Cardiac hypertrophy, substrate utilization and metabolic remodelling: cause or effect?
1. Metabolic remodelling in the heart occurs in response to chronically altered workload and substrate availability. Recently, the importance of the metabolic remodelling processes inherent in the hypertrophic growth response (whether primary or secondary) has been recognized. 2. Altered energy demand, shifts in substrate utilization and increased oxidative stress are observed in the hypertrophic heart. Both a shift away from carbohydrate usage (i.e. insulin resistance) and a shift to carbohydrate usage (i.e. pressure loading) are associated with disturbed cardiomyocyte Ca(2+) homeostasis and the development of cardiac hypertrophy. 3. A change in the balance of myocardial usage of fatty acid and glucose substrates must entail a degree of cellular oxidative stress. Increased throughput of any substrate will necessarily involve a regional imbalance between reactive oxygen species (ROS) production and breakdown. 4. In addition to a number of enzyme generators of ROS at various intracellular locations, the heart also contains a number of endogenous anti-oxidants, to restrict steady state ROS levels. The balance between ROS generation and their elimination by endogenous anti-oxidant mechanisms plays a critical role in preserving cardiac function; inappropriate levels of myocardial ROS likely precipitate impairment of myocardial function and abnormalities in cardiac structure. 5. Although different metabolic adaptations are associated with hypertrophic responses of contrasting aetiology, there is accumulating evidence that the joint insults of increased production of ROS and disturbed Ca(2+) handling in the cardiomyocyte comprise the primary lesion. These molecular signals operate together in a feed-forward mode and have the capacity to inflict substantial functional and structural damage on the hypertrophic myocardium.
Ritchie
Rebecca H
RH
Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Delbridge
Lea M D
LM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D005947:Glucose; D002118:Calcium