L20 CVS Physiology 11 Ischaemic heart disease

Overview

This lecture works from normal coronary supply to the ECG signature of infarction. It starts with coronary anatomy and the way flow fluctuates across the cardiac cycle (left ventricular flow occurs primarily during diastole, because systolic intramural pressure compresses the vessels), then the structural and functional adaptations that let the myocardium meet a high, inflexible oxygen demand (high capillary density, high basal flow, 65 to 75% oxygen extraction), and the local metabolic control that raises flow when demand rises. It then follows what happens when a stenosis prevents that matching: ischaemia, rapid contractile failure, a self-worsening loop through raised end-diastolic pressure, and at cell level ATP depletion, lactic acid, opening of ATP-sensitive K+ channels and K+ efflux. The altered action potential in the ischaemic zone generates the current of injury, which is what ST elevation and depression on the ECG actually represent and what allows the infarct to be localised.

Coronary anatomy

• Two major coronary arteries run from the base of the aorta to the left and right ventricles, then give off branches that run down the surface of the heart towards the apex.
• Right coronary artery supplies the right ventricle, parts of the septum, and the posterior wall of the left ventricle.
• Left coronary artery supplies the rest of the heart. Its major branch, the left anterior descending (LAD) artery, supplies part of the septum.
• Other named vessels on the anatomy diagram: posterior descending artery, circumflex artery.

Coronary flow during the cardiac cycle

Coronary flow shows marked fluctuations in rate depending on whether the ventricle is in systole or diastole.

Left ventricle

• During systole, intramural myocardial pressure rises and compresses the coronary blood vessels.
• That compression is primarily in the sub-endocardium.
• There is complete interruption of blood flow into the left ventricle during early systole, due to the high pressure development.
• Blood flow in the left ventricle thus happens primarily during diastole.

Right ventricle

• Intramural pressure is lower, so right coronary artery flow can occur during systole.
• Right coronary artery flow follows the fluctuations in aortic pressure.

Why the sub-endocardium is vulnerable

• Nutrient flow reaches the myocardium via vessels that penetrate the ventricular wall: epicardial artery to muscular branches to branches extending through the thickness of the wall, with anastomotic channels, running from the epicardial surface toward the endocardial surface.
• The endocardial regions, especially in the thick-walled left ventricle, lie at the “end of the line” of coronary flow.
• Because the coronary arteries traverse the wall, delivery to the left ventricular endocardium is influenced by intramyocardial pressure, so the sub-endocardial regions of the left ventricle are vulnerable to decreased blood flow.

Meeting myocardial oxygen demand

The myocardium has two requirements: maintain a high basal oxygen supply (the heart cannot stop for a rest) and increase oxygen delivery in proportion to demand, that is in proportion to cardiac work.

• Basal requirement: 8 ml O2/min/100 g, which is 20 times more than resting skeletal muscle.
• Coronary blood flow per gram of tissue is 10 times higher than the whole-body average.
• Despite that high flow, the myocardium must extract 65 to 75% of the oxygen delivered to meet demand.

Capillary density (skeletal vs cardiac muscle)

	Skeletal muscle	Cardiac muscle
Muscle fibre diameter	50 μm	18 μm
Capillaries per mm²	400	3000

High capillary density confers a big surface area for oxygen transfer and a short diffusion distance into the cardiomyocyte.

Extraction, shown on the oxygen dissociation curve

• Arterial point A sits at roughly 95 mmHg pO2 with an oxygen content of about 195 ml O2/litre.
• Mixed venous blood (pCO2 46 mmHg, 5.8 kPa) has a content of about 145 ml O2/litre, roughly 25% extracted.
• Coronary sinus blood (pCO2 58 mmHg, 7.3 kPa) has a content of about 50 ml O2/litre on a right-shifted curve, roughly 75% extracted.

Regulation of coronary blood flow

• At rest the heart already extracts much more oxygen from blood passing through it than other organs do.
• During exercise the heart needs more oxygen but cannot increase extraction further (it is already close to maximum), so the extra requirement must be met by increasing blood flow.
• Coronary flow increases by dilation of the coronary vessels and reduction in resistance.
• One of the strongest stimuli to dilate the coronary arteries is oxygen deficiency: even a 5% drop in coronary artery blood oxygen content leads to coronary vasodilation.
• Local metabolic control therefore appears to be the most important mechanism controlling coronary blood flow, matching an increase in oxygen consumption with an increase in coronary blood flow.

Adenosine (the most likely metabolic mediator)

1. Work or ischaemia creates an ATP imbalance: the rate at which the oxygen supply to the mitochondria can synthesise ATP is temporarily exceeded (oxygen supply exceeded).
2. ATP breaks down to form adenosine, in myocardial cells, during heavy exercise, hypoxia and ischaemia.
3. Adenosine leaves the cell into the extracellular space.
4. It acts on the arterial wall as a vasodilator.
5. Oxygen supply is restored and ATP is restored.

Nitric oxide

1. NO is synthesised in endothelial cells (released from healthy endothelium).
2. NO diffuses to nearby vascular smooth muscle (VSM) cells.
3. It increases cGMP concentration.
4. Intracellular Ca2+ falls.
5. VSM relaxes and the coronary artery dilates.

Neurogenic factors are both vasodilatory (β-adrenergic) and vasoconstrictory (α-adrenergic). On the figure, noradrenaline acts on vessel-wall α1/α2 receptors to produce neurogenic vasoconstriction, with an α2 inhibitory feedback loop and a feed-forward β component.

Coronary artery disease and stenosis

• Coronary artery disease can lead to coronary artery stenosis.
• Stenosis reduces coronary perfusion pressure in the distal segment of the diseased artery and induces ischaemia.
• Ischaemia leads to contractile failure.
• With increasing exercise, normal coronary flow rises steadily with myocardial oxygen consumption. In a diseased vessel flow rises only slightly and then plateaus: coronary atheroma prevents blood flow from matching demand, producing angina.

The 70% threshold

• Reductions in coronary lumen diameter of up to 70% do not cause major increases in resistance to flow.
• Beyond 70% reduction there is a dramatic increase in vascular resistance and a fall in blood flow.
• Resistance is proportional to $1/r^4$ (Poiseuille’s Law), which is why the resistance curve is nearly flat to about 70% stenosis and then rises steeply toward 90%.

Ischaemic contractile failure

The major effect of ischaemia is a decline in contractile function, and the loss is very rapid: 10 to 120 seconds after the onset of severe ischaemia.

Causes of the reduced contractility

• Depletion of creatine phosphate (CP) and ATP.
• Accumulation in the myocardium of products of ischaemia: lactic acid.
• Increased extracellular K+ concentration.

The self-worsening haemodynamic loop

1. Reduced contractility (the muscle operates on a lower Starling curve).
2. Reduced stroke volume.
3. Increased end-systolic volume.
4. Increased end-diastolic volume.
5. Increased end-diastolic pressure.
6. Raised end-diastolic pressure compresses sub-endocardial tissue.
7. Blood flow is further reduced, leading to increased ischaemia.

Early ischaemic K+ loss (cellular sequence)

1. Oxidative metabolism is inhibited (mitochondrial function fails).
2. Anaerobic metabolism from glucose and glycogen leads to production of lactic acid, with lactate- and H+ accumulating and Na+ movement across the membrane.
3. High-energy phosphate levels fall (CP and ATP decline, PO4 rises).
4. ATP-sensitive K+ channels, which need ATP to stay closed, open.
5. K+ leaves the cell and raises extracellular K+ for the surrounding cardiac muscle cells.

Effect of raised extracellular K+ on the action potential

• Normal extracellular fluid K+ is 3.5 to 5.5 mM.
• 7.5 mM will arrest the heart in diastole.
• Intermediate K+ concentrations markedly weaken cardiac contraction.
• Raised extracellular K+ lowers the potassium equilibrium potential, so the resting membrane potential of the surrounding cells becomes less negative. Traces recorded at K+o of 3, 10 and 16 mM show progressively less negative resting potential and altered action potential morphology.

Normal ventricular action potential phases and currents

Phase	Current
Resting membrane potential	Outward K+ current (i_K1/i_b)
Upstroke (phase 0)	Inward Na+ current, voltage-sensitive fast Na+ channel (i_Na)
Early repolarisation	Outward K+ current (i_to)
Phase 2, plateau	Inward Ca2+ current (i_Ca-L)
Phase 3, late repolarisation	Outward K+ current (i_K)

How the ischaemic action potential differs
The AP in the ischaemic area is altered in two ways: slower onset with reduced amplitude, and a shortened plateau with earlier late repolarisation. It is overall shorter.

1. Slower onset and reduced amplitude, all to do with the fast Na+ channels. Membrane potential in ischaemic cells is less negative than in normal myocardium, so some fast Na+ channels remain inactive. During depolarisation fewer Na+ channels open, the inward Na+ current is not as strong, and the upstroke is smaller and less perpendicular, that is slower.
2. Shortened plateau and earlier late repolarisation, all to do with the K+ channels. In normal cells repolarisation is due to the K+ current i_K and the ATP-sensitive K+ channel is closed. In ischaemic cells the ATP-sensitive K+ channel is open (driven by ATP to ADP + Pi), repolarisation occurs earlier than usual, the plateau is shorter, Ca2+ entry into the cell is reduced, and the force of contraction is weaker.

Current of injury and the ECG

• Normally all areas of the ventricles depolarise and repolarise together. When the muscle is fully depolarised or fully repolarised there is no current flow and the ECG shows an isoelectric line, for example the ST segment.
• When part of the muscle is ischaemic and part is normal, an abnormal current develops: the current of injury.

During mid-systole

• Normal tissue is more positive than the ischaemic area (diagram: -15 mV over the ischaemic zone, +5 mV over adjacent normal zones).
• Current flows from normal to ischaemic tissue, towards the detecting electrode.
• Major ECG change: elevation of the S-T segment.

During diastole

• The diagram shows -70 mV over the ischaemic zone and -90 mV over adjacent normal zones.
• Current flows from ischaemic to normal tissue, away from the detecting electrode.
• Major ECG change: depression of the baseline (T-Q segment).

Warning

The diastole slide reads “the ischaemic tissue is more positive than the ischaemic areas”, which is likely a source typo (probably intended “more positive than the normal areas”, given the diagram shows -70 mV in the ischaemic zone vs -90 mV in normal zones). Transcribed as printed, not corrected.

Localising the infarct

• Analysing which leads show a current of injury (ST elevation or depression) allows identification of which part of the heart is ischaemic.
• ST segment elevation is seen in leads that “look at” the infarcted part of the heart.
• ST segment depression is seen in leads opposite the infarction.
• Worked example, acute myocardial infarction of the inferior portion of the heart: ST elevation in leads III, aVF and II (the inferior sector of the lead-axis circle); ST depression in leads aVL and I (the opposite sector). Grouped together, the ECG data suggests the infarct is in the inferior part of the heart.
• Additional changes to look for: T wave inversion and pathological Q waves.

Annotated example ECGs

• An inferolateral infarct with ST elevation in II, III and aVF, with reciprocal change in V1 to V3.
• An anterior MI with ST-segment changes circled in V2, V3 and V4.
• A further 12-lead ECG record (rhythm strip V1, 25 mm/sec, 1 cm/mV) shown as a standalone example without case annotation.

Warning

The example ECGs carry transcript flags: one has no title, bullets or case annotation at all, and the handwritten headers, dates and annotations on the other two are partly or largely illegible, so only the legible text is recorded above.

Clinical case

A news article presented in the lecture: a woman in her 50s died of a cardiac arrest hours after being sent home from the emergency department at Palmerston North Hospital with chest pain. The care provided in 2018 was so concerning that the coroner referred it to the Health and Disability Commissioner. She had been experiencing chest pain for two days when she presented via ambulance. She had no history of a heart condition, but three of her siblings had suffered a heart attack in their mid-50s. After five hours, two electrocardiograms, and two tests for a protein found in the blood when heart muscle has been damaged by a heart attack, she was discharged from the ED. She suffered a cardiac arrest that night at home and died.

Self-test

1. State which regions of the heart the right coronary artery supplies.
2. Explain why left ventricular coronary flow happens primarily during diastole, and when flow is completely interrupted.
3. Distinguish right from left coronary artery flow across the cardiac cycle.
4. Explain why the sub-endocardium of the left ventricle is the region most vulnerable to reduced blood flow.
5. Give the myocardium’s basal oxygen requirement per 100 g and how it compares with resting skeletal muscle.
6. Compare skeletal and cardiac muscle on fibre diameter and capillary density, and say what the cardiac arrangement achieves.
7. Explain why the heart must meet an increased oxygen demand during exercise by raising flow rather than extraction.
8. Describe the steps by which adenosine mediates metabolic vasodilation in the coronary circulation.
9. Describe the steps by which nitric oxide dilates a coronary artery.
10. What degree of luminal diameter reduction is needed before resistance rises dramatically, and what physical law explains the steepness of that rise?
11. Describe the sequence by which ischaemic contractile failure further reduces coronary blood flow.
12. List the three causes given for reduced myocardial contractility in ischaemia.
13. Describe the steps of early ischaemic K+ loss from the cardiomyocyte.
14. What is the normal extracellular K+ range, and what concentration arrests the heart in diastole?
15. Explain why the upstroke of the action potential is slower and smaller in the ischaemic zone.
16. Explain why the plateau is shortened in the ischaemic zone and predict the effect on contractile force.
17. Explain what generates the current of injury and why it produces ST elevation in mid-systole.
18. A patient’s ECG shows ST elevation in II, III and aVF with ST depression in I and aVL. Where is the infarct, and what other ECG changes should you look for?
19. Integrative: trace the chain from a greater than 70% coronary stenosis during exercise through to ST-segment elevation on the ECG.

Answers

Reveal answers

1. The right ventricle, parts of the septum, and the posterior wall of the left ventricle.
2. During systole intramural myocardial pressure rises and compresses the coronary vessels, compression being primarily in the sub-endocardium, so flow happens primarily during diastole. Flow into the left ventricle is completely interrupted during early systole because of the high pressure development.
3. Left ventricular flow is compressed during systole and occurs primarily in diastole. In the right ventricle intramural pressure is lower, so right coronary flow can occur during systole and follows the fluctuations in aortic pressure.
4. The coronary arteries traverse the ventricular wall from the epicardial to the endocardial surface, so the endocardial regions of the thick-walled left ventricle lie at the “end of the line” of coronary flow and their perfusion is influenced by intramyocardial pressure.
5. 8 ml O2/min/100 g, which is 20 times more than resting skeletal muscle.
6. Skeletal muscle: fibre diameter 50 μm, 400 capillaries per mm². Cardiac muscle: fibre diameter 18 μm, 3000 capillaries per mm². The high cardiac capillary density gives a big surface area for oxygen transfer and a short diffusion distance into the cardiomyocyte.
7. At rest the heart already extracts 65 to 75% of delivered oxygen, far more than other organs, so extraction is already close to maximum and cannot rise further. The extra requirement must be met by increasing coronary blood flow, through vessel dilation and reduced resistance.
8. Work or ischaemia creates an ATP imbalance in which the rate of ATP synthesis supportable by the oxygen supply to mitochondria is exceeded; ATP breaks down to adenosine (during heavy exercise, hypoxia, ischaemia); adenosine leaves the cell into the extracellular space; it acts on the arterial wall as a vasodilator; oxygen supply and then ATP are restored.
9. NO is synthesised in endothelial cells, diffuses to nearby vascular smooth muscle cells, increases cGMP, reduces intracellular Ca2+, relaxes the smooth muscle and dilates the coronary artery.
10. More than 70% reduction in luminal diameter. Resistance is proportional to $1/r^4$ (Poiseuille’s Law), so once the radius is small the resistance rises steeply and blood flow falls.
11. Reduced contractility (lower Starling curve) reduces stroke volume, raising end-systolic volume, then end-diastolic volume, then end-diastolic pressure; the raised end-diastolic pressure compresses sub-endocardial tissue, further reducing blood flow and increasing ischaemia.
12. Depletion of creatine phosphate and ATP; accumulation of products of ischaemia, namely lactic acid; increased extracellular K+ concentration.
13. Oxidative metabolism is inhibited; anaerobic metabolism of glucose and glycogen produces lactic acid; high-energy phosphate levels (CP and ATP) fall; ATP-sensitive K+ channels, which need ATP to stay closed, open; K+ leaves the cell and raises extracellular K+ around neighbouring cells.
14. Normal extracellular fluid K+ is 3.5 to 5.5 mM. 7.5 mM will arrest the heart in diastole; intermediate concentrations markedly weaken contraction.
15. Raised extracellular K+ lowers the potassium equilibrium potential, so the resting membrane potential is less negative and some fast Na+ channels remain inactive. Fewer Na+ channels open on depolarisation, the inward Na+ current is weaker, and the upstroke is smaller and less steep.
16. In ischaemic cells the ATP-sensitive K+ channel is open (ATP having broken down to ADP + Pi), so repolarisation occurs earlier than usual and the plateau is shorter. Ca2+ entry into the cell is reduced, so the force of contraction is weaker.
17. Normally the whole ventricle depolarises and repolarises together, so fully depolarised or repolarised muscle gives an isoelectric line. When part of the muscle is ischaemic and part normal, an abnormal current of injury develops between them. In mid-systole the normal tissue is more positive than the ischaemic area, so current flows from normal to ischaemic tissue towards the detecting electrode, producing ST-segment elevation.
18. The infarct is in the inferior part of the heart: II, III and aVF are the leads that “look at” the infarcted region and show elevation, while I and aVL are opposite the infarction and show reciprocal depression. Also look for T wave inversion and pathological Q waves.
19. Above 70% diameter reduction, resistance rises dramatically (proportional to $1/r^4$) and flow falls, so flow cannot match rising demand during exercise and the distal segment becomes ischaemic. Oxidative metabolism is inhibited, lactic acid accumulates and CP and ATP fall; ATP-sensitive K+ channels open, K+ leaves the cell and extracellular K+ rises, making the resting potential less negative and shortening the action potential. The ischaemic zone now differs in potential from adjacent normal myocardium, generating a current of injury that flows from normal to ischaemic tissue in mid-systole, towards the detecting electrode, recorded as ST-segment elevation.