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STATE-OF-THE-ART PAPER

Insulin-Resistant Cardiomyopathy

Clinical Evidence, Mechanisms, and Treatment Options

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California.

Manuscript received June 15, 2007; revised manuscript received October 4, 2007, accepted October 22, 2007.

^_* Reprint requests and correspondence: Dr. Ronald M. Witteles, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Falk CVRC, Stanford, California 94305. (Email: witteles{at}stanford.edu).

Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.

Abbreviations and Acronyms   ATP = adenosine triphosphate   DPP = dipeptidyl peptidase   FFA = free fatty acid   GLP = glucagon-like peptide   GLUT = glucose transporter   HF = heart failure   IRCM = insulin-resistant cardiomyopathy   LVEF = left ventricular ejection fraction   PPAR = peroxisome proliferator-activated receptor   TZD = thiazolidinedione   VO 2max = peak oxygen consumption

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