Le Grice: Regulation of Cardiac Function 1 Flashcards
Cardiac Output = _____ x _______
Stroke volume = ______ x ______
Cardiac Output = HR x SV
Stroke volume = EDV - ESV
* learn the diagram
Redraw this diagram
….
Note
- if we increase preload we increase SV
- If we increase afterload (Pressure in the circulation), then we take longer to open aortic load, so we have a smaller ejection (smaller SV)
- after load is both the stretch and the tension/stress in the muscle cells
- Inotropic state can both increase and decrease SV
- heart Failure due to sick muscle cells → reduced inotropic state
Describe the definition of
Inotropy:
Chronotropy:
Lusitropy:
Dromotropy:
Inotropy: contractility of myocardium (calcium***)
Chronotropy: firing rate of SA node (heart rate)
Lusitropy: relaxation of myocardium (calcium removal)
Dromotropy: conduction velocity of AV node
Describe the process Ca2+ has in cardiac muscle contraction step-by-step
- During AP, Ca2+ comes in through the L-type Ca2+ channels in the T-tubules
- enters the cells and binds to RyR2 Ryanodine receptors on the junctional SR opening Ca2+ release channels
- Ca2+ rises in the cytoplasm and binds to Troponin C, unmasking active sites
- this allows myosin to interact → cross bring cycling and contraction occurs
Describe the input Ca2+ has in cardiac muscle relaxation step-by-step
Removal of Ca2+ from the cytoplasm cause relaxation
- Ca2+ pumped into the SR membrane by SERCA
- Transfers Ca2+ into SR then to storage sites in the JSR
- Ca2+ extruded by Na/Ca exchangers in the cell membrane
- passive process that relies on the Na + gradient produced by the Na/K pump
- Active Ca2+ pumping by the sarcolemma
These mechanisms ensure that Ca2+ in cytoplasm is maintained at low levels during diastole
It is vital that there is a balance of Ca2+ coming in and out of the cell during the heartbeat.
This balance can be impacted by?
- Magnitude and rate of Ca2+ release from SR
- amount of Ca2+ inSR
- Balance among fluxes
- Affinity of Troponin-C for Ca2+
- Sarcomere length dependent Ca2+ sensitivity of Troponin-C
These can be regulated by things such as sympathetic activation of certain channels etc
What is the effect of sympathetic activation on the cardiac muscle?
SNS stimulation of Inotropic state
- B1 receptor activated by adrenaline or NA and couple to G-protein coupled receptor
- if you stimulate this Gs → stim. adenylate cyclase → cAMP → PKA → protein phosphorylations a # of things
- One thing it phosphorylates is the L-type Ca2+ channel → more Ca2+ in the cell
- ALSO phosphorylates: phospholamban, RyR, Tnl and other proteins
When phospholamban gets phosphorylated due to sympathetic activation of B1 , what happens?
Phospholamban: increases the rate of SERCA, so that Ca2+ is taken up more rapidly.
THis works in conjunction with the phosphorylation of the Ca2+ channels which increases the release. Everything gets ‘speed up’ from both ends.
Therefore overall SNS caused phosphorylation leads to:
- Increased opening of L-type Ca2+ channels
- Stimulation of SR and cell membrane calcium pumps
- Faster Calcium kinetics
- Faster X-bridge cycling
- Hence SNS causes more vigorous and more rapid contraction (and relaxation)*
- There are many potential pathways to interfere* with drugs
Effects of Parasympathetic activation on cardiac muscle?
PNS effect on inotropic state
- PNS acts on the M2 receptor
- stimulate Gi → inhibition of adenylate cyclase → decr. levels of cAMP
- Gi directly opens K+ channels, via the By subunit → decreased AP duration
- therefore both SNS and PNS shorten AP duration when stimulated
These both lead to a negative inotropic effect in cardiac myocytes
Differences in Skeletal vs cardiac muscle force-length relationship and why….
Skeletal m. :
- Due to actin-myosin overlap, number of myosin heads acting.
Cardiac muscle:
- Steeper ascending limb
- actin/myosin overlap more than in skeletal muscle
- AND Length-dependent sensitivity of Troponin C
- Doesn’t have a descending limb:
- due to the passive curve, as it’s too stiff to pull in out to lengths where you get the descending limb, can’t be stretched any longer due to conenctive tissue in heart
- Can be stretched over time (heart failure)
Describe the Hypoxic state.
If O2 supply is reduced relative to demand….
- Reduced ATP
-
Reduced Na/K pump
- Reduced Na+ and K+ transmembrane conc gradients
- hyperkalaemia
- reduced resting MP
- reduced AP upstroke speed and magnitude
- shortened APD
- Reduced Na+/Ca2+ exchange
- Reduced myosin head detachment → less relaxation
-
Reduced SR calcium pump extrusion
- increased cytoplasmic Ca2+ → impaired relax/fill and electrical instability
-
Reduced pH (acidosis)
- H+ competes with Ca2+ on Troponin-C, reduced inotropic state and slow conduction
-
Reduced Na/K pump
Describe the cell wall architecture and why it is this way..
The heart as a cellular architecture is very complex. Heart wall thickening is required to pump blood out.
- Myocyte orientation changes by significant degrees within a heart beat.
- Collagen plays a huge role in heart architecture.
- Myocytes have to have this complex spiraling as muscle cells can only shorten by 12%. and thicken by 8%, and that is it.
- In order to do these complex things, the cells need to be arranged specifically in a layered structure to create complex 3D change.
Muscle cells are arranged in ______ with __________ seperating them, which have an ________ shape that contain _______.
Muscle cells are arranged in groups with cleavage planes separating them, which has a curving/arching shape that contains rods.
As the wall changes in thickness the orientation of the cleavage planes changes.
How is it that ‘more cells can be across the wall within a heartbeat’?
Because the structure of the heart wall changes its shape, and the layers of the heart wall tilt significantly.
The tissue of the heart reorganizes itself for every beat.
Inner wall changes dimension of the wall locally by 100%
Change orientation of cells → change in cell # across wall → big change in thickness
In order for the ‘shearing theory’ of cells of the inner wall moving in orientation to make a thicker heart wall, the inner septum cells needed to be shearing up, and the LV cells down. Does this occur
Yes.
Done via columns of beads highlighting inner cell shearing. In order to get to the septum, you need to go through the RV and put the heart on to two pumps. Cleared the blood from the RV, and cut a slice into RV wall to get to the septum.
By watching the beads move you can see (via Biplane xray to get 3D image) in very high speed as a heart beat (120 frames/sec), to measure the movement of beads from end diastole (QRS peak) to systole.
You can work out the stretch and shear from ED to ES, needs to be a Positive E23 at the LV and a negative E23 shear in the septum, as the wall thickens.
Both showed this at the inside surface, opposite movement of the two areas!! (equal and opposite)
Why do we need so many deformations during the cardiac cycle
In order to generate 85% Ejection Fraction, the lumen of the ventricle needs to contract down to almost nothing. In order to do this, you need some pretty complicated cardiac deformations
Lots of diastolic myocardial strains in the inner wall, not much occurs in the outer wall. THe blue line is the strain of the singular muscle fiber direction. Why is this constant?
Because cells can only do one thing and shorten by 12%
What can the progression to failure in hypertensive rats tell us?
- Rats mechanical function drops off over time (red line)
- Structure of heart wall over time, and the gaps where the cleavage planes used to be disappears and is scarred together by collagen, and as all the deformation requires sliding between these gaps, there is very little reorganisation of cells for effective contraction
- it’s not the amount of collagen but the location of it in the cleavage plane. Even if you got rid of the collagen via drug therapy there’s little left to function anyway!
- Over time as the # of cells decreases, there is little laminar structure left
- The happens also in human heart failure!!
