology, 47, 211–242.PubMedCrossRefGoogle Scholar
  205. 205.
    Garg, S., Narula, J., & Chandrashekhar, Y. (2005). Apoptosis and heart failure: Clinical relevance and therapeutic target. Journal of Molecular and Cellular Cardiology, 38(1), 73–79.PubMedCrossRefGoogle Scholar
  206. 206.
    Narula, J., Haider, N., Virmani, R., et al. (1996). Apoptosis in myocytes in end-stage heart failure. The New England Journal of Medicine, 335(16), 1182–1189.PubMedCrossRefGoogle Scholar
  207. 207.
    Olivetti, G., Abbi, R., Quaini, F., et al. (1997). Apoptosis in the failing human heart. The New England Journal of Medicine, 336(16), 1131–1141.PubMedCrossRefGoogle Scholar
  208. 208.
    Todor, A., Sharov, V. G., Tanhehco, E. J., Silverman, N., Bernabei, A., & Sabbah, H. N. (2002). Hypoxia-induced cleavage of caspase-3 and DFF45/ICAD in human failed cardiomyocytes. American Journal of Physiology. Heart and Circulatory Physiology, 283(3), H990–H995.PubMedGoogle Scholar
  209. 209.
    Morissette, M. R., & Rosenzweig, A. (2005). Targeting survival signaling in heart failure. Current Opinion in Pharmacology, 5(2), 165–170.PubMedCrossRefGoogle Scholar
  210. 210.
    Chandrashekhar, Y., Sen, S., Anway, R., Shuros, A., & Anand, I. (2004). Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction. Journal of the American College of Cardiology, 43(2), 295–301.PubMedCrossRefGoogle Scholar
  211. 211.
    Sung, M. M., Schulz, C. G., Wang, W., Sawicki, G., Bautista-Lopez, N. L., & Schulz, R. (2007). Matrix metalloproteinase-2 degrades the cytoskeletal protein alpha-actinin in peroxynitrite mediated myocardial injury. Journal of Molecular and Cellular Cardiology, 43(4), 429–436.PubMedCrossRefGoogle Scholar
  212. 212.
    Communal, C., Sumandea, M., de Tombe, P., Narula, J., Solaro, R. J., & Hajjar, R. J. (2002). Functional consequences of caspase activation in cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America, 99(9), 6252–6256.PubMedCrossRefGoogle Scholar
  213. 213.
    Aasum, E., Hafstad, A. D., Severson, D. L., & Larsen, T. S. (2003). Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes, 52(2), 434–441.PubMedCrossRefGoogle Scholar
  214. 214.
    Sidell, R. J., Cole, M. A., Draper, N. J., Desrois, M., Buckingham, R. E., & Clarke, K. (2002). Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes, 51(4), 1110–1117.PubMedCrossRefGoogle Scholar
  215. 215.
    Yue, T. L., Bao, W., Gu, J. L., et al. (2005). Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes, 54(2), 554–562.PubMedCrossRefGoogle Scholar
  216. 216.
    Johns, D. G., Ao, Z., Eybye, M., et al. (2005). Rosiglitazone protects against ischemia/­reperfusion-induced leukocyte adhesion in the zucker diabetic fatty rat. The Journal of Pharmacology and Experimental Therapeutics, 315(3), 1020–1027.PubMedCrossRefGoogle Scholar
  217. 217.
    Hoshida, S., Yamashita, N., Otsu, K., Kuzuya, T., & Hori, M. (2000). Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats. American Journal of Physiology. Heart and Circulatory Physiology, 278(1), H256–H262.PubMedGoogle Scholar
  218. 218.
    Greer, J. J., Ware, D. P., & Lefer, D. J. (2006). Myocardial infarction and heart failure in the db/db diabetic mouse. American Journal of Physiology. Heart and Circulatory Physiology, 290(1), H146–H153.PubMedCrossRefGoogle Scholar
  219. 219.
    Thakker, G. D., Frangogiannis, N. G., Bujak, M., et al. (2006). Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction. American Journal of Physiology. Heart and Circulatory Physiology, 291(5), H2504–H2514.PubMedCrossRefGoogle Scholar
  220. 220.
    Jones, S. P., Girod, W. G., Granger, D. N., Palazzo, A. J., & Lefer, D. J. (1999). Reperfusion injury is not affected by blockade of P-selectin in the diabetic mouse heart. The American Journal of Physiology, 277(2 pt 2), H763–H769.PubMedGoogle Scholar
  221. 221.
    Parish, R. C., & Evans, J. D. (2008). Inflammation in chronic heart failure. The Annals of Pharmacotherapy, 42(7), 1002–1016.PubMedCrossRefGoogle Scholar
  222. 222.
    Yndestad, A., Damas, J. K., Oie, E., Ueland, T., Gullestad, L., & Aukrust, P. (2006). Systemic inflammation in heart failure–the whys and wherefores. Heart Failure Reviews, 11(1), 83–92.PubMedCrossRefGoogle Scholar
  223. 223.
    Yndestad, A., Damas, J. K., Oie, E., Ueland, T., Gullestad, L., & Aukrust, P. (2007). Role of inflammation in the progression of heart failure. Current Cardiology Reports, 9(3), 236–241.PubMedCrossRefGoogle Scholar
  224. 224.
    Mueller, C., Laule-Kilian, K., Christ, A., Brunner-La Rocca, H. P., & Perruchoud, A. P. (2006). Inflammation and long-term mortality in acute congestive heart failure. American Heart Journal, 151(4), 845–850.PubMedCrossRefGoogle Scholar
  225. 225.
    Ingelsson, E., Arnlov, J., Sundstrom, J., & Lind, L. (2005). Inflammation, as measured by the erythrocyte sedimentation rate, is an independent predictor for the development of heart failure. Journal of the American College of Cardiology, 45(11), 1802–1806.PubMedCrossRefGoogle Scholar
  226. 226.
    Bozkurt, B., Mann, D. L., & Deswal, A. (2010). Biomarkers of inflammation in heart failure. Heart Fail Rev , 15(4):331-41.Google Scholar
  227. 227.
    Gullestad, L., Kjekshus, J., Damas, J. K., Ueland, T., Yndestad, A., & Aukrust, P. (2005). Agents targeting inflammation in heart failure. Expert Opinion on Investigational Drugs, 14(5), 557–566.PubMedCrossRefGoogle Scholar
  228. 228.
    von Eynatten, M., Hamann, A., Twardella, D., Nawroth, P. P., Brenner, H., & Rothenbacher, D. (2006). Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease. Clinical Chemistry, 52(5), 853–859.PubMedCrossRefGoogle Scholar
  229. 229.
    Hilfiker-Kleiner, D., Landmesser, U., & Drexler, H. (2006). Molecular mechanisms in heart failure focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. Journal of the American College of Cardiology, 48(9 suppl), A56–A66.CrossRefGoogle Scholar
  230. 230.
    Aukrust, P., Yndestad, A., Damas, J. K., & Gullestad, L. (2004). Inflammation and chronic heart failure-potential therapeutic role of intravenous immunoglobulin. Autoimmunity Reviews, 3(3), 221–227.PubMedCrossRefGoogle Scholar
  231. 231.
    Chao, W. (2009). Toll-like receptor signaling: A critical modulator of cell survival and ischemic injury in the heart. American Journal of Physiology. Heart and Circulatory Physiology, 296(1), H1–H12.PubMedCrossRefGoogle Scholar
  232. 232.
    Satoh, M., Minami, Y., Takahashi, Y., & Nakamura, M. (2008). Immune modulation: Role of the inflammatory cytokine cascade in the failing human heart. Current Heart Failure Reports, 5(2), 69–74.PubMedCrossRefGoogle Scholar
  233. 233.
    Aukrust, P., Gullestad, L., Ueland, T., Damas, J. K., & Yndestad, A. (2005). Inflammatory and anti-inflammatory cytokines in chronic heart failure: Potential therapeutic implications. Annals of Medicine, 37(2), 74–85.PubMedCrossRefGoogle Scholar
  234. 234.
    Heymans, S., Hirsch, E., Anker, S. D., et al. (2009). Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure, 11(2), 119–129.PubMedCrossRefGoogle Scholar
  235. 235.
    Aigner, F., Maier, H. T., Schwelberger, H. G., et al. (2007). Lipocalin-2 regulates the inflammatory­ response during ischemia and reperfusion of the transplanted heart. American Journal of Transplantation, 7(4), 779–788.PubMedCrossRefGoogle Scholar
  236. 236.
    Yndestad, A., Holm, A. M., Muller, F., et al. (2003). Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovascular Research, 60(1), 141–146.PubMedCrossRefGoogle Scholar
  237. 237.
    Madala, M. C., Franklin, B. A., Chen, A. Y., et al. (2008). Obesity and age of first non-ST-segment elevation myocardial infarction. Journal of the American College of Cardiology, 52(12), 979–985.PubMedCrossRefGoogle Scholar
  238. 238.
    Wee, C. C., Girotra, S., Weinstein, A. R., Mittleman, M. A., & Mukamal, K. J. (2008). The relationship between obesity and atherosclerotic progression and prognosis among patients with coronary artery bypass grafts the effect of aggressive statin therapy. Journal of the American College of Cardiology, 52(8), 620–625.PubMedCrossRefGoogle Scholar
  239. 239.
    Nissen, S. E., Nicholls, S. J., Wolski, K., et al. (2008). Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial. JAMA, 299(13), 1547–1560.PubMedCrossRefGoogle Scholar
  240. 240.
    Poirier, P., Giles, T. D., Bray, G. A., et al. (2006). Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of weight loss: An update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation, 113(6), 898–918.PubMedCrossRefGoogle Scholar
  241. 241.
    Klein, S., Burke, L. E., Bray, G. A., et al. (2004). Clinical implications of obesity with specific focus on cardiovascular disease: A statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: Endorsed by the American College of Cardiology Foundation. Circulation, 110(18), 2952–2967.PubMedCrossRefGoogle Scholar
  242. 242.
    Karason, K., Lindroos, A. K., Stenlof, K., & Sjostrom, L. (2000). Relief of cardiorespiratory symptoms and increased physical activity after surgically induced weight loss: Results from the Swedish Obese Subjects study. Archives of Internal Medicine, 160(12), 1797–1802.PubMedCrossRefGoogle Scholar
  243. 243.
    Klein, S., Fontana, L., Young, V. L., et al. (2004). Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. The New England Journal of Medicine, 350(25), 2549–2557.PubMedCrossRefGoogle Scholar
  244. 244.
    Padwal, R. S., & Majumdar, S. R. (2007). Drug treatments for obesity: Orlistat, sibutramine, and rimonabant. Lancet, 369(9555), 71–77.PubMedCrossRefGoogle Scholar
  245. 245.
    Fujioka, K., Seaton, T. B., Rowe, E., et al. (2000). Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes, Obesity & Metabolism, 2(3), 175–187.CrossRefGoogle Scholar
  246. 246.
    Derosa, G., Cicero, A. F., Murdolo, G., et al. (2005). Efficacy and safety comparative evaluation of orlistat and sibutramine treatment in hypertensive obese patients. Diabetes, Obesity & Metabolism, 7(1), 47–55.CrossRefGoogle Scholar
  247. 247.
    Zannad, F., Gille, B., Grentzinger, A., et al. (2002). Effects of sibutramine on ventricular dimensions and heart valves in obese patients during weight reduction. American Heart Journal, 144(3), 508–515.PubMedCrossRefGoogle Scholar
  248. 248.
    Guven, A., Koksal, N., Cetinkaya, A., Sokmen, G., & Ozdemir, R. (2004). Effects of the sibutramine therapy on pulmonary artery pressure in obese patients. Diabetes, Obesity & Metabolism, 6(1), 50–55.CrossRefGoogle Scholar
  249. 249.
    Sjostrom, L., Lindroos, A. K., Peltonen, M., et al. (2004). Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. The New England Journal of Medicine, 351(26), 2683–2693.PubMedCrossRefGoogle Scholar
  250. 250.
    Katzmarzyk, P. T., & Mason, C. (2006). Prevalence of class I, II and III obesity in Canada. CMAJ, 174(2), 156–157.PubMedGoogle Scholar
  251. 251.
    Hensrud, D. D., & Klein, S. (2006). Extreme obesity: A new medical crisis in the United States. Mayo Clinic Proceedings, 81(10 suppl), S5–S10.PubMedGoogle Scholar
  252. 252.
    Adams, T. D., Avelar, E., Cloward, T., et al. (2005). Design and rationale of the Utah obesity study. A study to assess morbidity following gastric bypass surgery. Contemporary Clinical Trials, 26(5), 534–551.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Gary Sweeney
  • Sheldon E. Litwin
  • Evan Dale Abel
    • 1
  1. 1.Division of Endocrinology, Metabolism and DiabetesUniversity of Utah School of MedicineSalt Lake CityUSA

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