The cardiac pressure-volume cycle & ions and action potentials

Question 1

What is the name of the circle of arteries on the underside of the base of the brain AND what is its physiological function?

Answer 1

• The Circle of Willis
• It provides redundancies in arterial blood supply to the brain, vouchsafing consistent perfusion to all regions (and protection from ischaemia) in cases where one major artery supplying the brain was temporarily blocked or narrowed

Question 2

Name TWO plasma secretions of the kidney that are central to the RAAS.

Answer 2

• Angiotensin converting enzyme
• Renin

Question 3

Name THREE aspects of the circulation of large skeletal muscles that make it a “special circulation”.

Answer 3

• Can use up to 80% of cardiac output during exercise
• Arterial supply vasodilates in response to sympathetic stimulation
• Muscle pump contributes directly to venous return.

Question 4

Name TWO aspects of the circulation of the brain that make it a “special circulation”.

Answer 4

• Auto-regulation (constancy of flow and pressure)
• Circle of Willis

Question 5

Name FOUR aspects of the special circulation of the skin that make it well-suited for thermo-regulation.

Answer 5

• Can regulate blood perfusion by up to 100-fold
• Arterio-venous anastomoses allow for thermal exchange without the resistance of a capillary bed
• Sweat glands turn fluid ultrafiltrate from plasma into a rapid heat loss system.

Question 6

Name THREE reactions of the special circulation of the skin that make its inflammatory response to trauma unique.

Answer 6

• Red reaction
• Flare
• Wheal.

Question 7

Draw a ventricular action potential. Include axes, units, and approximate values.

Answer 7

Question 8

List the heart valves, and for each one state the type of valve it is, and the regions it separates.

Answer 8

• Tricuspid Valve: AV valve, Right Atrium from Right Ventricle
• Pulmonic Valve: semilunar, Right ventricle from Pulmonary Arteries

•

•

• Mitral (bicuspid) Valve: AV valve, Left Atrium from left Ventricle
• Aortic Valve: semilunar, left ventricle from aorta

Question 9

Name the valve sounds and when they can appear in the cardiac cycle.

Answer 9

•S1: First heart sound (lub)

–When Mitral & Tricuspid Close

–during systole

–

•S2: Second heart sound (dub)

–When Aortic & pulmonic valves Close

–during diastole

–Diastole is longer than systole

Question 10

Align an ECG in time directly underneath a ventricular action potential

Answer 10

QRS complex lines up with depolarisation of ventricular AP

T wave lines up with repolarisation of ventricular AP

Question 11

Draw a nodal action potential. Include axes, units, and approximate values.

Answer 11

Nodal AP is in red

Question 12

Align an ECG in time directly underneath a nodal action potential

Answer 12

P wave lines up with depolarisation of SA Node

Question 13

List the phases of the ventricular action potential and state for each what channel is responsible for conducting that current.

Answer 13

0 Depolarisation: Na+ gates open in response to wave of excitation from pacemaker

1 Transient Outward Current: tiny amount of K+ leaves cell, this leads to a small amount of repolarisation

2 Plateau phase: Inflow of Ca2+ just about balances outflow of K+

3 Rapid repolarisation phase: Membrane potential falls as K+ leaves cell

4 Back to resting potential

Question 14

List the phases of the cardiac nodal action potential and state for each what channel is responsible for conducting that current.

Answer 14

0 Depolarisation: Ca2+ channels open in response to automaticity

3 Rapid repolarisation phase: Membrane potential falls as K+ leaves cell

4 Pacemaker potential

Question 15

Name 3 types of potassium channel that are important in cardiac rhythmic activity AND for each name its primary function.

Answer 15

• Delayed rectifier: repolarises the action potential
• Inward rectifier: clamps voltage near resting potential (in non-nodal myocytes). Also contributes to late repolarisation of AP
• Ach-activated K+ channel: slows down heart rate in response to vagal stimulation by decreasing the pacemaker potential’s slope upward.
• Could also mention:
• K(ATP) channels

Question 16

What is tetany, and why does it not occur in cardiac muscle?

Answer 16

Tetany is a state of maximal contraction in a skeletal muscle cell in which a high stimulation frequency is too rapid for recovery and relaxation, so the contractions effectively become continuous and stronger than possible with a single twitch. It occurs because calcium builds up in the cytosol due to the lack of time to pump it back into the SR. This does not happen in cardiac muscle because an extended contraction without relaxation would effectively stop the beating of that cell and prevent relaxation/diastole.

Question 17

What is the pacemaker potential and how does it come about?

Answer 17

The pacemaker potential is the upward drift in voltage that occurs between action potentials, which occurs in myocytes of SA node, AV node, and conduction system only. Also called: diastolic potential. It occurs instead of the resting potential (because these cells lack the inward rectifier K+ channels that would clamp the cell to the resting potential). The slope of PP determines the automatic rate of firing of the cell.

Question 18

Draw a graph of the pressure volume loop of a cardiac cycle of the left ventricle (ie graph pressure vs volume). Label the axes (including units and approximate values), and label each phase of the cardiac cycle. Draw arrows where each set of valves open and close.

Answer 18

4-1: Filling

1-2: isovol contr

2-3: ejection

3-4: isovol relax

AV valves

Open at 4

Close at 1

Semilunar valves

Open at 2

Close at 3

Question 19

Under what circumstances would you expect a systolic murmur? Or a diastolic murmur?

Answer 19

Systolic murmur: semilunar insufficiency/stenosis, AV valve regurgitation

Diastolic murmur: semilunar regurgitation, AV valve insufficiency/stenosis

Question 20

What is the molecular basis of cardiac muscle contraction?

Answer 20

This is the sliding filament model (explained in detail in module 102) where thick filaments pull on thin filaments from two opposing z-lines, thus shortening the sarcomere. The thick filaments are mostly made up of myosin (a “motor protein”) and the thin filaments are structurally based on actin. The thin filaments also have on them the regulatory proteins tropomyosin and troponin, which are essential in converting the calcium signal in the cytoplasm into contraction.

Question 21

In the Wiggers plot above:

Identify systole and diastole

Identify the four phases of the cardiac pressure cycle.

Identify when each pair of valves opens and closes.

Draw an ECG that aligns in time with the pressure plots.

Answer 21

IVC is defined as the time between when the mitral valve closes and the aortic valve opens. During this time the “contraction” of the left ventricle generates increasing pressure but without changing volume (ie there is force generation without extensive contraction in size because the blood fluid is not compressible, and the aortic valve has not yet opened). You can tell when the mitral valve is closed because the atrial pressure (red at bottom) and the ventricular pressure (black) are identical. When the mitral valve closes, the ventricular pressure become independent of the atrial pressure. Likewise, you can tell when the aortic valve is open because the aortic pressure (red, upper) and the ventricular pressure (black) become identical. When the aortic valve closes (as the ventricle starts to relax), the aortic pressure and the ventricular pressure split apart. At the end of IVR the mitral valve opens and the ventricle and the atrium have identical pressures.

Question 22

Given the normal ventricular pressure-volume (grey), explain what type of valve dysfunction is shown in red (at X) and explain the mechanism for why the valve changes result in the pressure-volume changes?

Answer 22

This aortic valve stenosis.

There is high afterload because the valve creates resistance during systole that obstructs blood from leaving. No change in preload

The high afterload manifests as very high pressure during ejection, and high volumes during isovolumic relaxation (because the stenotic valve interferes with ejection

Question 23

Given the normal ventricular pressure-volume (grey), explain what type of valve dysfunction is shown in red (at X) and explain the mechanism for why the valve changes result in the pressure-volume changes?

Answer 23

This is mitral stenosis.

The stenotic mitral valve interferes with filling (and thus reduces preload), so volume during isovolumic contraction is low..

Because preload is so much lower, afterload is lowered (because the ventricle generates so much less pressure) due to reduced Starling forces.

The lower afterload manifests as a low isovlumic relaxation. It also results in the lack of a corner because the previous systole did not pump so much blood, so there is less systemic back pressure on the aortic valve

Question 24

Given the normal ventricular pressure-volume (grey), explain what type of valve dysfunction is shown in red (at X) and explain why its pressure-volume relationship is round rather than square-ish?

Answer 24

This is aortic regurgitation.

The preload is much higher than normal (ie the right edge of the red curve is shifted leftward).

Preload is higher in all regurgitating valve anomalies. In aortic regurgitation, during diastole the aortic valve allows fluid to back-flow into the left ventricle, added to the fluid coming from the left atrium.

Both regurgitating valve pathologies have rounded PV curves (ie they do not have corners, or IVC and IVR phases). The straight lines of IVC and IVR occur when both valves are closed and the left ventricle is a sealed unit. In regurgitating valves, there is never a time when both valves are completely closed – one valve is always leaking

Question 25

Given the normal ventricular pressure-volume (grey), explain what type of valve dysfunction is shown in red (at X) and explain the mechanism for these changes in terms of preload and afterload.

Answer 25

This is mitral valve regurgitation.

This red graph shows low afterload (i.e. top is shifted down, and left side is shifted further left).

There is low afterload because during systole the blood can be ejected into the left atrium (through the regurgitating mitral valve), as well as into the aorta. This lowers the resistance against pumping.

There is much higher preload (right edge is shifted rightward). This happens because the excess blood in the left atrium (from the previous beat) is under high pressure, and it adds to the filling of the left ventricle, creating volume overload

Question 26

How is the rhythm of the heartbeat initiated and maintained?

Answer 26

Specialised nodal cells (in SA and AV node) have autorhythmicity. Instead of remaining at a resting potential between APs, they undergo a pacemaker potential, which is a slow depolarisation toward threshold due to net inward current of the funny current (If: Na+ inward AND K+ outward) . From the SA node signals are sent (via four branches) throughout the atria, and to the AV node, where the signal is delayed ~150 ms. The signal is then conducted via specialised conducting tissue in the His-Purkinje system, inferiorly toward the apex of the heart, and then superiorly and laterally back toward the base.

Question 27

How do the atria beat before the ventricles?

Answer 27

The entire heart is driven by the first cell to depolarize after the previous beat. The fastest cells to recover are (in a healthy heart) in the SA node. The impulse is then sent to the AV node via the atrial bundles, and there is a lengthy delay of the signal while it traverses the AV node. The His-Purkinje system then allows for relatively synchronous activity of the ventricles. Since contraction follows electrical activity, the atria contract first, and the electrical delay in the AV node leads to a contraction delay for the ventricle.

Question 28

What is the funny current, what effect does it have on nodal cells, and what ions mediate it?

Answer 28

The funny current is an inward ionic current found in nodal (and His-Purkinje) cells that has the unusual property that it is greatest (ie has the highest conductance) when the transmembrane voltage (Vm) is most negative.

This means that it drives the cell to depolarise when it is in diastole – this effect is called the Pacemaker Potential.

The ions conducted by the funny current are Na+ inward AND K+ outward, but the net effect is an inward current because the Na+ in is greater than the K+ out when Vm is close to EK. The reversal potential of the funny current is typically ~ -10 mV

Question 29

What is the dicrotic notch, and what does it represent?

Answer 29

The dicrotic notch is a sudden dip in pressure that can be seen in a Wiggers plot (in the graph of aortic pressure versus time) at the moment that ejection (during systole) ends. It represents the moment when LV pressure diminishes below aortic back pressure, leading to temporary back flow and closure of the aortic valve.

Question 30

Draw a graph showing left ventricular pressure vs. time. Include axes, units and approximate values. On that graph, draw where valve activity can be heard, and where the Isovolumetric relaxation occurs. Finally, on the same graph, draw a line showing aortic pressure vs. time

Answer 30

Question 31

What is the difference between the refractory period and the after-hyperpolarisation?

Answer 31

• The after-hyperpolarisation = a description of the membrane voltage
• The refractory period = a description of the cell’s functional state, i.e. whether the cell is ready to fire again.
• Usually the refractory period (a functional state) corresponds to the after-hyperpolarisation (a set of voltages), but technically these are two different issues.

Question 32

What channels are missing from the nodal action potential that make it so different in timing and shape from a ventricular action potential?

Answer 32

Inward rectifier potassium channels.

Question 33

Why does amlodipine overdose sometimes cause very high heart rates? Why doesn’t it does slow the heart down?

Answer 33

Amlodipine is a dihyropyridine Ca2+ blocker that is targeted more to the calcium channels of the vessels than to the channels of the heart. Because it does not target cardiac calcium channels, it does not substantially slow down the heart rate. The main effect of amlodipine is vasodilatation, and in cases of overdose the vasodilatation leads to severely low peripheral resistance and low blood pressure. This low BP is detected by baroreceptors, which homeostatically increase heart rate to attempt to correct the low blood pressure.

Question 34

Quinidine is antiarrhythmic drug (use prophylactically) whose main action is to block Na+ channels. In most patients it results in an increase in the rate of sinus rhythm. Why doesn’t it slow down the heart rate?

Answer 34

The main effect of Na+ channel blockers on the heart is to slow down conduction velocity between different regions of the heart; this happens because the reduced Na+ influx slows down depolarisation in the His-Purkinje system.

Sinus rate, which is controlled by cells in the SA node, is highly dependent on calcium influx for depolarisation. A Na+ channel blocker would not effect the SA node activity directly.