L12 CVS Cardiac Metabolism

Overview

The heart is an obligate aerobe with an enormous, constant ATP demand that it meets almost entirely through mitochondrial oxidative metabolism, switching flexibly between carbohydrate and lipid fuels depending on substrate availability, hormones, oxygen supply and workload. The lecture works through the pathways that generate this ATP (glycolysis, fatty acid oxidation, the TCA cycle, the electron transport chain), how the fed/fasted and physiological state shifts the fuel mix, how disease states (diabetes, hypertrophy, ischemia, hypoxia, reperfusion) derange this switching at a biochemical level, and how exercise and AMPK activation protect the heart.

Cardiac Energy Demand and Mitochondrial Density

• The heart uses 3.5-5 kg of ATP per day, beats around 100,000 times/day, pumps around 10 tons of blood/day, over a total travel distance of around 20,000 km/day.
• Electron micrographs show cardiac muscle cells packed with densely arranged, cristae-rich mitochondria filling the cytoplasm between myofibril striations, reflecting this high ATP demand.
• Mitochondrial structure: outer membrane (containing porin pores), inner membrane folded into lamellae/cristae, intermembrane space, intracristal/peripheral space, matrix (containing matrix granules, mitochondrial DNA and ribosomes), and ATP synthase and the electron transport chain complexes embedded in the inner membrane/cristae.

Fuel Selection Across Physiological States

• Multiple fuels are available to the heart, and the balance used shifts along a carbohydrate-lipid continuum depending on the state:
  • Fetal and neonatal heart (low pO2): most carbohydrate-dependent.
  • Exercise, hypoxia, hypertrophy, heart failure: shifted toward carbohydrate use relative to the normal adult.
  • Adult (resting, fed) heart: roughly 70% lipid / 30% carbohydrate (“70/30”).
  • Fasting or diabetes: most lipid-dependent.
• In a given situation, fuel utilisation is modulated by: substrate availability (fed vs fasted), hormones, oxygen availability, and workload (exercise vs rest).

ATP-Generating Pathways

• Carbohydrate route: glycogen ↔ glucose → glucose-6-phosphate (glycolysis consumes 2 ADP to yield 2 ATP) → pyruvate (in equilibrium with lactate) → Acetyl CoA (via PDH); amino acids can also feed into this pathway.
• Glucose uptake: glucose enters via the insulin-dependent GLUT4 transporter (translocates to the membrane in response to insulin) and the insulin-independent GLUT1 transporter.
• Fatty acid route: free fatty acids → fatty acyl CoA → carnitine carrier → intramitochondrial acyl CoA → beta-oxidation spiral, releasing 2H at each of three turns shown → Acetyl CoA.
• Fatty acid uptake and transport: albumin-bound long-chain fatty acids and VLDL (via lipoprotein lipase) enter the cell via CD36 and FATP6 transporters to form fatty acyl CoA. Malonyl CoA (produced from Acetyl CoA by ACC, broken down by MCD) inhibits CPT-1; CPT-1 together with CPT-2 and the carnitine shuttle carries fatty acyl CoA into the mitochondrion, where beta-oxidation converts it to Acetyl CoA. Increased fatty acid oxidation inhibits PDH, suppressing glucose oxidation.
• Convergence: Acetyl CoA from both routes (plus the 2H released during beta-oxidation) enters the TCA cycle (citric acid cycle = CAC = TCA = Krebs cycle), which generates NADH and FADH2. These feed the electron transport chain: NADH donates electrons to Complex I and FADH2 to Complex II; electrons pass via ubiquinone (Q) to Complex III, then via cytochrome c to Complex IV, where $2H^{+}+\frac{1}{2}{O}_2\to H_{2}O$. Complexes I, III and IV pump H+ into the intermembrane space, and the resulting gradient drives ATP synthase (Complex V), converting $ADP+P_i\to ATP$ as H+ flows back into the matrix. This ATP powers contractile work (ionic, electrical and other processes).
• Fatty acid oxidation contributes 60-70% of ATP when fasted, but only about 20% when fed.
• ATP yield to the cytosol: 32 ATP per glucose molecule, 105 ATP per palmitate molecule.

Substrate Use: Fed vs Fasting

• Fed state: carbohydrate contributes 50-75% and lipid 20% of substrate use. Raised insulin and glucose drive glucose into glycogen and into oxidation (50-75% of output); lactate contributes 30% to oxidised output. Free fatty acid supply is decreased because adipose lipolysis is decreased, and malonyl CoA is increased, inhibiting fatty acid uptake (“low uptake”).
• Fasting state: carbohydrate contributes 15-20% and lipid 60-70%. Glucose contributes only 5% and lactate 10% to the oxidised pool, entering via PDH (which is partially inhibited in this state). Free fatty acids are increased (around 60%, via increased adipose lipolysis driven by fasting or diabetes), alongside a triglyceride contribution.

Substrate Use in Disease

State	Metabolic consequence
Diabetes	Strongly increased reliance on FA oxidation, strongly decreased reliance on CHO oxidation
Hypertrophied heart	Decreased FA oxidation, increased glycolysis
Ischemic heart (flow-dependent)	Strongly decreased oxidative metabolism, transiently increased glycolysis
Hypoxic heart	Strongly decreased oxidative metabolism, increased glycolysis
Reperfused heart	Strongly increased reliance on FA oxidation, decreased reliance on CHO oxidation, normal glycolytic rates

Type 2 diabetes: biochemical detail

At the sarcolemma, GLUT4-mediated glucose uptake is decreased despite insulin receptor/IRS1 signalling, while fatty acid uptake (via FAT/CD36/FABPpm) and ketone body uptake (via MCT) are increased, driven by raised circulating fatty acids and ketone bodies; PKCθ is activated. Intracellularly, long-chain fatty acyl CoA and triglyceride accumulate; LCFA CoA promotes PPARα signalling, which upregulates CPT1 activity and favours fatty acids entering the mitochondrion. The glycolytic enzymes HK and PFK are decreased, lowering glucose-6-phosphate and pyruvate; PDH activity is decreased and further inhibited by citrate and LCFA CoA, reducing pyruvate’s conversion to Acetyl CoA via glycolysis, while fatty acid-derived Acetyl CoA (via CPT1/beta-oxidation) is increased and preferentially feeds the Krebs cycle and electron transport chain to generate ATP, NADH and FADH2.

Ischemia: biochemical detail

Ischemia initially triggers an AMPK-mediated increase in beta-oxidation with an initial decrease in carbohydrate utilisation, but this cannot be sustained once oxygen delivery becomes insufficient.

Mechanism: ischemia raises AMP, which activates AMPK (AMP kinase). Activated AMPK inhibits acetyl CoA carboxylase, decreasing malonyl CoA, which removes the inhibition of CPT1; CPT1 activity then rises, increasing long-chain fatty acid → acyl CoA → acyl carnitine carrier flux and hence beta-oxidation. Meanwhile glucose → pyruvate → PDH is impaired (PDH decreased), limiting Acetyl CoA generation via this route; the acetyl carnitine carrier (via CAT) shuttles between acetyl CoA pools, and excess acetyl CoA feeds the citrate cycle. However, because the ischemic heart cannot sustain the increased oxygen demand of raised beta-oxidation, acetyl CoA levels can fall and carbohydrate metabolism (especially glycolysis) rises instead. Oxidation of both carbohydrate and free fatty acid suffers under ischemia, depending on flow and demand.

Hypoxia and HIF1α

Hypoxia directly increases glycolysis through the transcription factor HIF1α, which increases expression of glycolytic genes (GLUT1, PFK, LDH) and reduces fatty acid oxidation by reducing PPARα signalling. In normoxia, the enzymes PHD and FIH use O2 to hydroxylate HIF1α; hydroxylated HIF1α is bound by the VHL E3 ligase complex, polyubiquitinated, and sent for proteasomal degradation. In hypoxia, PHD and FIH are inactive due to low O2, so HIF1α escapes hydroxylation and degradation, enters the nucleus, pairs with HIF1β and p300/CBP, and drives transcription of HIF target genes.

Ischemic Heart Disease

• Coronary blood flow is regionally distributed: the right coronary artery and the circumflex and anterior descending branches of the left coronary artery supply the anterior heart; the posterior descending branch of the right coronary artery and the left circumflex branch supply the posterior heart.
• An example coronary angiogram following an inferior MI showed 99% stenosis in a branch (labelled relative to the LAD and LCX), with distal TIMI 3 flow still present beyond the stenosis.
• Metabolic and cellular consequences of myocardial ischemia: decreased ATP, decreased phosphocreatine, altered membrane potential, altered ion distribution (increased intracellular Ca2+ and Na+), cellular swelling, and cellular acidosis.

Exercise, AMPK and Cardioprotection

• Exercise is cardioprotective: it improves cardiovascular conditioning and maximal cardiac output, improves stroke volume and contractility, and improves insulin sensitivity and glucose utilisation. Activation of AMPK accounts for a significant part of this benefit, though other contributors also exist.
• Endurance training enhances glucose tolerance (data from Clinical Case Tutorial 18: Diabetes): on an oral glucose tolerance test, a diabetic patient (Mr T.P.) showed the highest glucose peak (~9.7 mmol/L at 60 min) and the highest, most sustained insulin response (~145 μU/mL); controls showed an intermediate glucose peak (~6.7 mmol/L at 30 min) and insulin response (~95 μU/mL); athletes showed the lowest glucose peak (~5.9 mmol/L at 30 min) with the lowest, flattest insulin response (~30 μU/mL peak), illustrating improved insulin sensitivity with training.
• AMPK activation and effects (Storey, Functional Metabolism): a raised AMP/ATP ratio, exercise and cellular stress activate AMPKK (itself also activated by adiponectin and metformin) and inhibit PP2C; both converge to phosphorylate and activate AMPK. In muscle, activated AMPK: increases glycolysis and glucose uptake (via HK, GLUT4, UCP3); decreases SREBP-1, reducing lipogenic gene expression and cholesterol synthesis (via inhibition of HMG-CoA reductase); activates ACC (by phosphorylation), decreasing fatty acid synthesis; and activates MCD (by phosphorylation), increasing fat oxidation.
• Sequence of exercise-induced cardioprotection against infarction (Frasier et al.): triggers (adenosine, opioids, cytokines) act at the cell membrane via receptors, signalling through PKCε and AMPK (which is also fed by adenylate kinase converting 2 ADP to ATP + AMP within the myofibril). These converge on increased transcription factor activity and possible mitochondrial ROS production, with downstream effects on KATP/GLUT channel trafficking (via GLUT, SUR2a and Kir6.2). Roughly 24 hours later, this produces the end-effectors: increased sarcolemmal KATP channels, increased MnSOD, increased resistance to apoptosis, and decreased mitochondrial Ca2+ overload, together producing cardioprotection.

Self-test

1. State the approximate carbohydrate/lipid contribution to ATP production in the resting adult heart, and describe how this balance shifts in the fetal/neonatal heart and in fasting or diabetes.
2. List the four factors that modulate cardiac fuel utilisation in a given situation.
3. Describe the steps by which a long-chain fatty acid is taken up by a cardiomyocyte and converted to Acetyl CoA, naming the key transporters and the regulatory enzyme controlling mitochondrial entry.
4. Explain how malonyl CoA and CPT-1 regulate the rate of fatty acid oxidation.
5. Describe the steps of the electron transport chain from NADH/FADH2 to ATP synthesis, including which complexes accept electrons from each and which pump protons.
6. State the ATP yield to the cytosol per molecule of glucose and per molecule of palmitate.
7. Distinguish the fed-state substrate flux pattern of the heart from the fasting-state pattern, in terms of CHO%/lipid% contribution and the direction of change in insulin, free fatty acids and malonyl CoA.
8. List the five disease/physiological states covered in the substrate-use-in-disease table, with the metabolic consequence given for each.
9. Describe the biochemical mechanism by which AMPK increases fatty acid oxidation in early ischemia, and explain why this response cannot be sustained.
10. Explain how HIF1α is regulated differently in normoxia versus hypoxia, and describe its downstream metabolic effect on the cardiomyocyte.
11. Distinguish the metabolic derangement of the type 2 diabetic heart from the normal fed heart at the level of glucose and fatty acid handling, including the role of PDH.
12. List the six metabolic/cellular consequences of myocardial ischemia given in the lecture.
13. A sedentary patient begins a regular endurance exercise programme. Predict how their oral glucose tolerance test and insulin response curve would change relative to before training, and explain the underlying mechanism.
14. Describe the sequence of events, from initial trigger to end-effector, by which exercise protects the heart against infarction.
15. Explain how AMPK, malonyl CoA/CPT1, PDH and HIF1α act as shared regulatory points linking the fuel-switching seen in hypertrophy, hypoxia and ischemia.

Answers

Reveal answers

1. The resting adult heart derives energy roughly 70% from lipid and 30% from carbohydrate (“70/30”). The fetal/neonatal heart (low pO2) is the most carbohydrate-dependent state on the spectrum, while fasting and diabetes push the heart furthest toward lipid dependence.
2. Substrate availability (fed vs fasted), hormones, oxygen availability, and workload (exercise vs rest).
3. Albumin-bound long-chain fatty acids and VLDL (via lipoprotein lipase) enter via the CD36 and FATP6 transporters to form fatty acyl CoA. This is carried into the mitochondrion by CPT-1 (regulated, see Q4) together with CPT-2 and the carnitine shuttle; inside the mitochondrion, beta-oxidation converts fatty acyl CoA to Acetyl CoA.
4. Malonyl CoA (produced from Acetyl CoA by ACC, and broken down by MCD) inhibits CPT-1. When malonyl CoA is low, CPT-1 inhibition is relieved and more fatty acyl CoA is shuttled into the mitochondrion for beta-oxidation; when malonyl CoA is high, CPT-1 is inhibited and fatty acid oxidation is reduced.
5. NADH donates electrons to Complex I; FADH2 donates electrons to Complex II. Electrons from both pass via ubiquinone (Q) to Complex III, then via cytochrome c to Complex IV, where they combine with H+ and O2 to form water ($2H^{+}+\frac{1}{2}{O}_2\to H_{2}O$). Complexes I, III and IV pump H+ into the intermembrane space, and the resulting proton gradient drives ATP synthase (Complex V) to convert ADP + Pi to ATP as H+ flows back into the matrix.
6. 32 ATP per glucose molecule; 105 ATP per palmitate molecule.
7. Fed: CHO contributes 50-75%, lipid 20%; insulin and glucose are raised, free fatty acids are decreased (reduced adipose lipolysis) and malonyl CoA is increased (inhibiting fatty acid uptake). Fasting: CHO contributes only 15-20%, lipid 60-70%; free fatty acids are increased (raised adipose lipolysis) and malonyl CoA/insulin fall, permitting fatty acid uptake and oxidation.
8. Diabetes: strongly increased FA oxidation reliance, strongly decreased CHO oxidation reliance. Hypertrophied heart: decreased FA oxidation, increased glycolysis. Ischemic heart (flow-dependent): strongly decreased oxidative metabolism, transiently increased glycolysis. Hypoxic heart: strongly decreased oxidative metabolism, increased glycolysis. Reperfused heart: strongly increased FA oxidation reliance, decreased CHO oxidation reliance, normal glycolytic rates.
9. Rising AMP during ischemia activates AMPK, which inhibits acetyl CoA carboxylase, lowering malonyl CoA; this relieves inhibition of CPT1, increasing fatty acid entry into the mitochondrion and beta-oxidation. However, because the ischemic heart lacks sufficient oxygen to sustain this increased oxidative flux, acetyl CoA levels can fall and the heart shifts back toward carbohydrate metabolism, especially glycolysis.
10. In normoxia, PHD and FIH use O2 to hydroxylate HIF1α, which is then bound by the VHL E3 ligase complex, polyubiquitinated and degraded by the proteasome. In hypoxia, PHD and FIH are inactive due to low O2, so HIF1α escapes hydroxylation and degradation, enters the nucleus, pairs with HIF1β and p300/CBP, and drives transcription of target genes (GLUT1, PFK, LDH), increasing glycolysis and reducing FA oxidation via reduced PPARα signalling.
11. In the type 2 diabetic heart, GLUT4-mediated glucose uptake is decreased and glycolytic enzymes HK/PFK are decreased, lowering glucose-6-phosphate and pyruvate; PDH activity is decreased and further inhibited by citrate/LCFA CoA, limiting Acetyl CoA formation from glucose. Meanwhile fatty acid and ketone body uptake are increased, LCFA CoA and TAG accumulate, and PPARα-driven CPT1 activity is increased, so fatty acid-derived Acetyl CoA preferentially feeds the Krebs cycle instead. This contrasts with the normal fed heart, where glucose uptake and PDH activity are relatively higher and fatty acid uptake is suppressed by increased malonyl CoA.
12. Decreased ATP, decreased phosphocreatine, altered membrane potential, altered ion distribution (increased intracellular Ca2+/Na+), cellular swelling, and cellular acidosis.
13. Glucose tolerance would improve: blood glucose would rise less and return to baseline faster on the OGTT, and the insulin response would become lower and flatter, resembling the athlete curve rather than the untrained/diabetic curve. This reflects AMPK-mediated improvements in insulin sensitivity and glucose utilisation induced by exercise training.
14. Triggers (adenosine, opioids, cytokines) act via membrane receptors, signalling through PKCε and AMPK (also fed by adenylate kinase). This increases transcription factor activity and possibly mitochondrial ROS, altering KATP/GLUT channel trafficking. About 24 hours later this produces the end-effectors: increased sarcolemmal KATP channels, increased MnSOD, increased resistance to apoptosis and decreased mitochondrial Ca2+ overload, together conferring cardioprotection.
15. AMPK (activated by a rising AMP/ATP ratio in ischemia and exercise) lowers malonyl CoA and relieves CPT1 inhibition, promoting fatty acid oxidation; PDH is inhibited in ischemia and diabetes, limiting glucose-derived Acetyl CoA; and HIF1α, stabilised by hypoxia, transcriptionally boosts glycolytic enzymes while suppressing PPARα-driven fatty acid oxidation. Together these regulatory points explain why hypertrophy, hypoxia and (initially oxygen-limited) ischemia all show a shift away from fatty acid oxidation and toward glycolysis, even though the initial AMPK response favours fatty acid oxidation before oxygen limitation forces the switch back to carbohydrate.