Bioenergetics of the Failing Heart Flashcards
Definition of substrate omnivore
Changes substrate depending on the changing environment - metabolic flexibility
- Workload
- Substrate availability
- Circulating hormones
- Coronary flow
- Fuel metabolism
Heart activity in a day
Beats 100,000 times and pumps 10 metric tonnes of blood through the body
Energy consumption of heart
- 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.
What is creatine phosphate
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
How is creatine formed
C and CP cyclise at a slow but constant rate to form creatine - excreted in the urine
What does creatine excreted in urine indicate
- Muscle mass
- Monitor decrease in muscle mass
- Kidney malfunction
Fuel utilisation in cardiac muscle
FAs (60-80%)
lactate and glucose (20-40%)
small amounts of ketone bodies and some AAs
How is ATP generated in heart
98% of cardiac ATP is generated by oxidative means
2% derived from glycolysis
What is efficiency of ATP production dependent on
Substrate used
Effects of diverse cardiac pathologies on ATP production
Decreased efficiency of producing ATP or alterations in the efficiency of using ATP to produce contractile work
What are the pathways through which the heart mainly produces ATP
GLUCOSE OXIDATION (more O2 efficient) Glucose -> pyruvate -> Acetyl CoA -> ATP
FA BETA-OXIDATION (requires more O2 than glucose)
FA -> Acyl CoA -> Acetyl CoA -> ATP
How is glucose transported into the cardiocyte
Via GLUT1 & GLUT4 (90%) transporters
What is the functional difference between GLUT1 & GLUT4
Insulin stimulates GLUT4
Ischaemia stimulates GLUT4
Effect is additive
What does FA uptake into cardiac muscle require
- 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)
Effect of FA utilisation on O2 levels
Utilisation of FA costs 12% more O2 per unit of ATP generated
What happens during MI regarding energy metabolism
Shift from FA -> CHO metabolism
What happens in early stage heart failure
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
How can substrate utilisation become limiting for cardiac function in heart failure
Due to:
- Reduced substrate uptake
- Reduced oxidation
- Both
How does impaired oxidative phosphorylation affect heart function
Impaired ox phos reduces function by providing an insufficient supply of ATP to cardiomyocytes
What happens to mitochondria and consequential functions in heart failure
- 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
How does impaired ATP transfer & utilisation limit contractile function
- Decreases average [ATP]
- Reduction in ATP transfer capacity through creatine kinase so that insufficient high-energy phosphate bonds are transported from the mitochondria to the myofibrils
- An increase in [ADP]
Changes in ATP, PC, C and mCK throughout heart failure
- 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%
What are ischemic conditions in the heart
- During cardiothoracic surgery
- During MI
- Cardiac arrest
- Shock (BP) or hypoxia
- Birth asphyxia
What happens during ischemic conditions
- 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
