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CV Biochem > Bioenergetics of the Failing Heart > Flashcards

Bioenergetics of the Failing Heart Flashcards

1
Q

Definition of substrate omnivore

A

Changes substrate depending on the changing environment - metabolic flexibility

  • Workload
  • Substrate availability
  • Circulating hormones
  • Coronary flow
  • Fuel metabolism
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2
Q

Heart activity in a day

A

Beats 100,000 times and pumps 10 metric tonnes of blood through the body

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3
Q

Energy consumption of heart

A
  • Among the largest energy consumer organs in the body
  • Stored in the form of ATP and phosphocreatine (PCr - > 90% of energy is produced as PCr)
  • Consumes 1mM ATP/s => energy reserves lasts about 20 s normal activity => All ATP and PCr content should be renewed every 20 s
  • Produces > 90% of its energy from mitochondrial respiration - mitochondria occupy 30% of myocardial cell vol.
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4
Q

What is creatine phosphate

A

High energy compound that provides a small but rapidly mobilised reserve of high energy phosphates that can be reversibly transferred to ADP to make ATP during the first few minutes of intense muscular contraction

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5
Q

How is creatine formed

A

C and CP cyclise at a slow but constant rate to form creatine - excreted in the urine

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6
Q

What does creatine excreted in urine indicate

A
  • Muscle mass
  • Monitor decrease in muscle mass
  • Kidney malfunction
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7
Q

Fuel utilisation in cardiac muscle

A

FAs (60-80%)
lactate and glucose (20-40%)
small amounts of ketone bodies and some AAs

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8
Q

How is ATP generated in heart

A

98% of cardiac ATP is generated by oxidative means

2% derived from glycolysis

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9
Q

What is efficiency of ATP production dependent on

A

Substrate used

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10
Q

Effects of diverse cardiac pathologies on ATP production

A

Decreased efficiency of producing ATP or alterations in the efficiency of using ATP to produce contractile work

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11
Q

What are the pathways through which the heart mainly produces ATP

A 
GLUCOSE OXIDATION (more O2 efficient)
Glucose -> pyruvate -> Acetyl CoA -> ATP

FA BETA-OXIDATION (requires more O2 than glucose)
FA -> Acyl CoA -> Acetyl CoA -> ATP

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12
Q

How is glucose transported into the cardiocyte

A

Via GLUT1 & GLUT4 (90%) transporters

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13
Q

What is the functional difference between GLUT1 & GLUT4

A

Insulin stimulates GLUT4
Ischaemia stimulates GLUT4
Effect is additive

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14
Q

What does FA uptake into cardiac muscle require

A
  • FA-binding proteins
  • Carnitine palmitoyl transferase (CPT1) for transfer into mitochondria
    (different isoform expressed in fetal heart and that same one in the hypertrophied heart)
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15
Q

Effect of FA utilisation on O2 levels

A

Utilisation of FA costs 12% more O2 per unit of ATP generated

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16
Q

What happens during MI regarding energy metabolism

A

Shift from FA -> CHO metabolism

17
Q

What happens in early stage heart failure

A

Even in the absence of CAD there is an increased glucose uptake and oxidation and a reduced rate of FA oxidation
Known as REVERSION TO A FOETAL METABOLIC PHENOTYPE
- can result in 40% reduction in O2 consumption

18
Q

How can substrate utilisation become limiting for cardiac function in heart failure

A

Due to:

  • Reduced substrate uptake
  • Reduced oxidation
  • Both
19
Q

How does impaired oxidative phosphorylation affect heart function

A

Impaired ox phos reduces function by providing an insufficient supply of ATP to cardiomyocytes

20
Q

What happens to mitochondria and consequential functions in heart failure

A
  • Mitochondria have structural abnormalities and are probably increased in number
  • Activity of ETC complexes and ATP synthase capacity are reduced
  • The regulation of Ox Phos by phosphate acceptors ADP, AMP and creatine is impaired
  • Level of uncoupling proteins may be increased
21
Q

How does impaired ATP transfer & utilisation limit contractile function

A
  1. Decreases average [ATP]
  2. Reduction in ATP transfer capacity through creatine kinase so that insufficient high-energy phosphate bonds are transported from the mitochondria to the myofibrils
  3. An increase in [ADP]
22
Q

Changes in ATP, PC, C and mCK throughout heart failure

A
  • ATP levels remain normal until the advanced stages of heart failure
  • However, both phosphocreatine and total creatine levels decrease at earlier stages (30-70%)
  • Profound changes in the CK system in heart failure
  • mCK activity may be reduced to 20%
  • Myofibrillar CK activity decreases by up to 50%
23
Q

What are ischemic conditions in the heart

A
  1. During cardiothoracic surgery
  2. During MI
  3. Cardiac arrest
  4. Shock (BP) or hypoxia
  5. Birth asphyxia
24
Q

What happens during ischemic conditions

A
  • Blood flow is interrupted
  • Reduced oxygenated blood
  • Heart switches from aerobic to anaerobic metabolism
  • Rate of glycolysis increases
  • Accumulation of protons (via lactate formation) is detrimental
  • FFAs increase BUT unlike the normal heart, exposure of ischemic heart to FAs does not inhibit glycolysis & glycolytic rates are increased in the ischemic heart
25
Q

What happens when pyruvate cannot be converted to acetyl CoA

A
  1. Increase in anaerobic glycolysis
  2. Cell acidosis
  3. Calcium overload
  4. Cell damage
  5. Increased need for ATP for homeostasis
  6. Decrease in ATP
    => contractile dysfunction
26
Q

What happens to FAO in ischemia

A

Free FAs increase - FAO in response to catecholamine release

FAO becomes the primary residual oxidative pathway

27
Q

what is the energy substrate competition - the glucose/FA cycle (The Randle Cycle)

A

Inhibition is greatest at the level of PDH by Acetyl CoA and NADH from FAO

Glucose is rerouted to gluconeogenesis and/or anaplerosis

Nutrient mediated fine tuning along with more coarse hormonal control

=> Explains inhibition of glucose oxidation by FAs - glucose sparing

28
Q

Inhibition of FAO by glucose - mediator and process

A

Mediated by Malonyl CoA

Conc of malonyl CoA depends on ACC activity
-> Inhibits entry of LCFAyl-CoA moieties into mitochondria

29
Q

Heart metabolism beyond ATP production

A

Metabolic intermediates may act as regulators of many pathways not directly related to ATP production
- e.g. anabolic processes essential for maintaining cellular activities and promoting cell growth and proliferation

30
Q

What is the development of HF characterised by

A

Profound changes in cardiac structure and function

31
Q

Ischaemia vs heart failure

A

See photo

CV Biochem (2 decks)

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