Cardiac muscle structure and function

Question 1

Name the contractile proteins of heart muscle

Answer 1

a. Myosin: Two heavy chains and 4 light chains.
b. Actin: binds tropomyosin and Troponin
c. Thin filament regulatory proteins (TN= troponin)
i. TN-C: Contains only one Ca2+- binding site
ii. TN-I: highly regulated by phosphorylation (PKA sites)
iii. TN-T: Binds tropomyosin.
iv. Tropomyosin: Only alpha isoform

Question 2

Which myosin heavy chain has lower ATPase activity?

Answer 2

beta isoform- majority in humans

Question 3

Describe cardiac muscle structure

Answer 3

mononucleated cells with 85% of volume being myofibril and mitochondria. Cells are coupled electronically and mechanically

Question 4

Compare cardiac to skeletal muscle cells

Answer 4

Cardiac cells are not under direct neural control, shorter, narrower, richer in mitochondria, and have slower ATPase activity

Question 5

What are the connections between muscle cells

Answer 5

intercalated discs + desmosomes mechanically couple cells. Gap junctions electrically couple cells

Question 6

How is Ca regulated in cardiac cells?

Answer 6

a. Depolarization opens L-type calcium channels leading to calcium influx.
b. Calcium influx triggers more calcium release from the SR through the ryanodine receptors (CICR)
c. Calcium binding to TN-C triggers contraction
d. Calcium is removed by the SR Ca2+-ATPase, sarcolemmal Na-Ca exchanger or mitochondrial Ca uniporter

Question 7

Explain cross bridge cycle (sliding filament theory)

Answer 7

Ca binds troponin C, Tn C causes conformational change in troponin I then T which is bound to tropomyosin. Tropomyosin is moved, revealing active site and allowing myosin to bind.

Question 8

What are regulators of cardiac output?

Answer 8

Stroke volume x HR

Question 9

What are the regulators of stroke volume?

Answer 9

Pre-load, afterload & contractility

Question 10

Describe pre-load

Answer 10

length tension relationship: If you increase the muscle length (increased preload), the active tension developed dramatically increases. Peak tension occurs at a sarcomere length of 2.2 to 2.3um

Question 11

Describe afterload

Answer 11

Most closely associated with aortic (systemic) pressure.
Afterload can also be described as the pressure that ventricle has to generate in order to eject blood out of the chamber. Greater afterload = slower velocity of shortening

Question 12

What is contractility?

Answer 12

Force with which the heart contracts. Regulated by norepinephrine

Question 13

What is an ionotrope?

Answer 13

Substances that change contractility. Can be positive or negative

Question 14

What is the Frank-Starling law?

Answer 14

Increase in pre load (end diastolic volume) leads to an increase in stroke volume.

Question 15

What other factors affect Starlings law?

Answer 15

1. Cardiac titin isoform is very stiff (low compliance)
2. Ca2+-sensitivity of the myofilaments increases as sarcomeres are stretched (same calcium = greater force of contraction)
3. Closer lattice spacing – stretched sarcomeres have altered spacing between actin and myosin (which may result in more force generated per crossbridge).

Question 16

What is the mechanism behind length-tension relationship?

Answer 16

At the optimal length there is greater extent of overlap, higher sensitivity to Ca, and increased Ca release from stretch sensitive ion channels

Question 17

Describe force-velocity relationship and the affect that preload has on it

Answer 17

The greater the afterload, the slower the velocity of shortening. Increased preload changes force velocity curve

Question 18

Describe the general continuum of cardiac disease

Answer 18

Ischemic cardiomyopathy > Hypertrophic cardiomyopathy > dilated cardiomyopathy

Question 19

What type of cell growth occurs in hypertrophy? In dilation?

Answer 19

hypertrophy: concentric growth (grows in circumference)
Dilation: eccentric (elongates)

Question 20

Describe the contractility changes that occur in hypertrophy and dilation

Answer 20

hypertrophy: changes mainly in calcium sensitivity.
Dilation: changes in force output (maximal)

Question 21

What are the mechanisms for changes in conractility

Answer 21

i. Translational changes (isoform switching)
1. Sarcomeric proteins (upregulation of fetal proteins)
2. Changes in signaling proteins
ii. Post-translational changes of sarcomeric proteins (phosphorylation of contractile proteins reduces incorporation)

Question 22

What are the main translational changes that occur in HF?

Answer 22

TnT: more fetal pattern
Myosin heavy chain: Increased b-MHC, associated with lower ATPase and reduced ventricular contractility.
MLC: Atrial isoform switching in ventricles, temporally correlated to progression to failure.
Titin: Increase in N2BA isoform (more compliant than the N2B isoform), associated with reduced myocardial stiffness.