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Myocardial energetics in cardiac hypertrophy
1Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. zhang047@tc.umn.edu
Insights
Abnormal heart energy metabolism is linked to cardiac hypertrophy and heart failure. Further research is needed to understand if impaired ATP production causes these conditions.
Area of Science:
- Cardiology
- Biochemistry
- Physiology
Background:
- Cardiac hypertrophy and postinfarction left ventricular (LV) remodeling are associated with abnormal myocardial energetics.
- These energy metabolism abnormalities are most severe in hearts with congestive heart failure (CHF).
- The precise mechanisms linking altered myocardial energetics to cardiac dysfunction and progression to CHF remain unclear.
Purpose of the Study:
- To review studies on the functional and energetic consequences of cardiac hypertrophy and LV remodeling in porcine models.
- To explore the mechanisms of abnormal high-energy phosphate (HEP) metabolism in cardiac hypertrophy and CHF.
- To discuss the role of ATP synthesis and transport limitations in the pathogenesis of LV remodeling and failure.
Main Methods:
- Review of studies utilizing kinetic and thermodynamic models of myocardial energy metabolism.
- Analysis of myocardial steady-state levels of high- and low-energy phosphates (e.g., ATP, ADP, Pi).
- Examination of factors influencing reaction velocity, including enzyme activity, substrate/product concentrations, and Michaelis-Menten constants.
Main Results:
- Significant alterations in myocardial phosphocreatine (PCr), ATP, and ADP concentrations are observed in hearts with LV remodeling and CHF.
- Changes in myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are noted.
- A direct causal relationship between these metabolic alterations and the progression of cardiac dysfunction has not been definitively established.
Conclusions:
- Abnormal myocardial energetics are a hallmark of cardiac hypertrophy and heart failure.
- Further investigation, potentially using gene manipulation in animal models, is required to elucidate the role of ATP synthetic or transport capacity limitations in the pathogenesis of heart failure.
Abstract:
1. This review is presented with the intent of illustrating the representative studies of functional and myocardial energetic consequences of hearts with postinfarction left ventricular (LV) remodelling or with concentric hypertrophy and diastolic LV dysfunction in porcine models. 2. Both eccentric and concentric cardiac hypertrophy are associated with the abnormal myocardial energetics that are most severe in hearts with congestive heart failure (CHF). Presently, these abnormalities cannot be satisfactorily explained to be the cause(s) of the dysfunction of failing hearts or cause the progress from compensated cardiac hypertrophy to CHF. 3. Mechanisms governing abnormal myocardial high-energy phosphate (HEP) metabolism in hearts with cardiac hypertrophy and CHF are unclear. Myocardial energy metabolism studies use both kinetic and thermodynamic models. The thermodynamic studies examine the myocardial steady state levels of high- and low-energy phosphate, which indicate myocardial energy state or phosphorylation potential that is defined by the ratio of [ATP]/([ADP][Pi]). The kinetics studies examine the reaction velocity that is regulated by: (i) quantity and activity of the key enzymes; (ii) the concentrations of all the substrates and products; and (iii) the Michaelis-Menten constants of each substrate of the reaction. 4. Significant alterations in myocardial concentrations of phosphocreatine (PCr), ATP and ADP, myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are found in hearts with postinfarction LV remodelling and CHF. However, to define a causal relationship is a different matter. 5. Future studies of animal models of LV hypertrophy or heart failure using gene manipulation may provide additional insights to answer the persisting question of whether limitations of ATP synthetic or transport capacities contribute to the pathogenesis of LV remodelling or failure.