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QUARTERLY FOCUS ISSUE: HEART FAILURE: STATE-OF-THE-ART PAPER

The Adrenergic-Fatty Acid Load in Heart Failure

Lionel H. Opie, MD, DPhil, DSc^_*,_* and Juhani Knuuti, MD, PhD

^_* Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa
Turku PET Centre, University of Turku, Turku, Finland

Manuscript received April 28, 2009; revised manuscript received July 15, 2009, accepted July 27, 2009.

^_* Reprint requests and correspondence: Dr. Lionel H. Opie, Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, 7935 Observatory, South Africa (Email: Lionel.Opie{at}uct.ac.za).

The hypothesis proposed is that heart failure (HF) is associated with a reactive hyperadrenergic state that increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. We propose that increased FFA-induced mitochondrial uncoupling and substantial oxygen wastage is closely associated with the generation of reactive oxygen species, inflammatory markers, and the development of insulin resistance. The therapeutic aims of metabolic therapy are as follows: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are achieved, respectively, by the following: 1) the use of beta-adrenergic blockade and all measures that relieve the mechanical load on the heart; 2) the use of drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline), although without clinical evidence that the heart is their major site of action in HF; and 3) increase of the transport of glucose into the cells by exercise and metformin. Of these measures, only data concerning the reduction of mortality as the result of exercise are available. Of all the other measures, there are substantial positive data on the use of trimetazidine that demonstrate metabolic and clinical benefit with almost no side effects, but data from a large outcome trial are lacking. Our data suggest a major extracardiac site of trimetazidine action. Ranolazine, which inhibits the late sodium inward current, requires testing in human HF. Insulin to reduce hyperglycemia and FFAs is untested in HF, with incretins such as glucagon-like peptide-1 on the horizon. Other future therapies may include malonyl-coenzyme A regulators to inhibit fatty acid oxidation, fish oil omega-3, and activators of protein kinase C-epsilon.

Key Words: adrenergic • fatty acids • oxygen wastage

Abbreviations and Acronyms   AMPK = adenosine monophosphate-activated kinase   ATP = adenosine triphosphate   CoA = coenzyme A   FAO = free fatty acid oxidation   FFA = free fatty acid   GLUT = glucose transporter   HF = heart failure   LV = left ventricular   NE = norepinephrine   PKC = protein kinase C   PPAR = peroxisome proliferator-activated receptor   ROS = reactive oxygen species   TMZ = trimetazidine   UCP = uncoupling protein

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J. Am. Coll. Cardiol. 2009 54: A26. [Full Text] [PDF]