B3W2 Flashcards
What are the two pathologies of force production that lead to systolic heart failure
decrease in the amount of cross bridges formed, decreasing force
decreasing the amount of Ca removed by SERCA
B adrenergic receptors cause ….
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
What is lusitropy
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
How are HF and ionotrophy related
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
In heart failure patients there are …. b adrenergic receptors and they are …..
less receptors, and receptors are desensitized
How is the formation of ROS in heart failure patients leading to problems in dilation
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
How does the decrease in PKG levels affect HF patients
decreasing PKG leads to increasing contractility (PKG is a relaxant)
overuse of contractility leads to hypertrophy and hypertrophy leads to ventricular remodeling
Physiological vs Pathological hypertrophy
Physiological - reversible changes (pregnancy/exercise)
pathological - irreversible (hypertension, MI
Connentric vs eccentric hypertrophy
concentric: increasing ventricular thickness, decreasing ventricular volume
eccentric: decrease in ventricular thickness, increasing ventricular volume
Current Ionotropic Therapies
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
What medications will not work for heart failure
beta agonists - there is a decreased sensitivity and decreased density of receptors so they will not work
How do you indirectly increase ionotrophy
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
How do you directly increase ionotrophy
Ca levels stay the same
increase contractility which stays the same, keeps BP and O2 demand the same while increasing efficiency
what are cMyBPC-KO mice
cardiac myosin binding protein C knock out mice
they have decreased ejection time and act as a model for human hypertrophy
What does OM stand for
Omecamtiv Mecarbil
What is OM
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
What step of the muscle cross bridge cycle does OM act?
acts when Pi releases (the rate limiting step)
Describe the OM mouse experiment
-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
How does OM work in heart failure patients
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)
Conclusions of OM
-increases systolic function without increasing HR
-increases force generation by enhancing XB recruitment
-delays post powerstroke
-
Disadvantages of OM
delays diastolic relaxation and filling
Why cant humans regenerate ?
-restricted proliferation in adults
-low number of progenitors
What organisms can regenerate?
zebrafish/neonatal mammals
Hypertrophy v hyperplasia
hypertrophy - enlargement of a muscle (enlargement of individual myocytes)
hyperplasia - increases number of cells due to proliferation/cell division (increases in number of myocytes)
