Myocardial metabolism

Question 1

Myocardial metabolism

Answer 1

• High ATP production rate needed
  o 5% of total ATP consumed each beat
• Limited energy reserve in the heart
  o Need continuous supply of O2
   FA is preferred substrate: >70%
• 138ATP produced
• Only metabolized in well O2 heart
   Change in heart failure
  o Limited O2 supply: competition FA vs glycolysis for limited O2
  o Anaerobic glycolysis (pyruvate => lactate); max 5-7% of energy needs (2ATP vs 38ATP w aerobic)
   Glycogen/TG stored in heart can support fct for 6-12min

Question 2

Myocardial O2 consumption

Answer 2

basal requirements = 20%
o Determined by: basal requirements, myocardial contractility, systolic wall stress, HR

Question 3

Metabolism: 3 steps

Answer 3

o ¢ acquisition of substrate
o Use of substrate to produce ATP
o Processes that govern the use of ATP

Question 4

Lipid metabolism

Answer 4

• Major source of energy for heart and in fasting state
• Long chain FA (LCFA) bound to albumin in blood => passive diffusion through ¢ membrane
  o Stored intra¢ by FA binding protein
  o Major myocardial fuel

Question 5

Role of carnitine

Answer 5

• Fatty acid (FA) => converted to acetyl CoA
  o Complex to carnitine → acylcarnitine
  o Carnitine shuttle transport into mitochondria: shuttle in form of esters of acylcarnitine
   Detoxifying agent: binds acyl groups/other toxic metabolites => transport out of mitochondria as esters of carnitine
  o B oxidation => Acetyl Coa + ATP => krebs cycle
  o Malonyl CoA formation: via acetyl CoA carboxylase if excess FFA reach mitochondria

Question 6

How does lipid metabolism inhibit carbohydrate metabolism

Answer 6

o incr ATP, decr AMP/Pi
o Slow glycogen breakdown => inhibit phosphorylase b
o decr glycolysis => decr phosphofructokinase 1 activity + glucose 6P levels => slow hexokinase
o incr citrate => decr PDH phosphatase

Question 7

Glucose transport

Answer 7

Passive diffusion through ¢ membrane with [glucose] gradient
o GLUT 1 and 4
o Stimulated with incr glycemia
o Inhibited with incr [FA] = fed state + diabetes

Question 8

Role of insulin

Answer 8

incr glucose uptake
o decr release of FA by adipose tissue
o incr # of active glucose carriers: translocate GLUT 1 and 2 from internal sites to ¢ membrane
o Bind to specific R: A and B subunit
 Bind to A => phosphorylation of B=> activate peptide kinase => phophorylate tyrosine => incr activity of insuline R substrate 1

Question 9

Main steps of glycolysis

Answer 9

a) Glucose carried across  membrane (facilitated diffusion) → ↑ by insulin, anoxia, ↑ heart work
b) Glycogen synthesis if excess intracell glucose
c) Glycogenolysis: glycogen breakdown → secondary to cAMP or ↓ intracell Pi
d) Glycolysis: glucose → pyruvate and ATP
e) Krebs cycle or lactate: pyruvate metabolism

Question 10

Glycogen formation

Answer 10

• Excess in glucose converted to glycogen: constant turnover
  o incr fed state, after incr heart work or ischemia because of reduced stores
  o decr fasting
  o When FA are oxidized: glucose oxidation is inhibited => incr glycogen production
   = glucose sparing effect of FA oxidation

Question 11

• 2 mechanisms for breakdown glycogen

Answer 11

o incr cAMP (incr symp activity)
o Ischemia => decr Pi levels

Question 12

Effect of B stim on glucose metabolism

Answer 12

stimulate glycolysis
o Mobilize FA from adipose tissue => promote metabolic condition similar to fasting

Question 13

Effect of leptin on glucose metabolism

Answer 13

regulate food intake + incr blood FA
o decr food intake
o incr symp activity in hypothalamus => incr FA release
o Directly stimulate FA metabolism in the heart

Question 14

Pathways of glycolysis

Answer 14

• Anaerobic: glucose => pyruvate → lactate
  o Limited ability to generate ATP → cannot meet heart E needs
• Aerobic: glucose => 2pyruvate + 2ATP +NADH
  o Generate only fraction of E used by normal heart
  o Phosphofructokinase: regulate flux
   incr activity with hypoxia
  o Coordinated intra¢ control: incr activity in response to incr heart work
  o Fructose 2-6 biphosphonate: additional product => capacity of potent stimulation of phosphofructokinase
  o O2: pyruvate => Acetyl CoA => krebs cycle
• Controlled by changes in work load, substrate availability, hormones

Question 15

What is pyruvate and how is it formed

Answer 15

Pyruvate: 3C compound
* From glycolysis or lactate
* Lactate contribution: incr blood [lactate] => incr % of E
o Lactate => lactate DH => pyruvate
* Aerobic: substrate for krebs cycle
o Must be converted by pyruvate dehydrogenase in inner mitochondrial membrane
o PDH:
 Activated by incrheart work, catecho, incr glycolytic rates of fed state
 Inhibited by NADH2: ischemia, hypoxia, FA oxidation
* Anaerobic => lactate

Question 16

Malate aspartate cycle

Answer 16

• Remove NADH2 continuously generated
  o Hypoxia/ischemia: decr accumulation because NADH2 converted back => NAD
  o NADH2 accumulation = incr H+ => acidosis
  o Inhibit PDH