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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EWhile several major disturbances contribute to the pathogenesis of congestive heart failure, perhaps the most difficult to understand and the most complex is insulin resistance.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiometabolic Disorder\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHeart Failure\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EWhile several major disturbances contribute to the pathogenesis of congestive heart failure (CHF), perhaps the most difficult to understand and the most complex is insulin resistance.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EIn a study by Ingelsson and colleagues, insulin resistance was found to predict CHF incidence independently of other factors, including diabetes, suggesting that the longstanding association between obesity and CHF may be mediated by insulin resistance [Ingelsson E et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2005]. Meanwhile, a study by Doehner and colleagues found that lower insulin sensitivity was associated with higher mortality in patients with CHF, regardless of weight, suggesting that impaired insulin sensitivity might contribute to CHF disease progression [Doehner W et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2005].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EHowever, the question of whether insulin resistance is a mediator or a marker of heart failure remains.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EInsulin resistance is defined as \u201cthe diminished ability of cells to respond to the action of insulin in transporting glucose from the bloodstream into muscle.\u201d The essence of insulin resistance and its metabolic derangements are an excess in fuel supply (glucose) and a decrease in fuel oxidation.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EIn diabetes, the fuel supply is primarily dysregulated through increased lipolysis, hepatic lipogenesis, hepatic gluconeogenesis, and hepatic glucose production. These processes affect the entire body, as well as the heart, through increased blood glucose and free fatty acid levels.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe heart itself is somewhat insulin-resistant, even in healthy individuals, possibly to protect itself from being flooded with fuel. The evidence for this theory comes from biochemical, physiological, and immunological scientific findings, as well as anecdotal evidence that is found in the so-called \u201cobesity paradox,\u201d in which some individuals who are quite obese do not develop cardiovascular abnormalities [Kolka CM et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2010; Jagasia D et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2001; Srinivasan M et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2005; Hotamisligil GS et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 1995].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EIn one study that supports this theory, an insulin infusion in patients with type 2 diabetes mellitus (T2DM) decreased sinus blood flow rather than increasing perfusion, as typically occurs in normal, nondiabetic individuals [Jagasia D et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2001]. In another study, myocardial blood flow was measured at rest and during adenosine stress under normal metabolic conditions and then during a hyperinsulinemic euglycemic (HE) clamp or hyperinsulinemic hyperglycemic (HH) clamp. Myocardial blood flow at rest and during adenosine administration decreased in the HH group but not in the HE group, suggesting that substrate delivery to the heart had already decreased at the capillary level [Srinivasan M et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2005].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EThus, a dysregulated fuel supply impairs cardiac function.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EYet, it is also known that impaired fatty acid oxidation significantly affects cardiovascular (CV) health, resulting in an extremely lipophilic heart muscle with contractile dysfunction in both animal and human models [Haemmerle G et al. \u003Cem\u003EScience\u003C\/em\u003E 2006; Chiu HC et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2001; Sharma S et al. \u003Cem\u003EFASEB J\u003C\/em\u003E 2004]. Approximately one-third of patients with nonischemic CHF who are referred for cardiac transplantation demonstrate lipotoxicity, particularly if they are obese and\/or diabetic [Sharma S et al. \u003Cem\u003EFASEB J\u003C\/em\u003E 2004].\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ECHF also involves impaired fatty acid oxidation. This is important, since obesity and diabetes increase fatty acid delivery. The resulting intramyocardial lipid overload results in reactive oxygen species, diacylglycerol production, and protein kinase C activity, leading to insulin resistance; ceramide accumulation, which triggers apoptosis; and altered gene expression, resulting in contractile dysfunction [Sharma S et al. \u003Cem\u003EFASEB J\u003C\/em\u003E 2004].\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EIn other words, the impaired fatty acid oxidation appears to occur first, followed by insulin resistance and the resulting glucotoxicity. Thus, it appears that insulin resistance is a marker, not a mediator, of premature death and disability from CHD.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EDiabetic Cardiomyopathy: A Dynamic Phenotype\u003C\/h2\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EThere appear to be two distinct diabetic cardiomyopathy phenotypes: congestive dilated cardiomyopathy with left ventricular (LV) hypertrophy and fibrosis; and a more restrictive cardiomyopathy with normal ejection fraction (EF), a small LV cavity, delayed diastolic relaxation, and increased filling pressure. There may also be an increased ratio of early transmitral velocity to tissue diastolic velocity in this latter type [Marwick. Diabetic Cardiomyopathy In: Crawford MH, DiMarco JP, Paulus WJ, eds. Cardiology, 3\u003Csup\u003Erd\u003C\/sup\u003E Edition. Philadelphia: Elsevier; 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EWhile the two CHF types are distinct, there is evidence that one may evolve from the other. The concept of phenotypic evolution is not new; it was first discussed in the original description of diabetic cardiomyopathy by Zarich and colleagues in 1988, in which high diastolic LV stiffness was identified as the earliest manifestation of diabetes-induced LV dysfunction [Zarich SW et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 1988].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ELongitudinal studies also provide evidence. In the Olmsted County cohort, Lam and colleagues found that patients with CHF and normal EF had more impaired relaxation and increased diastolic stiffness compared with patients without CV disease or those with hypertension only (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Lam CS et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2007]. This suggests that cardiac remodeling continues in the same direction, creating a smaller LV cavity with more pronounced diastolic dysfunction. Lieb and colleagues revealed similar results as part of the Framingham cohort. The greater a participant\u0027s CV risk factors were over time, the greater their increase in LV mass [Lieb W et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/14\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022From Hypertension without HF to HF with Normal EF.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-711236230\u0022 data-figure-caption=\u0022From Hypertension without HF to HF with Normal EF.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/14\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/14\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/9\/14\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11503\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-16\u0022 class=\u0022first-child\u0022\u003EFrom Hypertension without HF to HF with Normal EF.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReprinted from \u003Cem\u003ECircluation\u003C\/em\u003E. Volume 115, Issue 15, Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmstead County Minnesota, CS Lam et al, pages 1982\u20131990, Copyright 2007, with permission from Wolters Kluwer.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EThus, it is clear that a phenotypic evolution is occurring, although they are two very distinct phenotypes and should be considered as separate entities.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EGlucotoxicity or Lipotoxicity: Which is the Culprit in CHF?\u003C\/h2\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EAnother question in diabetic cardiomyopathy is whether glucotoxicity or lipotoxicity is the \u201cculprit\u201d for the underlying pathogenesis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EAs noted earlier, a major problem in the diabetic heart is an overabundance of substrate, whether fatty acids or glucose, and the inability to oxidize it completely. This, in turn, increases oxidative stress, decreases free fatty acid oxidation, increases rapid oxidation, and results in lipid accumulation and associated increases in nitrogenous stress. This stimulates cellular death pathways and can lead to decreases in diastolic function and increased CV morbidity and mortality.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EThe two processes are intertwined, with each affecting the other. For instance, increased fatty acid oxidation further impairs glycolysis. The additional glucose increases oxidative stress.\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EHowever, as noted earlier, fatty acid production increases with insulin resistance prior to any increased glucose output. Thus, it appears that the heart responds first to an increased fatty acid burden. Even when glucotoxicity occurs, the effects are relatively benign, primarily hypertrophy, which is often protective. Lipotoxicity phenotypes include premature death, LV dysfunction, and lipid accumulation, suggesting that fatty acids are a greater \u201cculprit\u201d than glucose [Fulop N et al. \u003Cem\u003EAm J Physiol Cell Physiol\u003C\/em\u003E 2007; Zhou YT et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2000].\u003C\/p\u003E\n         \u003Cp id=\u0022p-22\u0022\u003EIndeed, there is evidence that individuals with T2DM have significantly higher myocardial triglyceride content than healthy volunteers (p\u0026lt;0.05) and significantly impaired diastolic function, suggesting that the presence of a lipotoxic pattern is associated with decline in diastolic function [Rijzewijk LJ et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2008]. In addition, other evidence finds that increases in CV lipids, but not glucose, reduce myocardial energetics, particularly in people with diabetes [Scheuermann-Freestone M et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-23\u0022\u003EThere also appear to be gender differences in the ability to metabolize CV lipids and glucose. Peterson and colleagues demonstrated a progressive increase in fatty acid metabolism in healthy, obese individuals, with higher fatty acid metabolism in women than men, likely due to their greater body fat content. However, while lean men exhibited greater glucose utilization, this dropped precipitously as the men gained weight, with little change in women [Peterson LR et al. \u003Cem\u003EJACC Cardiovasc Imaging\u003C\/em\u003E 2008]. Other evidence that is currently in publication demonstrated that women have a greater decline in diastolic function once they develop diabetes than men, while men experience a very dramatic decline in myocardial glucose utilization with obesity, even as women experience an increase [Peterson et al. \u003Cem\u003EObesity\u003C\/em\u003E. In press]. These findings suggest that women may be more susceptible to the toxic effects of glucose on the heart and that men are more susceptible to lipotoxicity. Indeed, these findings may also help explain gender differences in response to antidiabetic drugs, particularly the insulin sensitizers and metformin [Lyons et al. \u003Cem\u003ECirculation\u003C\/em\u003E. In press].\u003C\/p\u003E\n         \u003Cp id=\u0022p-24\u0022\u003EThe impact of insulin resistance, glucotoxicity, and lipotoxicity on diabetic cardiomyopathy remains quite complex; further elucidation of the intertwined connections between these and other metabolic processes may provide important data for the development of new, much-needed therapeutic approaches.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2010 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/10\/9\/14.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmnw2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmnw2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}