Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism
Paul F. Kantor, MBBCh*,
Murray A. Robertson, MD, PhD ,
James Y. Coe, MD, MBChB and
Gary D. Lopaschuk, PhD*
* Cardiovascular Research Group, University of Alberta, Edmonton, Canada
Division of Pediatric Cardiology, University of Alberta, Edmonton, Canada
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Figure 1 Changes in energy balance and fatty acid oxidation in the newborn heart. Dominant pathways are indicated by darker typeface, and bold arrows; those indicated in gray are diminished. The inner mitochondrial membrane has been omitted for clarity. ACC = acetyl CoA carboxylase; AMP = adenosine monophosphate; AMPK = 5'-AMP–activated protein kinase; ATP = adenosine triphosphate; CAT = carnitine acyl transferase; CoA = coenzyme A; CoASH = uncombined CoA; CPT 1 = carnitine palmitoyl transferase-1; Pi = inorganic phosphate; TCA = tricarboxylic acid. After birth, a fall in plasma insulin (which is an inhibitor of AMPK expression) levels, together with a decrease in available glucose and lactate substrate lead to a rise in AMPK activity. 5'-Adenosine monophosphate–activated protein kinase phosphorylates and inactivates ACC, resulting in a decrease in malonyl CoA production. Malonyl CoA in turn has a key role in inhibiting the activity of CPT 1, the rate limiting translocating protein which allows acylated long chain fatty acids to enter the mitochondrion. Thus the heart is prepared to utilize fatty acids in the postnatal period, as the level of malonyl CoA, the inhibitor effect of CPT 1, is greatly reduced. With the onset of suckling, a pronounced rise in plasma fatty acid levels, together with these low levels of malonyl CoA, facilitate the influx of fatty acyl CoA into the mitochondrion, and an increase in beta-oxidation occurs. Glycolysis and lactate oxidation, both important pathways in fetal life, decline in their relative contribution as energy sources in the newborn heart.
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Figure 2 Transthoracic echocardiography of control (A) and stented (B) animals displaying gross dilation of the left ventricle, and accompanying left ventricular (LV) wall thickening. (C) Aortic root angiogram confirms the ductal flow from the descending aorta to the pulmonary circulation immediately after stent placement. (D) Explanted specimen showing the juxtaductal aorta and patent (stented) ductus arteriosus. RV = right ventricular.
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Figure 3 Acetyl coenzyme A (CoA) carboxylase activity measured in the cytosolic fraction of left ventricular (LV) and right ventricular (RV) myocardial tissue of newborn pigs, 3-week old control pigs and 3-week old pigs with volume overload hypertrophy. Data are mean ± SEM of 8 to 10 animals. *p < 0.05 (hypertrophy vs. control) (analysis of variance).
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Figure 4 5'-Adenosine monophosphate (5'-AMP)–activated protein kinase activity measured in the cytosolic fraction of left ventricular (LV) and right ventricular (RV) myocardial tissue from newborn pigs, 3-week old control pigs, and 3-week old pigs with volume overload hypertrophy. Data are mean ± SEM of 8 to 10 animals. *p < 0.05 (hypertrophy vs. control) (analysis of variance).
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Figure 5 Expression of acetyl coenzyme A (CoA) carboxylase (ACC) in left ventricular (LV) myocardium of fetal pigs, newborn pigs, 3-week old control pigs and 3-week old pigs with volume overload hypertrophy. Inset shows a representative Western transfer of the 265- and 280-kDa fractions comprising cardiac ACC, probed with peroxidase-labeled Streptavidin. Densitometric analysis is expressed as a percentage of expression in fetal LV myocardium, with the mean in each group determined from 6 to 14 individual hearts each analyzed once. C = control; F = fetal; H = hypertrophy; Nb = newborn. *p < 0.05 (newborn vs. fetal) (analysis of variance).
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Figure 6 Expression of 5'-adenosine monophosphate–activated protein kinase (AMPK) (alpha2 subfraction) in left ventricular myocardium of fetal, newborn, 3-week old control and volume-overloaded animals. Inset shows a representative Western transfer, probed with ovine raised anti-alpha2AMPK antibodies demonstrating the 63-kDa region comprising cardiac AMPK. Densitometric analysis is expressed as a percentage of expression in fetal LV myocardium with the mean in each group determined from 6 to 14 individual hearts each analyzed once. Abbreviations as in Figure 5. *p < 0.05, newborn and control vs. fetal; p < 0.05, hypertrophy vs control (analysis of variance).
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