L3: the determinants of cardiac output

Why is it important to regulate cardiac output CO

1. needs to be sufficient to ensure adequate perfusion of all the tissues

   • this means it must increase as metabolic demands rise in exercise

2. Critical in determining arterial blood pressure (ABP)

Heart’s control of CO, experiement

1. Replaced right atria of dogs with high-output pumps

2. reducing pumping capacity below normal→ reduced cardiac output

however:

3. increasing the pumping capacity→ NOT INCREASE in CO

This experiment illustrated two circulatory concepts

1. The heart is necessary to maintain CO

but

2. The heart does not normally limit CO

Why can’t the increase in heart pumping, increase its own CO?

Circulation is a closed system

• like a balloon with fluid

  • can’t change the average pressure in the balloon

  • certainly can’t inflate or deflate it

• A pump or fan inside the balloon CANNOT change the MEAN pressure in the balloon

• It can onlyuse pressure gradients

Explanation

1. Heart takes blood from the veins→ reducing venous pressure Pv

2. puts it in the arteries→ increases arterial pressure PA

3. This pressure difference then drives flow through our model system according to:

   • Q=(PA-Pv)/R

If the closed system was made of rigid tubing…

• greater pump activity could produce ever-increasing pressure gradients

  • and hence flows

However, if the tubing is not rigid:

Important constraint appears:

• if Pv becomes negative (with respect to atmosphere pressure)

• then tubing will collapse

similarly:this provides exaplnanation for figure 7

• real veins collapse when pressure within them drops

• more than 1 or 2 mmHg below atmospheric pressure

1. Pascal’s principle→ pressure the same everywhere

2. LaPlace→ all tension largest where vessel diameter greatest

Why can’t the heart increase the ateriovenous pressure difference (PA-PV) beyond the point at which Pv becomes signficantly negative

• because if Pv becomes, negative

• venous collapse limits venous return

→ cardiac output

veins are floppy walled like a balloon

Due to veins being collapsable

Although Q=PA-Pv/R

• If Pv becomes negative, veins collapse

THEREFORE: PV must decrease to increase PA

if R is constant

What do direct measurements show

• of the right atrial pressure

  • by inserting a catheter via the jugular vein

• Confirms:

  • a healthy heart reduces central venous pressure to almost zero

    • even at rest

What does this mean

• Increasing heart rate or myocardial contractility in isolation

  • e.g by stimulating the cardiac sympathetic nerves or electrically pacing the heart

• cannot significantly increase cardiac ouput

  • unless venous return is also increased

    • in this experiment, accomplished by connecting the aorta to the vena cava

Evidence 1: What this shows

• Heart rate does not change cardiac output

• stroke volume changes reciprocally

however:

• Give the heart more blood

  • i.e surgically

  • the heart can now pump more

How can Mean Styemeic filling pressure be changed?

1. Add volume

2. Constrict circulation→ decrease capacitance

This leads to the question of…

• if increasing cardiac pumping capacity is not sufficient to increase cardiac output

  • what else is necessary?

What is the main determinant of cardiac output

• Mean systemic filling pressure

In order to increase PA

• the pump must reduce Pv

However

Pv is normally close to zero and so cannot be reduced

The solution?

• raise the mean pressure in the whole system

Model to exmplain this

1. Imagine the mean pressure was0

2. Implies that Pv would become negative as soon as the pump started and prevent any flow of blood

next

1. IMagine the mean pressure was 10mmHg

2. now it is possile for pumping to produce a significant arterio-veous pressure gradient without collpasing the veins

Therefore, the mean pressure determines…

• The maximum flow rate for a given distance

Check that this model applies to real life

1. circulating volume: Low Med high→ shows:

   • Med→ Right atrial pressure at 0

   • Low→ less blood= lower MSP, lower CO

   • High→ pumps all blood it can, CO increases

2. Splanchnic vs non-splanchnic stimulation (venoconstriction)

   • venoconstriction→ increased CO

   • MSP increase→ heart can respond to MSP to cahnge CO

   • not correlated with heat rate

What is mean systemic filling pressure (MSFP)

• mean pressure in the system

  • equvalently, the pressure that would eventually exist everywhere in the system if the heart stopped

Like a balloon, MSFP can be increased by…

1. Extra filling

   1. blood transfusion, drinking isotonic water

2. Constricting the filled volume

   1. venoconstriction→ because 65-70% of the blood is in the veins

Understanding the real circulation, beyond the model 1

1. Start with empty circulation: 70-80ml/kg of body mass→ 5l for 70kg

2. if this is added to empty circulation→ first 0% does not cause a rise in pressure

   1. pressure stays at 0 until the vessel walls begin to stretch

Unstressed volume

The unstressed volume

• volume of blood that just fills the circulation without stretching the vessel walls

Understanding the real circulation, beyond the model 2

1. Add last 20% of normal blood volume 

2. mean pressure in he system will rise

   1. Extra volume: stressed volume

   2. normally gives rise to mean presure of 7-10 mmHg in the circulation

Understanding the real circulation, beyond the model 3: heart starts to pump

1. blood transferred from the veins to the arteries

2. changes the venous and arterial presures according to their compliance

Compliance

change in volume/change in pressure

high compliance: Large change in volume for a low change in pressure

Compliance: Veins

• Very compliant in the psyhiological range

• In non physiological (very overstretched)→ VERY stiff

  • greatt for using saphenous vein graft to replace blocked coronary artery

What does high venous compliance ensure?

• if pressure without cardiac activity was 7mmHg everywhere

• the reduction in venous pressure with cardiac actitivty would be relatively small

Compliance: arteries

• Much less compliant

• causes a steep ris in presure due to movement of blood

Understanding the real circulation, beyond the model 4: venous and arterial pressures change until…

1. venous pressure is close to zero

2. Mean arterial pressure is about 90-95 mmHg

What does this mean

• the heart is working normally:

  • Arteries are more filled

  • veins are less filled

  • Than they would be if the heart stopped

Understanding the real circulation, beyond the model 5

1. The ateriovenous pressure difference then drives blood flow

2. from the arteries via the capillaries

3. to the veins

→ Circulation

Because veins can collapse if the veous pressure falls below atmospheric pressure…

• the maximum arteriovenous pressure difference is set by the mean filling pressure

This implies:

1. The heart cannot change the mean pressure

2. the mean pressure determines the maximum cardiac output

Recap of the abbreviations

Mean systemic filling pressure is therefore…

• a critical determinant of cardiac output

How is MSFP determined

1. by the volume of blood

2. mean tension in blood vessel walls

MSFP can be doubled by

• increasing the blood volume by 20%

Why is this?

• this doubles the stressed volume

What does this also double?

• The cardiac output

loss of 20% of cirulating volume…

• reduces the MSFP ( and hence CO) to zero

• because only the last 20% of blood actually stresses vessel walls

Fortuantely, mean tension in the blood vessel walla can be regulated

• 60% of blood is in thhe venules and small veins

  • → venoconstriction can reduced the capactiy of the circulation

  • such that MSFP can be maintained above zero until about 40% of the circulating volume is lost

How is this accomplished?

• sympathetic venoconstriction 

→ can up to treble MSFP

Note: venoconstriction and Total peripheral pressure

• Venoconstriction does not significantly influence TPR

What is TPR determined by

• Resistance of the arterioles

But why does arteriolar constriction increase TPR but not influence MSFP

• because (as seen in the graph) less than 1%  of blood is contained within the arterioles

Quantifying cardiac output

1. Darcy’s law: Flow=pressure difference/resistance

2. therefore arteriovenous pressure difference produces blood flow:

   • CO= (ABP-RAP)/TPR

   • arterial blood pressure-right atrial pressure/total preipheral resistance

Arteriovenous pressure difference (ABP-RAP)

• created by the action of the heart

• limited by MSFP

TPR

• ‘lumped parameter’

• treats all resistances as the varous vascular pathways as a single resistance

but

• primarily determined by arteriolar resistances

RAP

• usually so small compared to ABP

  • can often be omitted from the equation

How can CO be measured?

• cannot be directl measured  anywhere in the body

• it is regulated to maintain ABP

The heart is able to respond to changing physiological need through…

1. intrinsic

and

2. extrinsic  mechanisms

1. Intrinsix regulation of cardiac output: Starling’s ‘law of the heart’: Frank-Starling mechanism

• Responsible for increasing CO when MSFP increases

Preload and afterload

1. Preload→ right atrial pressure

2. Afterload→ arterial blood pressure

Increase in preload and afterload does what

1. stretches the cardiac muscle

This increases the mycocardial contractile force by at least two mechanisms

1. stretching ardiac muslce incrases the overlap between myosin and actin filaments

   • → allowing greater crossbridge formation

2. Stretch of cardiac muscle increases its sensitvity to Ca2+ such that greater force is produced at any given Ca2+ concentration

The steep response of the heart to increased RAP ensures that… 

• increased MSFP produces increased CO

The increase in myocardial contractility with increased afterload ensures that…

• an increase in TPR

  • by generalised arteriolar vasoconstriction

• does not reduce CO

instead: causes an increase in ABP because (ABP= COxTPR)

This is supported by evidence from miscrosphere experiments

1. microspheres injected into dogs bloack manny arterioles

2. more than doubling TPR

Result…

• This did not reduce CO

THEREFORE: ABP more than doubled

RAP is therefore a key point of control in circulation…

• If CO stayed constant

• then an increase in MSFP would  incrase RAP

Why does this happen?

• the pressure would increase throughout the circulation

  • the greatest percentage increase would be at the right atrium

  • where pressure was initially lowest

However, in real life CO would…

not stay constant

• from starling’s experiments we know

  • that the increased RAP 

    • i.e increased pre-load)

  • will increase stroke volume and hence

  • CO (and ABP by ABP =CO x TPR)

Form figure 8, by considering Starling mechanism…

1. Increased MSFP causes increased CO under normal physiological conditions

2. Decrased MSFP decreases the maximum CO

This is why blood loss…

• decreases blood pressure 

• And one reason why exericise is impaired by severe dehydration

2. Extrinsic control of cardiac output: if heart rate changes in isolation…

• stroke volume drops and cardiac outpute barely changes

• → the heart cannot ‘pull’ more blood from the veous system

However, increased heart rate in exercise…

• facilitates increased cardiac output by shifting the curve CO vs RAP

In addition…

• sympathetic stimulation

• e.g during exercise

• enhances Ca2+ entry

in diagram: transplant= sympatheic fibres are severed→ so it is the heart that is responding to exercise and not the symathetic but this shows that both are happening

May be easier to look at the corculation in two parts: Guyton’s curves

1. part which pressure if above MSFP

2. part which pressure is below MSFP

Then we consider cardiac output and venous return separately (even though they must be equal)

• Where TPR is the resistance prior to the ‘pivotal point’

• where pressure = MSFP

• RvR → resistance to venous return→ the reamining resistance

RvR is a bit of an oddity…

• best to think of it as a term that reflects the difficulties blood has in returning to the heart

  • the fact that capillary pressure in the feet is insufficient to drive blood more than a meter upwards to the heart

• so that venous return from the lower legs must wait for voluntary muscle movements to pump blood back

Therefore…

• RvR can change→ expeically in exercise

  • but this is specifically regulated

The venous return equation allows us to…

• consider venous blood flow at different values of RAP

Figure 15 suggests that…

• venous return drops as RAP increases:

  • The differencebetween MSFP nad RAP gets smaller

• RAP at a venous return of 0→ which is the mean systemic filling pressure

Rasing MSFP by increasing circulating volume or venoconstriction would…

• increase the slope without changing MSFP

  • i.e→ it would not change the intersection of the line with the X-axis

But RAP does not just influence venous return…

• Starling mechanism→ incrased RAP increases cardiac output

Cardiac output and venous return must be

• The same

• This is where the curves cross

  • for this system, at an RAP of 0mmHg and CO of 5 lmin'-1

If RAP was 5 mmHg…

• CO would transiently exceed venous return

• which would cause RAP to drop until VR and CO became equal again

These curves are helpful because… guyton curves

1. MSFP only shifts

• → VR curve and TPR

or

2. changes in myocardial contracility only shift→ CO curve

What does figure 14 show: without stimulation

Considers two effects of sympathetic stimulation sparately

1. Without stimulation→ the system rests at a point A

What does figure 14 show: with sympathetic venoconstriction  

1. Symathetic venoconstriction→ increases MSFP

   • hence shifts the venous return curve higher at any RAP (as VR=MSFP-RAP)

this upward shift means: 

1. for a moment

2. VR Exceeds CO 

3. but this increases RAP

4. CO increases

5. system settles at point B→ raised RAP and raised CO

What does figure 14 show: with sympathetic sstimulation of heart only

1. cardiac output curve shift to igher outputs at any RAP

however:

2. as this drives RAP negative→ so the CO cannot incrase any further

3. the increase in CO is minimal to point C

What does figure 14 show: with sympathetic sstimulation of heart AND venoconstriction (BOTH EFFECTS COMBINED)

• the curve both overal at point D

  • a higher cardiac output with RAP remaining at zero

Why are guyton’s curves helpful

• help in considering the effect of various changes to the circulation

  • e.g to imagine what would happen in heart was failing

Curves to imagine waht would happen in heart was failing:

→ CO reduced at every RAP:

result:

1. crossing point would slide down the VR curve

2. such that CO would reduce somewhat 

3. RAP would increase significantly

However,

• it should be clear that these curves are a simple model

• it is also possible to think about th circulation in terms of a single pressure/flow relationship

But waht id he heart is unable to incrase output?→ Cardiac disease

→ will be considered next…