CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Ronald M. Witteles, MD* and
Michael B. Fowler, MB, FACC
* Acting Assistant Professor of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Falk CVRC 158, Stanford, California 94305-5406 (Email: witteles{at}stanford.edu).
We thank Dr. Doehner and colleagues for their insightful comments about our recent study (1). We agree that the peripheral effects of insulin resistance are likely also to have a major role in the pathophysiology of heart failure (HF). It is clear that myocardial energy metabolism is strongly influenced by both systemic and local myocardial factors.
As an example of systemic factors, peroxisome proliferator-activated receptor (PPAR)- agonist treatment results in dramatic myocardial metabolic changes (2), despite the fact that there is little to no myocardial expression of the PPAR- receptor (3). Clearly, the effects must be indirect, likely because of improvements in whole-body insulin sensitivity and the resultant decrease in circulating free fatty acids. As an example of local myocardial factors, cardiac-specific overexpression of the GLUT1 receptor prevents HF in mice; this cannot be a systemic effect, as the receptor overexpression is restricted to the heart (4).
In addition to the direct role that insulin resistance plays in leading to cardiomyopathy, a vicious cycle exists in which the hormonal dysregulation and metabolic derangements of HF lead to worsened whole-body insulin resistance, which in turn leads to worsening of the metabolic derangements themselves. Not surprisingly, therefore, worsened whole-body insulin resistance correlates with worsened outcomes in patients with HF (5). Whether treating whole-body insulin resistance will positively affect HF patients remains unclear, though preliminary evidence (6–8) favors using metabolic-modulating agents, which specifically result in increased myocardial glucose metabolism. Fortunately, most systemic treatments with metabolic modulators and/or insulin-sensitizing agents will serve the best of both worlds: affecting whole-body insulin sensitivity as well as cardiac metabolism.
We share the enthusiasm of Dr. Doehner and colleagues in urging further mechanistic/treatment studies to better define optimal treatment of the insulin-resistant cardiomyopathy population.
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1. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy: clinical evidence, mechanisms, and treatment options J Am Coll Cardiol 2008;51:93-102.[Abstract/Free Full Text]2. Hallsten K, Virtanen KA, Lonnqvist F, et al. Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone Diabet Med 2004;21:1280-1287.[CrossRef][Web of Science][Medline] 3. Gilde AJ, van der Lee KA, Willemsen PH, et al. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism Circ Res 2003;92:518-524.[Abstract/Free Full Text] 4. Liao R, Jain M, Cui L, et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice Circulation 2002;106:2125-2131.[Abstract/Free Full Text] 5. Paolisso G, Tagliamonte MR, Rizzo MR, et al. Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease Am J Cardiol 1999;83:1338-1344.[CrossRef][Web of Science][Medline] 6. Aussedat J, Ray A, Kay L, Verdys M, Harpey C, Rossi A. Improvement of long-term preservation of isolated arrested rat heart: beneficial effect of the antiischemic agent trimetazidine J Cardiovasc Pharmacol 1993;21:128-135.[Web of Science][Medline] 7. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure J Am Coll Cardiol 2006;48:992-998.[Abstract/Free Full Text] 8. Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment Circulation 2005;112:3280-3288.[Abstract/Free Full Text]
Related Article
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Insulin Resistance in Chronic Heart Failure
- Wolfram Doehner, Stephan von Haehling, and Stefan D. Anker
J. Am. Coll. Cardiol. 2008 52: 239.
[Full Text]
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