Le Grice: Regulation of Cardiac Function 1

Question 1

Cardiac Output = _____ x _______

Stroke volume = ______ x ______

Answer 1

Cardiac Output = HR x SV

Stroke volume = EDV - ESV

* learn the diagram

Question 2

Redraw this diagram

Answer 2

….

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
  • in someone with HF they have a larger volume and according to LaPlaces law will have a higher amount of afterload tension for the same pressure.
• Inotropic state can both increase and decrease SV
  
  • heart Failure due to sick muscle cells → reduced inotropic state

Question 3

Describe the definition of

Inotropy:

Chronotropy:

Lusitropy:

Dromotropy:

Answer 3

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

Question 4

Describe the process Ca²⁺​​ has in cardiac muscle contraction step-by-step

Answer 4

1. During AP, Ca²⁺ comes in through the L-type Ca²⁺ channels in the T-tubules
2. enters the cells and binds to R_yR₂ Ryanodine receptors on the junctional SR opening Ca²⁺ release channels
3. Ca²⁺ rises in the cytoplasm and binds to Troponin C, unmasking active sites
4. this allows myosin to interact → cross bring cycling and contraction occurs

Question 5

Describe the input Ca²⁺​ has in cardiac muscle relaxation step-by-step

Answer 5

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

Question 6

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?

Answer 6

1. Magnitude and rate of Ca²⁺ release from SR
   
   • amount of Ca²⁺ inSR
   • Balance among fluxes
2. 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

Question 7

What is the effect of sympathetic activation on the cardiac muscle?

SNS stimulation of Inotropic state

Answer 7

• B₁ receptor activated by adrenaline or NA and couple to G-protein coupled receptor
  
  • if you stimulate this G_s → 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, R_yR, Tnl and other proteins (net effect makes dynamics faster - release and uptake)

Question 8

When phospholamban gets phosphorylated due to sympathetic activation of B₁ , what happens?

Answer 8

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.

Question 9

Therefore overall SNS caused phosphorylation leads to:

Answer 9

• 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

Question 10

Effects of Parasympathetic activation on cardiac muscle?

PNS effect on inotropic state

Answer 10

1. PNS acts on the M₂ receptor
   
   • stimulate G_i → inhibition of adenylate cyclase → decr. levels of cAMP
   • G_i directly opens K⁺ channels, via the B_y 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

Question 11

Differences in Skeletal vs cardiac muscle force-length relationship and why….

Answer 11

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)

Question 12

Describe the Hypoxic state.

Answer 12

If O₂ supply is reduced relative to demand….

• Reduced ATP
  
  • Reduced Na/K pump
    
    • Reduced Na⁺ and K⁺ transmembrane conc gradients
    • hyperkalaemia leads to…
    • reduced resting MP (less negative)
    • reduced AP upstroke speed and magnitude (reduced as already slightly depolarised)
    • shortened APD
    • Reduced Na⁺/Ca²⁺ exchange (leads to a Ca build up)
  • Reduced myosin head detachment → less relaxation (due to decreased ATP)
  • 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

Question 13

Describe the cell wall architecture and why it is this way..

Answer 13

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.

Question 14

Muscle cells are arranged in ______ with __________ seperating them, which have an ________ shape that contain _______.

Answer 14

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.

Question 15

How is it that ‘more cells can be across the wall within a heartbeat’?

Answer 15

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

Question 16

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

Answer 16

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)

Question 17

Why do we need so many deformations during the cardiac cycle

Answer 17

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

Question 18

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?

Answer 18

Because cells can only do one thing and shorten by 12%

Question 19

What can the progression to failure in hypertensive rats tell us?

Answer 19

• 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!!