B3W2

Question 1

What are the two pathologies of force production that lead to systolic heart failure

Answer 1

decrease in the amount of cross bridges formed, decreasing force

decreasing the amount of Ca removed by SERCA

Question 2

B adrenergic receptors cause ….

Answer 2

Gs pathway to increase AC, increase cAMP, increase PKA to phosphorylate RYR, PLB, L type Ca Channels, TnI

Increases Ca cystolic levels

Increases SR Ca uptake by the SERCA pump

Question 3

What is lusitropy

Answer 3

enhanced ability to relax due to sympathetic response causing faster contraction by building SR stores of Ca

ex. activation of PLB enhancing the ability to relax a muscle

Question 4

How are HF and ionotrophy related

Answer 4

Because HF causes a decrease in SERCA activity and an increase in NCX

decreased ionotrophy due to Ca leaking through the RYR and a decreased ability to uptake Ca through the SERCA

**this leads to less Ca to be available for the next contraction

Question 5

In heart failure patients there are …. b adrenergic receptors and they are …..

Answer 5

less receptors, and receptors are desensitized

Question 6

How is the formation of ROS in heart failure patients leading to problems in dilation

Answer 6

ROS inhibit NOS and inhibit sGC (which help relxation) therefore there is no dilation

overuse of contractility leads to hypertrophy and hypertrophy leads to ventricular remodeling

Question 7

How does the decrease in PKG levels affect HF patients

Answer 7

decreasing PKG leads to increasing contractility (PKG is a relaxant)

overuse of contractility leads to hypertrophy and hypertrophy leads to ventricular remodeling

Question 8

Physiological vs Pathological hypertrophy

Answer 8

Physiological - reversible changes (pregnancy/exercise)

pathological - irreversible (hypertension, MI

Question 9

Connentric vs eccentric hypertrophy

Answer 9

concentric: increasing ventricular thickness, decreasing ventricular volume

eccentric: decrease in ventricular thickness, increasing ventricular volume

Question 10

Current Ionotropic Therapies

Answer 10

Digoxin (inhibits Na-K pump), Ca sensitizer (levosimednan)(binds to TnC when Ca is too high), cAMP mediated ionotropic stimulation (dobutamine may impair survival in CAD pts) , PDE Inhibitors

Question 11

What medications will not work for heart failure

Answer 11

beta agonists - there is a decreased sensitivity and decreased density of receptors so they will not work

Question 12

How do you indirectly increase ionotrophy

Answer 12

increase intracellular Ca 2+ leading to PKA activation

which increases contractility, which increases HR, which decreases BP, which increases O2 demand, which decreases efficiency, which causes a risk of more arrythmias

Question 13

How do you directly increase ionotrophy

Answer 13

Ca levels stay the same

increase contractility which stays the same, keeps BP and O2 demand the same while increasing efficiency

Question 14

what are cMyBPC-KO mice

Answer 14

cardiac myosin binding protein C knock out mice

they have decreased ejection time and act as a model for human hypertrophy

Question 15

What does OM stand for

Answer 15

Omecamtiv Mecarbil

Question 16

What is OM

Answer 16

cardiac myosin activator which promotes actin dependent phosphatase to bind actin more tightly, producing more force, increases contractility, improves systolic function

also speeds up the process of actin myosin releasing the Pi to have a faster power stroke

slows the rate of XB detachment and increases XB recruitment at low Ca levels

increases systolic ejection time by recruiting more XB complexes and makes them contract for a longer period of time

Question 17

What step of the muscle cross bridge cycle does OM act?

Answer 17

acts when Pi releases (the rate limiting step)

Question 18

Describe the OM mouse experiment

Answer 18

-OM is activated at low levels of Ca
-OM increases Ca sensitivity
-OM increases cooperative binding at low calcium activations
-OM decreases XB cycling in cMyBPC KO mice
-slows rate of XB detachment, increases XB recruitment

Question 19

How does OM work in heart failure patients

Answer 19

HF patients have a reduced phosphorylation levels of contractile proteins because of a decrease in adrenergic density and sensitivity

OM increases Ca sensitivity which increases the time XB happens (prolonging cooperativity, prolongs time to get back to force)

Question 20

Conclusions of OM

Answer 20

-increases systolic function without increasing HR
-increases force generation by enhancing XB recruitment
-delays post powerstroke
-

Question 21

Disadvantages of OM

Answer 21

delays diastolic relaxation and filling

Question 22

Why cant humans regenerate ?

Answer 22

-restricted proliferation in adults
-low number of progenitors

Question 23

What organisms can regenerate?

Answer 23

zebrafish/neonatal mammals

Question 24

Hypertrophy v hyperplasia

Answer 24

hypertrophy - enlargement of a muscle (enlargement of individual myocytes)

hyperplasia - increases number of cells due to proliferation/cell division (increases in number of myocytes)

Question 25

Concentric v eccentric when comparing ventricular wall size, decreased volume, and overload

Answer 25

concentric: thick ventricular walls, decreased volume, increased pressure overload

eccentric: decreased ventricular thickness, increased volume, volume overload

Question 26

How do humans and zebrafish respond to traumatic heart problems?

Answer 26

Humans: hypertrophy increases volume in an organ due to the enlargement of myocytes

zebrafish: hyperplasia increases the number of cells by proliferation/ cell division

Question 27

How do zebrafish cells differentiate

Answer 27

cardiomyocyte - de-differentiation to proliferating immature cardiomyocyte to differentiation to mature state

Question 28

Mouse regenerative studies (injury after 1 day vs injury after 7 days)

Answer 28

injury after 1 day has full recovery

injury after 7 days does not recover

Question 29

Allogenic transplant

Answer 29

same species (require antirejection with host)

Question 30

autologous transplant

Answer 30

same individual

Question 31

xenotransplant

Answer 31

cross species transplant