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Am J Physiol Heart Circ Physiol 294: H954-H960, 2008. First published December 14, 2007; doi:10.1152/ajpheart.00557.2007
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Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Lufang Zhou,1 Hazel Huang,2 Celvie L. Yuan,3 Wendy Keung,4 Gary D. Lopaschuk,4 and William C. Stanley2,3,5

Departments of 1Biomedical Engineering, 2Physiology and Biophysics, and 3Nutrition, Case Western Reserve University, Cleveland, Ohio; 4Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada; and 5Division of Cardiology, Department of Medicine, University of Maryland, Baltimore, Maryland

Submitted 13 May 2007 ; accepted in final form 11 December 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 ± 5% vs. 26 ± 5%, P < 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.

acetyl-CoA carboxylase; AMP-activated protein kinase; exercise; fatty acids; heart; mitochondria

ONE OF THE MAJOR DETERMINANTS of myocardial oxygen consumption (MVO2) at a given rate of left ventricular (LV) power generation is mitochondrial substrate selection (23, 44). Under normal resting conditions, fatty acid oxidation is the predominant source of energy for cardiac power generation (60–80%); however, studies in humans (39), dogs (30, 31), and pigs (25) in vivo and in isolated perfused rat (3, 21) and mouse (20) hearts show that, with high rates fatty acid oxidation, the external power is reduced for a given MVO2 (3, 30, 39). In the failing heart or during acute ischemia and/or reperfusion, pharmacological treatment with agents that inhibit myocardial fatty acid oxidation (5, 6) or directly activate carbohydrate oxidation (2, 28, 41) increases LV function without affecting MVO2 and, therefore, improves LV mechanical efficiency (defined as the ratio of external LV power to LV energy expenditure). However, the effect of inhibition of fatty acid oxidation on cardiac function and MVO2 during high cardiac workloads in the healthy heart is not known.

Under normal or ischemic conditions, fatty acid oxidation strongly inhibits the mitochondrial enzyme pyruvate dehydrogenase, which inhibits oxidation of pyruvate and, thus, glucose and lactate uptake and oxidation (35). On the other hand, it has been shown that inhibition of fatty acid oxidation increases pyruvate oxidation and glucose uptake and oxidation at rest and during exercise (26, 41, 45). Fatty acid oxidation in the heart is regulated at the level of the mitochondrial outer membrane by the activity of carnitine palmitoyltransferase I (CPT-I), which is inhibited by malonyl-CoA on the cytosolic side of the enzyme (22, 44). Several studies have shown an inverse relationship between myocardial malonyl-CoA content and fatty acid oxidation (9, 24, 37, 40, 43) and, specifically, that adrenergic stimulation corresponds with a reciprocal increase in fatty acid oxidation and decrease in malonyl-CoA content (13–16, 24, 36). Malonyl-CoA is produced by acetyl-CoA carboxylase (ACC), which is inhibited when phosphorylated at serine 79 by AMP-activated protein kinase (AMPK), whereas AMPK is activated by phosphorylation at threonine 172 (10). We previously found that the reduction in malonyl-CoA content when MVO2 was increased by adrenergic stimulation was not associated with reduced ACC activity or increased AMPK activity in pigs (15); however, tissue was sampled 15–30 min after the initiation of stimulation. It is not known whether there are changes in malonyl-CoA content and activation of ACC and AMPK during the initial minutes of the transition from a low to a high cardiac workload.

The present study evaluated the effect of inhibition of fatty acid oxidation on myocardial LV function and mechanical efficiency. We hypothesized that a switch in myocardial energy substrate use from fatty acid to carbohydrates would increase LV power without affecting oxygen consumption and, therefore, improve myocardial energy efficiency. The second aim of the present study was to determine whether there is a decrease in malonyl-CoA content with an abrupt short-term increase in cardiac workload. We hypothesized that, with 5 min of increased cardiac workload, the myocardial content of malonyl-CoA would decrease due to activation of AMPK and inhibition of ACC, resulting in greater fatty acid oxidation, as previously observed with longer-duration adrenergic stimulation (13–16, 24, 36). Studies were performed in an established open-chest pig model, with animals subjected to an abrupt 5-min increase in cardiac workload induced by simultaneous adrenergic stimulation, parasympathetic blockade, and aortic constriction (24, 38, 48). Oxfenicine, a CPT-I inhibitor, was used to inhibit fatty acid oxidation at the level of transport into the mitochondria. There are numerous approaches to inhibition of fatty acid oxidation (29, 42). In the present study, oxfenicine was selected, because it is devoid of cardiovascular effects under normal conditions (5, 7, 38, 48), has a rapid onset of action (19), and consistently reduces fatty acid oxidation in the pig heart under conditions of increased cardiac workload (24, 38, 48).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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Studies were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996) and with prior approval of the Institutional Animal Care and Use Committee at Case Western Reserve University. Twenty-four domestic pigs of either sex (35.1 ± 1.1 kg body wt) were entered into the study. Data from these studies on the regulation of pyruvate dehydrogenase activity, NADH, glycogen concentration, and basic hemodynamics have been reported separately (48).

Surgical preparation. The surgical preparation has been previously described in detail (24, 38, 48). Briefly, overnight-fasted pigs were sedated with tiletamine-zolazepam (Telazol, 6 mg/kg im), anesthetized with isoflurane by mask (5%), ventilated with 100% O2, and maintained on isoflurane (0.75–1.5%) and ketamine (4 mg·kg–1·min–1 iv) to keep PCO2 and pH in the normal range (>100 mmHg PO2, 35–45 mmHg PCO2, and pH 7.35–7.45). A femoral artery and vein were catheterized for blood sampling and infusion, respectively, and the animals were treated with heparin (200 U/kg bolus followed by 100 U·kg–1·min–1 iv) to prevent clotting and thrombus formation. The heart was exposed via a midline sternotomy, and the left atrium was catheterized for infusion of dobutamine and atropine. A vascular occluder was placed around the ascending aorta and constricted during dobutamine treatment. The cardiac anterior interventricular vein was catheterized for coronary venous blood sampling, and a Doppler ultrasonic flowmeter was placed around the proximal left anterior descending coronary artery (LAD) to record blood flow continuously (Transonics). Four sonomicrometry crystals were placed at midmyocardial depth in the base, apex, and septum of the lateral wall of the LV to continuously measure LV volume with an online commercial system (Sonometrics). A high-fidelity pressure transducer (Millar Instruments) was positioned in the LV, the signal was integrated with LV volume, and the LV pressure-volume loop area was calculated for each beat.

Experimental protocol. Three groups of pigs were studied: 1) an untreated group subjected to increased cardiac workload with dobutamine infusion (DOB, n = 8), 2) an oxfenicine-treated group that was subjected to increased cardiac workload (DOB + OXF, n = 8), and 3) a control group (CON, n = 8) with sham instrumentation and normal cardiac workload. At the beginning of the protocol, [9,10-3H]oleate tracer was infused (40 µCi/h iv) for the measurement of fatty acid oxidation, and oxfenicine treatment was initiated in the DOB + OXF group (30 mg/kg iv bolus oxfenicine followed by an infusion at 30 mg·kg–1·min–1). After a 50-min equilibrium period, animals in the DOB and DOB + OXF groups were subjected to 5 min of increased cardiac work induced by constriction of the aortic cuff sufficient to maintain the peak LV systolic pressure at ~190 mmHg, during simultaneous infusion of dobutamine (100 µg/kg as a bolus followed by 40 µmol·kg–1·min–1) and atropine (2 mg iv bolus) into the left atrium to increase heart rate and contractility. Arterial and venous blood samples for measurement of blood glucose and lactate concentrations were taken before (–5 and –1 min) and during (20, 45, and 75 s and 2, 3, 4, and 5 min) dobutamine treatment, and samples were drawn for plasma free fatty acid and 3H2O concentrations at –5 and –1 min and 3, 4, and 5 min of dobutamine infusion. After 5 min of increased workload, a large (~3 g) punch biopsy was rapidly excised from the LAD bed, immediately freeze clamped on aluminum blocks precooled in liquid nitrogen, and stored at –80°C for later analysis (40). The CON group received the same infusion of [9,10-3H]oleate, arterial and coronary venous blood samples were drawn at 50–60 min, and a myocardial biopsy was immediately obtained as described for the other two groups.

Analytic methods. Arterial and venous O2 saturation and hemoglobin were measured spectrophotometrically with a hemoximeter (A-VOX System, San Antonio, TX), and pH, PCO2, and PO2 were measured in a blood gas analyzer (Nova Biomedical, Waltham, MA). Subsequent biochemical analysis was performed with the investigator blinded to treatment. Blood samples were analyzed for concentrations of glucose and lactate, and plasma was assayed for free fatty acids, [3H]oleate, and 3H2O, as previously described (24, 38). Malonyl-CoA and adenine nucleotide contents were assayed by high-pressure liquid chromatography with UV detection, as previously described (40). All tissue concentrations were expressed per gram wet weight of tissue. The amounts of total and phosphorylated ACC and AMPK were assessed by Western blot using specific antibodies for phosphorylated (serine 79) ACC and phosphorylated (threonine 172) AMPK, as previously described (24, 27). AMPK activity was measured on myocardial homogenates, as previously described (11).

Calculations. Myocardial blood flow was measured from the ultrasonic flowmeter and normalized by dividing by the weight of the heart being perfused by the LAD (34, 40). The net uptakes (µmol·kg–1·min–1) of glucose, lactate, free fatty acids, and oxygen were calculated as arterial-venous difference x blood flow. The rate of exogenous fatty acid oxidation (µmol·g–1·min–1) was calculated as [release of 3H2O (disintegrations per minute per milliliter) x myocardial blood flow] ÷ arterial specific radioactivity of free fatty acids (disintegrations per minute per micromole) (38).

Stroke volume was calculated as LV end-diastolic volume – LV end-systolic volume and cardiac output as stroke volume x heart rate. LV stroke work (J) was calculated as LV pressure (Pa) x volume and LV power (W) as LV stroke work x heart rate (4). LV energy expenditure was calculated from MVO2 with the assumption of 20.2 J/ml of O2 (46) and LV mechanical efficiency as LV power ÷ LV energy expenditure.

Statistical analysis. All hemodynamic variables; rates of free fatty acid, glucose, and lactate uptake; rate of fatty acid oxidation; and tissue metabolite concentrations were compared between resting conditions and increased cardiac work and between DOB and DOB + OXF groups using a one- or two-way ANOVA with Bonferroni's post hoc test for multiple comparisons, as appropriate. Significance was set at P < 0.05, and values are means ± SE.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
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As recently published separately from these experiments, there was a significant increase in heart rate, peak LV pressure, myocardial blood flow, and MVO2 in the DOB and DOB + OXF groups compared with the CON group, whereas there were no differences between the DOB and DOB + OXF groups (48). Cardiac output, stroke work, and LV energy expenditure increased to a similar extent in the DOB and DOB + OXF groups (Table 1). Oxfenicine significantly increased LV power compared with the DOB group (1.72 ± 0.35 vs. 1.28 ± 0.13 W at 45 s and 1.70 ± 0.33 vs. 1.27 ± 0.23 W at 5 min; Fig. 1), despite no effect on LV energy expenditure (Table 1). As a result, a significant improvement in mechanical efficiency was seen in the DOB + OXF group compared with the DOB group (Fig. 1).


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  		Table 1. Hemodynamic responses to short-term increased cardiac power with or without pretreatment with oxfenicine in pigs

 

Figure 1
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  		Fig. 1. Effect of oxfenicine (OXF) on myocardial left ventricular (LV) external power and mechanical efficiency under normal conditions and at 45 s and 5 min of increased cardiac workload. *P < 0.05 vs. baseline (Pre). {dagger}P < 0.05 vs. untreated (dobutamine) at the same time.

 
The arterial concentrations of lactate, glucose, and fatty acids were unchanged over the course of the study, and values were similar among the three experimental groups (data not shown). Increased cardiac work significantly increased glucose and fatty acid uptake in the DOB group (Fig. 2). Pharmacological inhibition of CPT-I suppressed fatty acid uptake in the DOB + OXF group under resting and high cardiac work conditions and further enhanced glucose and lactate uptakes compared with the DOB group (Fig. 2). Myocardial fatty acid oxidation was also suppressed by oxfenicine at rest (14 ± 9 vs. 49 ± 14 nmol·g–1·min–1, P < 0.05) and at a high cardiac workload (Fig. 3). Lactate uptake was decreased in the DOB and DOB + OXF groups in the 1st min of increased cardiac energy expenditure (Fig. 2B), with 4 of 8 pigs in the DOB group and 2 of 8 pigs in the DOB + OXF group showing a net release of lactate at 20 and/or 45 s.


Figure 2
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  		Fig. 2. Net myocardial glucose, lactate, and fatty acid uptake as a function of time for dobutamine (DOB) and DOB + OXF groups at rest and during increased cardiac energy expenditure.

 

Figure 3
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  		Fig. 3. Myocardial malonyl-CoA content and rate of fatty acid oxidation (FAO) at the end of the protocol. *P < 0.05 vs. control (CON).

 
The rate of free fatty acid oxidation was greater in the DOB group than in the DOB + OXF group before (data not shown) and during dobutamine treatment (Fig. 3). Malonyl-CoA concentration was greater in the DOB and DOB + OXF groups than in the CON group (P < 0.05), with no significant difference between these two groups (Fig. 3). Neither the amount of total and phosphorylated ACC nor the ratio of phosphorylated to total ACC was different among the groups (Table 2). Although total AMPK was not different among groups, phosphorylated AMPK and the ratio of phosphorylated to total AMPK was significantly reduced in the DOB group compared with the CON group, whereas the DOB + OXF group was not different from the other two groups.


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  		Table 2. Summary of Western blot assessment of total and phosphorylated AMPK and ACC

 
The cardiac content of AMP and ADP was not different among the groups (Table 3), although ATP content was 20% lower in the DOB and DOB + OXF groups than in the CON group. Interestingly, using a less precise luciferase assay to measure ATP and ADP content on these same samples, we previously showed approximately twice the variability but, again, no differences among the groups (48).


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  		Table 3. Myocardial content of adenine nucleotides

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results of the present study show that, despite the expected increase in myocardial fatty acid oxidation during an acute work jump, there was a paradoxical increase in the tissue content of malonyl-CoA, an established inhibitor of CPT-I and cardiac fatty acid oxidation. In addition, the increase in malonyl-CoA was not due to activation of ACC but did correspond to a decrease in AMPK activation. Oxfenicine had little effect on malonyl-CoA content, despite a 75% decrease in fatty acid oxidation, suggesting that the increase in malonyl-CoA was largely independent of changes in fatty acid oxidation.

The second main finding of the present study is that inhibition of fatty acid oxidation with oxfenicine increases LV power without increasing cardiac energy expenditure. This phenomenon has been observed under conditions of normal workload, during demand-induced ischemia, and with postischemic reperfusion (41, 44). The present study extends this concept to conditions of high workload similar to intense exercise in healthy people and suggests the provocative idea that CPT-I inhibition might improve exercise performance in short-term intense aerobic athletic events. These observations are consistent with previous studies showing that switching from fatty acid to carbohydrate utilization increases LV energy efficiency (2, 3, 20, 21, 25, 30, 32, 39). Compared with fatty acids, carbohydrates are more oxygen efficient (i.e., for a given amount of ATP synthesis, fatty acid oxidation requires 11% more oxygen consumption than pyruvate), and high concentrations of fatty acids have also been shown to uncouple oxidative phosphorylation and increase oxygen utilization in isolated mitochondria and cells (44). Thus the improved efficiency with oxfenicine is likely attributed to greater ATP synthesis per oxygen consumption and/or more effective ATP use by the heart.

We previously observed that 15–30 min of intense adrenergic stimulation in pigs results in a reciprocal decrease in malonyl-CoA content and an increase in fatty acid uptake and oxidation (12, 26, 38), suggesting that less malonyl-CoA inhibition of CPT-I is a primary mechanism for the increase in cardiac fatty acid oxidation observed with physiological stresses such as an acute bout of exercise (15, 16, 24). In contrast, the present investigation found that the rate of fatty acid oxidation increased with dobutamine treatment, despite a 2.5-fold increase in tissue malonyl-CoA concentration (Fig. 3). Since malonyl-CoA exists in cytosol and mitochondria (18, 22, 47), it is possible that the cytosolic malonyl-CoA decreased, while mitochondrial malonyl-CoA increased. Malonyl-CoA inhibits CPT-I on the cytosolic side of the enzyme (22, 44) and is produced in the cytosol and mitochondrial matrix from acetyl-CoA (44). The supply of acetyl-CoA is a major regulator of malonyl-CoA formation (36, 37). The increase in workload in the present experiment caused a 50% increase in the acetyl-CoA concentration (48), presumably due to the rapid stimulation of acetyl-CoA formation by pyruvate dehydrogenase, which may have triggered a selective increase of malonyl-CoA in the mitochondrial matrix. Thus the increased tissue malonyl-CoA content may be due to a specific increase in mitochondrial malonyl-CoA, as previously suggested (24). It is impossible to prove this on the basis of current experimental results, since malonyl-CoA was measured in whole tissue without distinguishing cytosolic and mitochondrial compartments. Future studies should rapidly separate the cytosol and mitochondria and measure these CoAs in these two compartments, although accurate measurements of cytosolic and mitochondrial malonyl-CoA have yet to be made because of technical difficulties with this approach. In any case, the results of the present study clearly indicate that a fall in total tissue malonyl-CoA content is not essential for the increase in cardiac fatty acid oxidation in response to an acute increase in cardiac workload.

Consistent with our previous studies in pigs (15, 24), there was no increase in the activation of AMPK or ACC phosphorylation with increased cardiac workload. Studies in working perfused rat hearts also found no increase of AMPK activity 1 or 15 min after a two- to threefold increase of cardiac power (1). In addition, mice expressing a cardiac-specific dominant-negative AMPK{alpha}2 subunit have normal ATP content and glycogen depletion in response to acute exercise stress, stress echocardiography, and have a normal maximal exercise capacity (33). On the other hand, 10 min of treadmill running in rats approximately doubled AMPK activity and phosphorylated (at threonine 172) AMPK and also doubled the amount of phosphorylated (at serine 79) ACC (8). The results of the present study and our previous work in pigs (15, 24) consistently suggest that AMPK is not activated nor is ACC inhibited in response to high-dose dobutamine and increased aortic pressure in pigs. Although AMPK appears to play a central role in the regulation of cardiac energy metabolism under many conditions (10), the results of the present in vivo study show that, despite a significant decrease in phosphorylated AMPK and AMPK activity (Fig. 4), glucose uptake, glycogenolysis, and fatty acid oxidation are stimulated (Table 1, Figs. 1–3) (48). Taken together, activation of AMPK is not an essential regulatory component of the metabolic response to a step increase in cardiac workload.


Figure 4
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  		Fig. 4. Myocardial phosphorylated AMP-activated protein kinase (P-AMPK)-to-total AMPK ratio as measured by Western blot and myocardial AMPK activity. *P < 0.05 vs. CON.

 
Cardiac ATP content, as measured by high-pressure liquid chromatography, was decreased by 20% under conditions of high workload; however, AMP and ADP were not increased, suggesting a net loss of adenine nucleotides during the 5 min of increased cardiac workload. This is consistent with our previous observation of an increased adenosine production and efflux with dobutamine-induced work in pigs (17). In terms of metabolic regulation, since there was also no increase in AMP or phosphorylated AMPK, it appears that the modest fall in ATP is not a major regulator of the energetic response to an acute jump in workload.

In conclusion, the results of the present study show that inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV contractile power without affecting MVO2 during an acute bout of high workload. This finding suggests a novel approach to improving LV mechanical efficiency at high cardiac workloads with drugs that optimize myocardial energy metabolism and presents the possibility that inhibition of CPT-I could potentially enhance performance in athletic events that are limited by cardiac pump function. In addition, we observed a paradoxical elevation of malonyl-CoA concentration and fatty acid oxidation at high workloads. Lastly, we observed a significant fall in AMPK activation under high energy demand, which further illustrates that activation of AMPK is not an essential component of the metabolic response to the increase in cardiac workload.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health Grants HL-074237 and GM-66309 and by a grant from the Canadian Institutes of Health Research. G. D. Lopaschuk is a Medical Scientist of the Alberta Heritage Foundation for Medical Research.


   ACKNOWLEDGMENTS
 
The authors thank Drs. Monika Duda, Isidore Okere, and Naveen Sharma for assistance with the animal experiments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. C. Stanley, Division of Cardiology, Dept. of Medicine, Univ. of Maryland-Baltimore, 20 Penn St., HSF2, Rm. S022, Baltimore, MD 21201 (e-mail: wstanley{at}medicine.umaryland.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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