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 |
|
Related Article
-
Inside This Issue
J. Am. Coll. Cardiol. 2009 54: A26.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
H. Ardehali, H. N. Sabbah, M. A. Burke, S. Sarma, P. P. Liu, J. G. F. Cleland, A. Maggioni, G. C. Fonarow, E. D. Abel, U. Campia, et al.
Targeting myocardial substrate metabolism in heart failure: potential for new therapies
Eur J Heart Fail,
February 1, 2012;
14(2):
120 - 129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. K. M. Steinbusch, J. J. F. P. Luiken, R. Vlasblom, A. Chabowski, N. T. H. Hoebers, W. A. Coumans, I. O. C. M. Vroegrijk, P. J. Voshol, D. M. Ouwens, J. F. C. Glatz, et al.
Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice
Am J Physiol Endocrinol Metab,
October 1, 2011;
301(4):
E618 - E627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Polak, M. Kotrc, Z. Wedellova, A. Jabor, I. Malek, J. Kautzner, L. Kazdova, and V. Melenovsky
Lipolytic Effects of B-Type Natriuretic Peptide1-32 in Adipose Tissue of Heart Failure Patients Compared With Healthy Controls
J. Am. Coll. Cardiol.,
September 6, 2011;
58(11):
1119 - 1125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bucci, R. Borra, K. Nagren, R. Maggio, H. Tuunanen, V. Oikonen, S. Del Ry, T. Viljanen, M. Taittonen, S. Rigazio, et al.
Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities
Am J Physiol Endocrinol Metab,
July 1, 2011;
301(1):
E105 - E112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. D. Abel and T. Doenst
Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy
Cardiovasc Res,
May 1, 2011;
90(2):
234 - 242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Lionetti, W. C. Stanley, and F. A. Recchia
Modulating fatty acid oxidation in heart failure
Cardiovasc Res,
May 1, 2011;
90(2):
202 - 209.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tuunanen and J. Knuuti
Metabolic remodelling in human heart failure
Cardiovasc Res,
May 1, 2011;
90(2):
251 - 257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Des Rosiers, F. Labarthe, S. G. Lloyd, and J. C. Chatham
Cardiac anaplerosis in health and disease: food for thought
Cardiovasc Res,
May 1, 2011;
90(2):
210 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. H. Opie, D. M. Yellon, and B. J. Gersh
Controversies in the cardiovascular management of type 2 diabetes
Heart,
January 1, 2011;
97(1):
6 - 14.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Abozguia, P. Elliott, W. McKenna, T. T. Phan, G. Nallur-Shivu, I. Ahmed, A. R. Maher, K. Kaur, J. Taylor, A. Henning, et al.
Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy
Circulation,
October 19, 2010;
122(16):
1562 - 1569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Halbirk, H. Norrelund, N. Moller, O. Schmitz, L. Gotzsche, R. Nielsen, J. E. Nielsen-Kudsk, S. S. Nielsen, T. T. Nielsen, H. Eiskjaer, et al.
Suppression of circulating free fatty acids with acipimox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function
Am J Physiol Heart Circ Physiol,
October 1, 2010;
299(4):
H1220 - H1225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
