L49: Metabolic Features Of Cardiac Tissue

Question 1

Myocardial ATP production under normal aerobic conditions

Answer 1

• Non-esterified FA —> 60-70% ATP

- glucose: 30% ATP

Question 2

Sources of non-esterified fatty acid

Answer 2

Diet TAG —> chylomicron —> metabolised by LPL on Heparan sulphate proteoglycan (receptor)

Question 3

ATP generation in cardiomyocyte: Glucose vs FA oxidation

Answer 3

Glucose: glycolysis —> pyruvate —> TCA cycle (in mitochondria) —> NADH, FADH2 —> oxidative phosphorylation

Fatty acid: Fatty acyl Co-A —> acyl Co-A —> FA β-oxidation (in mitochodria) —> NADH, FADH2, Acetyl-CoA (can feed into TCA cycle) —> oxidative phosphorylation

Question 4

Long chain fatty acids into mitochondria

Answer 4

***Function of Carnitine: helps transport Fatty acyl CoA into mitochondria

Outer membrane: Fatty acid —(Acyl CoA synthase)—> Fatty acyl CoA

Fatty acyl CoA + Carnitine —(CPT1)—> Fatty acylcarnitine + CoA

Fatty acylcarnitine —(CPT2)—> Fatty acyl CoA —> β oxidation

Question 5

Trasnport of acetyl CoA into mitochondria

Answer 5

Membrane:
Acetyl CoA + Carnitine —(mitochondrial ACT)—> Acetylcarnitine + CoA

Cytosol:
Acetylcarnitine + CoA —(cytosolic ACT)—> Acetyl CoA + Carnitine

Question 7

Function of Malonyl CoA

Answer 7

Inhibit carnitine:palmitoyl transferase (CPT1)

—> inhibit Fatty acyl CoA transport into mitochondria

Question 8

Myocardial ATP production in ischaemia

Answer 8

1. Oxygen deprivation —> increase in NADH and Acetyl CoA (since NADH cannot be fed into oxidative phosphorylation) —> inhibition of β oxidation and PDH
2. Accumulation of fatty acyl CoA and fatty acylcarnitine intermediates
3. Ischaemia
   - Mild ischaemia: glycogenolysis and glycolysis are stimulated (PFK stimulated by ADP and AMP)
   - Severe ischaemia: glycolysis is stopped (lactate and H+ inhibit PFK and Glyceraldehyde-3-phosphate DH) —> no more ATP —> cell injury and death

Question 9

Myocardial metabolism during reperfusion

Answer 9

Oxygen-derived free radicals react with polyunsaturated membrane lipids
—> membrane damage
—> effects amplified by the accumulation of fatty acyl CoA and fatty acylcarnitine intermediates during hypoxia

Therefore

1. cannot do reperfusion too quickly
2. need to suppress FA / promote use of glucose before membrane recover

Question 10

Drugs to ↓ FA metabolism and ↑ glucose metabolism

Answer 10

Reason: glucose oxidation require less oxygen consumption than β oxidation
—> preserve energy metabolism in cells exposed to ischaemia

1. Inhibitors of CPT-1
   - Oxfenicine (IV)
   - ↑ glucose utilisation
   - ↑ lactate and pyruvate production
   - ↑ time to onset of angina during atrial pacing
2. Inhibitor of cytosolic Malonyl CoA decarboxylase
   - ↑ Malonyl CoA to inhibit CPT1
3. Triiodothyronine (T3) administration
   - improved coupling of glycolysis to glucose oxidation
4. Glucose/insulin/potassium (GIK) or Intralipid-heparin infusion
   - compete with HSPG for LPL —> limit FA entry into muscle

Question 11

Fatty acid vs glucose utilisation in cardiomyocyte

Answer 11

Reciprocal regulation in myocytes:

High FA utilisation: Acetyl CoA from β oxidation is preferentially channeled into TCA cycle (instead of glycolysis)
1. NADH from β oxidation inhibits PDH (pyruvate dehydrogenase)
2. Citrate (during TCA cycle in mitochondria) inhibits PFK (phosphofructose kinase)
(PFK stimulated by ADP and AMP)

High glucose utilisation: PDH is stimulated to produce Acetyl CoA
1. Acetyl CoA inhibits 3-ketoacyl thiolase (in β oxidation)
2. Acetyl CoA stimulates ACC (Acetyl CoA Carboxylase)
—> stimulate Acetyl CoA into Malonyl CoA
—> Malonyl CoA inhibit CPT1
(L-carnitine stimulate PDH activity)