Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism

Kantor, Paul F.; Robertson, Murray; Coe, James Y.; Lopaschuk, Gary D.

doi:10.1016/s0735-1097(99)00063-7

Cited by 49 publications

(38 citation statements)

References 24 publications

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“…Therefore, whether the expressional changes observed can be extrapolated to the left ventricle, and as such, whether these changes occur at the whole heart level remains unknown. Our previous report examining the maturation of fatty acid oxidation in the newborn pig heart (21 d of age) reveals that there is no difference in the content of malonyl CoA, or the activities of either ACC or AMPK in the setting of volume overload hypertrophy between the right and left ventricles (17). However, there are currently no published reports characterizing possible differences in the regional expression of MCD, ACC, and AMPK between the right and left ventricles, as such this issue remains to be addressed.…”

Section: Discussionmentioning

confidence: 97%

“…Changes in ACC activity have been demonstrated to contribute to the maturation of fatty acid oxidation in hearts obtained from both newborn rabbits (1 and 7 d of age) (9,17,28), as well as hearts obtained from newborn pigs (14 d of age) (9,17,28). As we did not observe any age-dependent alteration in the phosphorylation of ACC (indicative of ACC inhibition), the data in this study suggests that in the newborn human heart the synthesis of malonyl CoA and maturation of fatty acid oxidation is not regulated by ACC activity, but is rather regulated by the extent of ACC expression.…”

Section: Discussionmentioning

confidence: 99%

“…1), whereas malonyl CoA decarboxylase (MCD), is primarily responsible for the degradation of cardiac malonyl CoA (16). In newborn rabbit and pig hearts, a decrease in ACC activity and an increase in MCD activity is responsible for the decrease in malonyl CoA and the subsequent increase in fatty acid oxidation after birth (10,16,17). The decrease in ACC activity is attributed to an increase in 5Ј-AMP activated protein kinase (AMPK) activity, which phosphorylates and inhibits ACC (10,17,18) (Fig.…”

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confidence: 99%

“…In the adult, myocardial hypertrophy is associated with dramatic changes in energy metabolism, particularly a switch to a fetal glycolytic phenotype (20 -22). In the newborn pig, myocardial hypertrophy delays the maturation of fatty acid oxidation due to persistently elevated malonyl CoA levels, elevated ACC activity, and decreased AMPK activity (17). This delay in the maturation of fatty acid oxidation may result in the newborn heart relying on glycolysis as a primary source of ATP, a metabolic shift also observed in the hypertrophied adult heart (20 -22).…”

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Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

et al. 2008

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After birth dramatic decreases in cardiac malonylCoA levels result in the rapid maturation of fatty acid oxidation. We have previously demonstrated that the decrease in malonyl CoA is due to increased activity of malonyl CoA decarboxylase (MCD), and decreased activity of acetyl CoA carboxylase (ACC), enzymes which degrade and synthesize malonyl CoA, respectively. Decreased ACC activity corresponds to an increase in the activity of 5Ј-AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. These alterations are delayed by myocardial hypertrophy. As rates of fatty acid oxidation can influence the ability of the heart to withstand an ischemic insult, we examined the expression of MCD, ACC, and AMPK in the newborn human heart. Ventricular biopsies were obtained from infants undergoing cardiac surgery. Immunoblot analysis showed a positive correlation between MCD expression and age. In contrast, a negative correlation in both ACC and AMPK expression and age was observed. All ventricular samples displayed some degree of hypertrophy, however, no differences in enzyme expression were found between moderate and severe hypertrophy. This indicates that increased expression of MCD, and the decreased expression of ACC and AMPK are important regulators of the maturation of fatty acid oxidation in the newborn human heart. T he adult heart has an extremely high energy demand which is met by the oxidation of fatty acids, accounting for 60 -80% of cardiac ATP (ATP) production (1-5). Glycolysis, glucose oxidation, and lactate oxidation are responsible for the remainder of ATP production (2). Interestingly, cardiac energy substrate preference differs between the fetal and neonatal heart. In the fetal heart blood levels of fatty acids are low (6) and the heart has a low circulatory workload and meets its energy demands from glycolysis and lactate oxidation (6 -8). At birth, major cardiovascular changes occur, including a reduction in pulmonary vascular resistance and closure of the ductus arteriosus and foramen ovale. These changes are coupled to an increase in peripheral vascular resistance, and an increased workload on the newborn heart. With circulating substrate and hormonal changes there is a switch in the energy substrate preference of the heart, from glucose and lactate metabolism to fatty acid oxidation (6 -8).Although plasma fatty acid levels rapidly rise to levels seen in the adult immediately after birth (6), newborn rabbit studies have shown that the heart undergoes a transition from oxidizing glucose to oxidizing fatty acids during the 7 d immediately after birth (9,10). The time frame responsible for the maturation of fatty acid oxidation in the human newborn heart is not yet known.The increase in fatty acid oxidation after birth in the newborn rabbit heart is related to dramatic decreases in cardiac malonyl CoA levels (10,11). Malonyl CoA is a potent inhibitor of carnitine palmitoyl transferase-1 (CPT-1), the rate limiting enzyme of mitochondrial fatty acid uptake (12). Acetyl CoA Carboxy...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

et al. 2008

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“…While adult cardiac hypertrophy results in a fetal-like metabolic phenotype (38), the effect(s) of hypertrophy on the neonatal heart, in the midst of a fetal-to-adult transition, is unclear. We previously showed that newborn cardiac hypertrophy in pig hearts delays the maturation of key fatty acid oxidation enzymes (20). However, the effects of hypertrophy on energy metabolic rates in the neonatal heart have not been directly determined.…”

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Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Oka

Lam

Zhang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower ( P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% ( P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.

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Enhanced detection of genetic association of hypertensive heart disease by analysis of latent phenotypes

Flores

Fuentes

et al. 2008

Genetic Epidemiology

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Hypertension and hypertensive heart disease (HHD) are inter-related phenotypes frequently observed with other comorbidities such as diabetes, obesity, and dyslipidemia, which probably reflect the complex gene-gene and/or gene-environment interactions resulting in HHD. The complexity of HHD led us to examine intermediate phenotypes (e.g., echocardiographically-derived measures) for simpler clues to the genetic underpinnings of the disease. We applied the method of independent component analysis to a prospective study of the metabolic predictors of left ventricular hypertrophy and extracted latent traits of HHD from panels of multi-dimensional anthropomorphic, hemodynamic echocardiographic and metabolic data. Based on the latent trait values, classification of subjects into different risk groups for HHD captured meaningful subtypes of the disease as reflected in the distributions of primary clinical indicators. Furthermore, we detected genetic associations of the latent HHD traits with single nucleotide polymorphisms in three candidate genes in the peroxisome proliferator-activated receptors complex, for which no significant association was found with the original clinical indicators of HHD. Consensus analysis of the results from repeated independent component analysis runs showed satisfactory robustness and estimated about 3-4 separate unseen sources for the observed HHD-related outcomes.

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Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism

Abstract: Early onset LV volume overload with hypertrophy results in a delay in the normal maturation of fatty acid oxidation in the newborn heart.

Cited by 49 publications

References 24 publications

Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Enhanced detection of genetic association of hypertensive heart disease by analysis of latent phenotypes

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