Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Cardio Week 2 > Lecture 22: Alterations in Myocardial Metabolism > Flashcards

Lecture 22: Alterations in Myocardial Metabolism Flashcards

1
Q

What is ischemia?

A

A temporary lack of blood supply in a tissue or organ

Dependent on metabolic activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is hypoxia?

A

A temporary lack of oxygen concentration in a tissue or organ
Substrate removal from tissue is still normal
Not the same as anoxia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is hypoxic-hypoxia?

A

When arterial oxygen content is below normal but there is adequate blood flow to deliver glucose and remove lactate
Different from ischemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Why does heart use so much oxygen during rest and exercise?

A

High mitochondrial content (30%)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What can MI do to the heart?

A

Leads to cardiomyopathy like DCM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What leads to the further loss of cells in MI?

A

The thickening and fibrosis
So drugs that prevent fibrosis will save myocytes from apoptosis
ACE inhibitors will prevent fibrosis (because angiotensin II promote fibrosis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the preferred fuel source for the heart?

A

Fatty acids
Up to 90% of oxidative energy is derived from fatty acids
Fatty acids are broken down to acetyl CoA for energy use

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What binds fatty acids in blood?

A

Bound to albumin, transported as triglycerides bound to apoliporprotein in VLDL or contained in chylomicron

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the role of lipoprotein lipase?

A

Releases fatty acids and glycerol from triglycerides
Secreted by capillary endothelium and myocytes
Allows fatty acids to diffuse into the myoplasm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the function of CPT1?

A

The enzyme that delivers the fatty acid into the mitochondria
The key regulatory point of fatty acid oxidation
So this is a target of drugs
Decrease fatty acid oxidation = improve symptoms by decreasing cytoplasmic H+ content

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the function of Carnitine acyl translocase?

A

Brings acyl carnitine (what the fatty acid becomes once it passes outer mitochondrial membrane) into the inner mitochondrial membrane
Once inside inner mitochondrial membrane, fatty acyl CoA will get degraded into acetyl CoA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the relation between malonyl –CoA and CPT1?

A

Malonyl CoA is a powerful inhibitor of CPT1

MalonylCoA is formed by the reaction catalyzed by acetyl-CoA carboxylase (ACC)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the significance of acetyl-CoA carboxylase (ACC)?

A

More ACC activity = more malonyl CoA = more inhibition of CPT1 = decrease in fatty oxidation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the significance of AMP?

A

The most important sensor of metabolism of the heart

Signals heart to increase ATP production by inhibiting ACC activity and increasing fatty oxidation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What does myokinase do?

A

An enzyme in the heart that takes 2 ADPs and forms ATP and AMP
That’s why AMP can inactivate acetylCoA carboxylase and increase malonyl CoA (thereby inhibiting CPT1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the predominant receptor for glucose during fetal development?

A

GLUT 1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the predominant receptor for glucose after birth?

A

GLUT 4

Upregulated by insulin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is the primary control point for glycolytic flux?

A

At the level of phosphofructokinase (PFK) under non-ischemic conditions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is the significance of GAPDH?

A

GAPDH = glyceraldehyde-3-phosphate dehydrogenase
Most important regulatory point during ischemia
GAPDH activity can indicate what the heart has just gone through because it produces NADH
NADH is sensitive to cellular redox state
As NADH goes up, glycolysis slows down to allow for more fatty acid oxidation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the relationship between lactate and heart uptake in healthy exercise?

A

If the heart is healthy, the heart takes up lactate, turns it into pyruvate and drives oxphosph
Lactate comes from skeletal muscle breakdown

21
Q

What are the key regulators of cardiac metabolism?

A
  1. Glucose utilization is inhibited by fatty acid and/or ketone oxidation
  2. Fatty acid oxidation is inhibited by glucose catabolism
  3. glucose utilization is stimulated by inhibition of oxidative phosphorylation
22
Q

What are the key HORMONAL regulators of cardiac metabolism?

A
  1. insulin increases carbohydrate metabolism by stimulating GLUT-4 translocation and glucose uptake and utilization
  2. Insulin lowers plasma fatty acid levels, and increases ACC activity, which in turn decreases fatty acid oxidation by increasing malonyl CoA levels
  3. Epi and NE increase myocardial conractility/energy demand/increase glycolysis + fatty acid oxidation
23
Q

Why do the mitochondria not have to be located so near to the capillaries?

A

Because myoglobin is present that will allow adequate transport of oxygen

24
Q

What is myoglobin? Significance?

A

An oxygen carrying molecule that is found WITHIN all muscle tissue
This allows muscle tissue to distribute oxygen to itself on its own terms
Allows muscle to survive when you hold your breath
Myoglobin helps oxygen get to the mitochondria far from the capillaries in the heart

25
Q

What is the phosphocreatine shuttle?

A

A facilitated diffusion system
Allows for ATP and ADP levels to stay the same
Equation = PCr + ADP + H+  ATP + Cr
Creatine and PCr are the ones that fluctuate in concentration while ATP and ADP levels stay the same
That’s why this system is known as an ATP level buffer!

26
Q

What is the significance of creatine kinase?

A

Catalyzes the reaction of the phosphocreatine shuttle
Allows heart to maintain a high ATP/ADP ratio even if the energy demand transiently exceeds rate of ATP synthesis
This high ATP:ADP allows for maximal calcium pumping and power output from contractile apparatus

27
Q

What can you use to gauge oxygen consumption of heart?

A

PCr and creatine ratio because this is the buffer that is used to maintain ATP levels

28
Q

What is SERCA?

A

Sarcoplamic reticulum Ca ATPase

Transfers Ca from cytosol to lumen of SR

29
Q

What is the role of phospholamban?

A

When bound to SERCA (dephosphorylated), phospholamaban inhibits SERCA activity and promotes Ca retention in cytosol
When phosphorylated, phospholamban detaches from SERCA, thereby increases calcium uptake in SR

30
Q

What happens to ryanodine receptor in heart failure?

A

May leak calcium
This overloads mitochondria
-triggers free radicals and apoptotic cascade
So overload of calcium can lead to apoptosis!

31
Q

What is phospholemman?

A

A sarcolemmal protein that regulates contractility and Ca homeostasis

32
Q

What is stunning?

A

A cellular consequence of transient ischemia
Symptoms include
i. diminished oxphosph
ii. ATP partially buffered with phosphocreatine
iii. Acidosis
iv. Increased cytoplasmic calcium levels and buffering by mitochondria
v. Restoration of oxygen renews oxidative phosphorylation, but leads to generation of oxygen free radicals
vi. proteolysis of a number of cardiac proteins due to free radicals
Contractile ability of the heart is DIMINISHED (protective because heart is not using as much ATP to recover from ischemia)

33
Q

What are the key characteristics of infarction?

A

Prolonged ischemia (as opposed to transient ischemia in stunning) characterized by
i. severe depletion of ATP and Phosphocreatine
ii. intracellular acidosis
iii. permanently impaired contractility
iv. disrupted calcium homeostasis
v. reoxygenation results in oxygen free radical generation
vi. cell death
This is different from an area that has been stunned or hibernated because the ischemic regions are FOREVER FUCKED
That’s the significance of this lol

34
Q

What types of cellular consequences of ischemia can the heart come back from?

A

Stunning

Hibernation

35
Q

What are the key characteristics of hibernation?

A

Chronic, sub-lethal ischemia
Describes regions of the heart with greatly decreased contractility, arising from a period of acute ischemia followed by continuing subacute ischemia
Myocytes survive with decreased function
Shifts expression to lower energy consuming isoforms, increased expression of enzymes needed for anaerobic glycolysis, activates ATP sensitive K cahnnels

36
Q

How do you get cell death as a result of ischemia?

A

Rise in free radicals due to
i. loss of glutathione peroxidase activity
ii. acidic pH in tissue from hypoxic state contributes to increased free radical production in oxphosph
Free radicals then damage proteins and DNA leading to activation of the death receptor pathway
Caspase activation and apoptosis
Also, fibrosis leads to stretch of the muscle fibers which leads to erroneous apoptotic signals as well

37
Q

During cardiac hypertrophy, what energy source is utilized?

A

Increased glucose and lactate oxidation

Decreased fatty acid oxidation

38
Q

What happens to the metabolic requirements of the heart during heart failure?

A

Heart switches over to net lactate production
Intracellular pH decreases (increase in H+) which leads to decrease in calcium sensitivity
Because of decreased calcium sensitivity, myocyte tries to compensate by increasing Ca retention in cytoplasm by decreasing SERCA activity (and increasing phospholamban activity)
More calcium uptake by mitochondria = more ROS generation
More ROS generation = apoptosis

39
Q

What does an increased intracellular H+ level do?

A

Decreases calcium sensitivity of cardiac tissue because of downregulation of L-type calcium channels

40
Q

What is the significance of the MMP and TIMP ratio?

A

The more MMPs and the less TIMP (which serves to inhibit MMP), the more collagen is produced extracellularly
More MMP activity = more pathologic myocardium ECM remodeling

41
Q

What is TIMP?

A

Tissue inhibitor of matrix metalloproteinases

42
Q

What are the targets for therapeutic interventions for ischemia?

A
  1. metabolic therapy
  2. calcium handling
  3. blocking free radical production or blocking apoptosis
  4. increasing NO (nitric oxide)
43
Q

What are the characteristics of metabolic therapy for cardiac ischemia?

A

Decrease fatty acid oxidation while increasing glucose oxidation
-glucose + insulin
-inhibitors of fatty acid beta oxidation (ranolazine, trimetazidine)
Rationale: fatty acid utilization = more H+ in myocyte
So blockage of fatty acid utilization = less H+ and acidity

44
Q

What are the characteristics of calcium handling for cardiac ischemia?

A

Increase calcium pumping into SR by increasing SERCA or inhibiting phospholamban (phosphorylating it)
Correcting RyR leak (Rycals)
Ischemia therapeutic interventions
Rationale: decrease mitochondrial activity (by using Ca) and therefore decrease ROS formation

45
Q

What are the characteristics of blocking the free radical production or block apoptosis as therapy for cardia ischemia?

A

SOD and catalase mimetics
Blocking mitochondrial transition pore opening
Shows promise in stunning but ineffective at blocking infarction associated with ischemia-reperfusion
Overexpression of Bcl-2 blocks apoptosis

46
Q

How do you increase NO (as mechanism for ischemia therapy)?

A 
Inhibiting PDE5 (increasing cGMP)
Increasing NOS (nitric oxide synthase) or arginine
47
Q

What is SOD?

A

Super oxide dismutases
Enzymes that catalyze dismutation of a free radical into a non-free radical
An important antioxidant

48
Q

What is catalase?

A

Direct inhibitors of fatty acid metabolism

Slows progression of cell death by decreasing acidity or H+ content in myocyte

49
Q

Why is blocking apoptosis useful to block cardiomyopathy?

A

Because the cells that are being apoptosed are normal and are only being signaled for death because it is being stretched by neighboring fibrosi

Cardio Week 2 (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions