Alterations in Myocardial Metabolism

Question 1

What is the metabolite of choice for energy in cardiac myocyte?

Answer 1

mostly fatty acids but also glucose

Question 2

Which cardiac cells secrete lipoprotein lipase?

Answer 2

endothelial cells and myocytes

Question 3

What is the major control point of fatty acid processing in cardiac myocytes?

Answer 3

CPT1/Carnitine palmitoyltransferase I –> actively delivers acylcoA to the inner mitochondrial membrane by producing acylcarnitine

Question 4

How does acylcarnitine get across the inner mitochondrial membrane?

Answer 4

carnitine acyl translocase splits acyl carnitine into carnitine (returned to membrane space by CPT2) and fatty acyl coA

Question 5

What biochemical state determines the flux through CPT1?

Answer 5

ratio of acetyl coa carboxylase and malonyl coa (inhibitor of CPT1)

Question 6

What is the sensor for ATP levels in the heart?

Answer 6

AMP/AMPK

Question 7

What is the primary glucose transporter in fetal heart?

Answer 7

Glut1 –> not insulin sensitive –> glucose is main source of energy for fetal heart

Question 8

What is the primary glucose transporter in adult heart?

Answer 8

Glut4 –> insulin regulation of glucose consumption by heart

Question 9

What happens to phosphofructokinase during ischemia?

Answer 9

during ischemia heart becomes acidic and slows flux through glycolysis

Question 10

What is the major control point for glycolysis during mild/mediate ischemia?

Answer 10

GAPDH b/c as oxphos gets impaired, NADH utilization decreases –> builds up–> cannot regenerate NAD which is required for this step

Question 11

Glucose utilization is inhibited/supported by fatty acid and/or ketone oxidation.

Answer 11

inhibited

Question 12

Glucose utilization is inhibited/stimulated by inhibition of oxphos.

Answer 12

stimulated

Question 13

Role of myoglobin

Answer 13

buffer oxygen levels in mitochondria to facilitate diffusion

Question 14

Role of PCr

Answer 14

buffer ATP levels in myocytes –> ensures that ATP usage doesn’t lead to a buildup of ADP but rather creatine

Question 15

What is stunning?

Answer 15

cellular consequence of transient ischemia –>

1. diminished oxphos
2. atp partially buffered with Pcr
3. acidosis
4. increased cytoplasmic calcium buffered by mitchondria
5. proteolysis of a number of cardiac proteins

–> restoration of oxygen restores oxphos but leads to generation of free radicals

Question 16

What are the cellular consequences of prolonged ischemia?

Answer 16

1. severe depletion of ATP/PCr
2. intracellular acidosis
3. permanently impaired contractility
4. disrupted calcium homeostasis
5. cell death/necrosis

–> restoration of oxygen leads to oxygen radical formation

Question 17

What are the cellular consequences of chronic sub-lethal ischemia?

Answer 17

adaptation by shifting to expression of low-energy consuming isoforms of proteins, increased expression of anaerobic glycolytic enzymes, activation of ATP-K channles that reduce AP duration, decreasing calcium influx

Question 18

During cardiac hypertrophy, there is increased/decreased utilization of glucose/lactate.

Answer 18

increase –> expressing more fetal genes

Question 19

During heart failure, what happens to glucose and lactate utilization?

Answer 19

glucose utilization remains high but lactate production occurs with decreased pH, decreased PCr, and ATP

Question 20

4 targets for therapeutic intervention in dealing with ischemia

Answer 20

1. inhibit fatty acid beta oxication
2. increase calcium pumping into SR by increasing SERCA or inhibiting phospholamban
3. blocking free radical production/apoptosis
4. increase NO