L23 CVS Physiology 12 Heart failure

Overview

Chronic cardiac failure is approached here as a pump problem: reduced myocardial contractility depresses the ventricular function (Starling) curve, so the heart can only sustain output by operating at a raised filling pressure. The lecture works outward from that single defect. First, why resting cardiac output can look normal (compensated) or be subnormal (decompensated), and why ejection fraction is a better index of function than stroke volume. Second, why exercise unmasks the failure, since both the Frank-Starling reserve (flat curve) and the sympathetic reserve (down-regulated ${\beta }_1$-adrenoceptors) are lost. Third, the compensatory responses (adrenergic activation and renal salt and water retention via the renin-angiotensin-aldosterone system) and the price they carry: raised venous and capillary pressure disturbs Starling’s equilibrium and produces pulmonary or peripheral oedema. Finally, the consequences of the resulting ventricular dilation via the Law of Laplace, and the physiological aims of treatment.

Definition and the central defect

• Chronic heart failure (congestive heart failure) is defined as a chronic inability of the heart to maintain adequate perfusion of the tissues at a normal filling pressure.
• It has multiple causes, but the main pathophysiological feature is reduced myocardial contractility. Put simply, it is not such a good pump.
• The consequence on the ventricular function curve: reduced contractility shifts the Starling curve down (downward and rightward), so a lower stroke volume is generated for any given end-diastolic pressure.

Stroke volume, compensation and the Starling curve

• Expected effect of the depressed curve is a fall in stroke volume and therefore cardiac output, but initially things may not be as bad as they seem.
• At the normal resting end-diastolic pressure (about 8 cmH2O), the failing ventricle would deliver a stroke volume of only about 33 ml against about 68 ml for the normal ventricle.
• In mild failure, stroke volume can be brought back to near normal (about 68 ml) by a compensatory increase in end-diastolic volume and pressure, raising end-diastolic pressure from about 8 to about 20 cmH2O.
• Therefore, at rest, cardiac output in cardiac failure may be either:
  • almost normal (compensated failure), or
  • subnormal (decompensated failure).
• Because of this, stroke volume is not a good indication of cardiac function in cardiac failure.

Ejection fraction

• Ejection fraction is a useful measure of cardiac performance because it puts stroke volume in the context of end-diastolic volume.
• $\text{Ejection fraction (\%)}=\frac{SV}{EDV}$
• At rest in the normal heart, ejection fraction is approximately 50 to 70%.
• Healthy person: ejection fraction about 66% at rest, rising to about 80% on exercise. The rise is produced by two things: an increased end-diastolic volume/pressure, and sympathetic nervous system activation.
• Cardiac failure patient: ejection fraction is reduced at rest (about 60% in the example given) and falls further with exercise (to about 45%), the opposite of the healthy pattern.

Why exercise unmasks the failure

Two mechanisms normally raise stroke volume on exercise, and both are compromised in heart failure.

1. Increased venous return raises stroke volume by the Frank-Starling mechanism, which is movement along the same ventricular function curve (rest at end-diastolic pressure about 8 with stroke volume about 68 ml, to exercise at about 9 to 10 with stroke volume about 78 ml).
2. Sympathetic activation increases contractility, which is a rise onto a higher Starling curve, making it a better pump. This is distinct from movement along a single curve.

In failure:

• The failing curve is flat, so there is much less benefit from an increased end-diastolic pressure. A huge increase in end-diastolic pressure would be needed just to maintain stroke volume.
• The ${\beta }_1$-adrenoceptor mediated increase in contractility in response to adrenaline and noradrenaline is impaired, because of down-regulation of ${\beta }_1$-adrenoceptors in myocardial cells. The shift onto higher curves does not occur.
• The ${\beta }_1$-adrenoceptor mediated increase in heart rate is also impaired, because of down-regulation of ${\beta }_1$-adrenoceptors in the SA node. A rise in adrenaline/noradrenaline levels during exercise does not always increase heart rate.
• Net result: cardiac output fails to increase on exercise, giving exercise intolerance.

Cardiovascular variables: normal versus ischaemic cardiac failure

Values from rest versus a cycle test.

Healthy at rest: baseline values for cardiac output, heart rate, stroke volume, end-diastolic and end-systolic left ventricular volume, and ejection fraction.

Healthy during exercise

• Cardiac output rises to about 300%.
• Heart rate rises to about 180 per minute.
• Stroke volume rises to about 100 ml.
• End-diastolic volume rises a little.
• End-systolic volume falls.
• Ejection fraction rises to about 80%.

Cardiac failure at rest

• Cardiac output normal-ish.
• Heart rate normal or high.
• Stroke volume normal-ish.
• End-diastolic volume high.
• End-systolic volume a little high.
• Ejection fraction decreased.

Cardiac failure during exercise

• Cardiac output only rises about twofold.
• Heart rate shows a limited increase.
• Stroke volume shows a reduced increase.
• Ejection fraction falls to about 45%.
• End-diastolic and end-systolic volumes roughly double.
• A sustained increase in end-diastolic volume will eventually lead to ventricular dilation.

Compensation in cardiac failure

Two compensatory mechanisms.

1. Increased adrenergic activity causing vasoconstriction

• Even at rest, the patient with chronic cardiac failure may have problems maintaining mean arterial pressure because of the low cardiac output.
• Peripheral vasoconstriction increases total peripheral resistance and so maintains mean arterial pressure, since $MAP=CO\times TPR$.
• Venoconstriction also occurs, which increases venous return and hence end-diastolic volume and stroke volume, within limits.
• These effects are achieved by three things: increased sympathetic nerve activation, elevated plasma angiotensin II, and elevated plasma endothelin-1.

2. Renal retention of sodium and water

• This increases extracellular fluid volume, which increases the mean circulatory filling pressure to the heart and so, by Starling’s Law, helps maintain cardiac output (increased ventricular end-diastolic volume, increased stroke volume).
• Because cardiac output is reduced, the output there is gets preferentially distributed to the heart (coronary flow), the brain (cerebral flow) and skeletal muscle.
• Blood flow is reduced to the kidney (renal flow), the skin (cutaneous flow) and the gut (splanchnic flow). In the example, cardiac output falls from 5.8 l/min (normal) to 4.4 l/min (congestive cardiac failure), with gut, skin and kidney flow cut back most.
• The kidneys respond to decreased perfusion by retaining salt and water, expanding the extracellular fluid volume by up to 30%. This retention is due to activation of the renin-angiotensin-aldosterone system.

The renin-angiotensin-aldosterone system

Pathway in order:

1. An acute fall of plasma volume or of blood pressure stimulates renin release.
2. Renin cleaves angiotensinogen to angiotensin I, a 10-residue peptide (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu).
3. Converting enzyme cleaves angiotensin I to angiotensin II, an 8-residue peptide (His-Leu removed).
4. Angiotensin II then: increases appetite for salt; increases thirst; reduces GFR and renal blood flow; stimulates aldosterone secretion; and causes systemic vasoconstriction.
5. These converge on salt and water retention and increased salt and water uptake, restoring plasma volume and blood pressure.
6. Restoration of plasma volume/blood pressure inhibits further renin release, closing the negative feedback loop.

Oedema and Starling’s equilibrium

• Fluid retention supports cardiac function to some extent by Starling’s Law, but the excess fluid does not simply stay in the blood.
• Reduced cardiac function plus increased plasma volume elevates venous pressure, which raises capillary pressure, which disturbs Starling’s equilibrium, which increases interstitial fluid volume and forms oedema.
• Oedema of the lungs and/or the periphery is a prominent feature of chronic cardiac failure.
• About 4 to 5 litres of excess fluid are needed before oedema is clinically detectable.

Starling’s equilibrium at the capillary

• Fluid is driven out of capillaries into the interstitial space by hydrostatic pressure (filtration), and drawn back in by colloid osmotic pressure (reabsorption). The two are essentially in balance.
• Normal values (mmHg):

	Arteriolar end	Venular end
Hydrostatic, blood	32	15
Hydrostatic, interstitial fluid	-2	-2
Net hydrostatic gradient	34	17
Colloid osmotic, blood	25	25
Colloid osmotic, interstitial fluid	0	0
Net colloid osmotic gradient	25	25
Net (hydrostatic minus colloid osmotic)	9, favouring ultrafiltration	8, favouring reabsorption

• In heart failure the raised venous pressure raises the venular-end capillary hydrostatic pressure from 15 to 30 mmHg, so the net hydrostatic gradient falls from 34/17 to 28 at the venular end and the net venular balance changes from 8 favouring reabsorption to 3, that is, the balance shifts toward filtration.
• If the net rate of filtration exceeds lymph flow, fluid accumulates in the interstitial space and causes oedema.

Pulmonary oedema (left ventricular failure)

Mechanism in order:

1. Increased end-diastolic volume.
2. Increased end-diastolic pressure.
3. Decreased left atrial to left ventricular pressure gradient.
4. Increased left atrial volume and left atrial pressure.
5. Increased pulmonary venous pressure.
6. Increased pulmonary capillary pressure, shifting fluid out of pulmonary capillaries into the lung interstitium, producing pulmonary oedema.

Consequences:

• Pulmonary interstitial congestion reduces lung compliance (the lungs get stiffer), which reduces ventilation and causes dyspnoea/shortness of breath.
• Eventually fluid may leak into the alveolar spaces, which is not a good thing. In severe pulmonary oedema fluid floods the alveolar spaces and oxygen transport is impaired.
• Dyspnoea is more marked at night, giving paroxysmal nocturnal dyspnoea. The supine position distributes blood centrally, which exacerbates the failure, increases pulmonary venous congestion, increases filtration out of the capillaries, increases oedema and so increases shortness of breath. In addition, the distribution of fluid within the lungs when lying down has a more negative effect than in the upright position.
• Radiographic appearance: chest X-rays show bilateral perihilar/interstitial shadowing in interstitial oedema, progressing to denser, more extensive bilateral airspace/alveolar shadowing in more severe alveolar oedema.

Peripheral oedema (right heart failure)

Mechanism in order:

1. Increased end-diastolic volume.
2. Increased end-diastolic pressure.
3. Decreased right atrial to right ventricular pressure gradient.
4. Increased right atrial volume and right atrial pressure.
5. Increased systemic venous pressure.
6. Increased systemic capillary pressure, disrupting Starling’s equilibrium and producing oedema.

Clinical features in right heart failure (or biventricular / congestive cardiac failure):

• Oedema at the ankles in the ambulant patient.
• Oedema over the sacrum in bed-bound patients.
• Elevated jugular venous pulse.
• Enlarged liver.
• Clinically, bilateral pitting oedema of the lower legs and feet with swollen, taut, shiny skin.

Ventricular dilation and the Law of Laplace

• Increasing end-diastolic volume is of some use via Starling’s Law, but the resultant dilatation causes other problems.
• The muscle tension that must be generated to develop a given ventricular pressure depends on the radius of the ventricle and the thickness of the ventricular wall (Law of Laplace).
• $T=\frac{P\times r}{w}$ where T is wall tension, P is transmural pressure, r is radius and w is wall thickness. Thus $T\propto P$, $T\propto r$, and $T\propto 1/w$.
• For the same transmural pressure, a larger-radius, thinner-walled chamber requires greater wall tension. Dilation of the left ventricle in heart failure both increases r and decreases w, so tension rises on both counts.

Problems faced by the failing heart

• Dilation of the ventricle:
  • By the Law of Laplace, the increased tension increases myocardial oxygen demand.
  • By the length-tension curve, active tension development is reduced, so contraction of the dilated heart is less efficient.
• Increased cardiac work is needed to maintain arterial blood pressure.
• In the greatly dilated heart the atrioventricular valves may become leaky, reducing the effective ejection fraction and so reducing stroke volume, cardiac output and mean arterial pressure.

Principles of treatment

The aims of treatment from a physiological point of view are:

1. To reduce cardiac work.
2. To reduce the excessive plasma volume and cardiac dilation.
3. To improve myocardial contractility.

Important

Treatment must not undermine the compensatory mechanisms, for example the raised end-diastolic volume that is keeping stroke volume near normal in mild failure. Gently does it.

Self-test

1. Define chronic heart failure.
2. State the main pathophysiological feature of chronic cardiac failure and describe its effect on the ventricular function (Starling) curve.
3. Explain why resting cardiac output can be near normal in some patients with heart failure, and name the two states this distinction produces.
4. Give the formula for ejection fraction and the normal resting range.
5. Explain why stroke volume is a poor index of cardiac function in heart failure whereas ejection fraction is better.
6. Describe how ejection fraction changes from rest to exercise in a healthy person and in a patient with cardiac failure, with the approximate values given.
7. Distinguish the two mechanisms that normally raise stroke volume on exercise, in terms of the Starling curve.
8. Explain why both of those mechanisms fail in the heart failure patient.
9. List the changes in cardiac output, heart rate, stroke volume, end-diastolic volume, end-systolic volume and ejection fraction on exercise in a healthy person.
10. List the same six variables at rest in a patient with ischaemic cardiac failure.
11. Describe how increased adrenergic activity compensates in cardiac failure, and name the three mediators responsible.
12. Predict which organs receive preferentially preserved blood flow in congestive cardiac failure and which have flow reduced.
13. Describe the steps of the renin-angiotensin-aldosterone system from the fall in plasma volume through to restoration of plasma volume.
14. List the five actions of angiotensin II given in the lecture.
15. Describe the steps by which fluid retention in chronic cardiac failure leads to oedema.
16. State the normal net pressure balance at the arteriolar and venular ends of a capillary, and explain what a rise in venous pressure does to it.
17. What volume of excess fluid is needed before oedema becomes detectable?
18. Describe the steps by which left heart failure produces pulmonary oedema, and its effect on lung mechanics.
19. Explain why dyspnoea is worse at night in a patient with pulmonary oedema.
20. List the clinical features of peripheral oedema in right heart failure.
21. State the Law of Laplace for the ventricle and explain why ventricular dilation is harmful.
22. List the problems faced by the failing, dilated heart.
23. State the three physiological aims of treatment in cardiac failure and the caution that applies to them.
24. Integrative: a patient with mild compensated heart failure is given aggressive diuresis. Using the Starling curve and the compensatory mechanisms, predict what may happen to stroke volume and explain why.

Answers

Reveal answers

1. A chronic inability of the heart to maintain adequate perfusion of the tissues at a normal filling pressure. Also called congestive heart failure.
2. Reduced myocardial contractility. It depresses the Starling curve downward and rightward, so stroke volume is lower for any given end-diastolic pressure.
3. A compensatory increase in end-diastolic volume and pressure (from about 8 to about 20 cmH2O) moves the failing ventricle along its curve back to a near-normal stroke volume of about 68 ml. Resting cardiac output can therefore be almost normal (compensated failure) or subnormal (decompensated failure).
4. Ejection fraction (%) = SV/EDV. At rest in the normal heart it is about 50 to 70%.
5. Stroke volume can be held near normal by compensatory increases in end-diastolic volume, so it may not reveal impaired function. Ejection fraction puts stroke volume in the context of end-diastolic volume and so exposes the dilated, poorly emptying ventricle.
6. Healthy: about 66% at rest rising to about 80% on exercise, driven by increased end-diastolic volume/pressure and sympathetic activation. Cardiac failure: reduced at rest (about 60% in the example) and falling further with exercise, to about 45%.
7. First, increased venous return raises stroke volume by the Frank-Starling mechanism, which is movement along the same curve. Second, sympathetic activation increases contractility, which is a rise onto a higher curve.
8. The failing curve is flat, so a rise in end-diastolic pressure gives little extra stroke volume and a huge rise would be needed to maintain it. The sympathetic mechanism fails because of down-regulation of ${\beta }_1$-adrenoceptors in myocardial cells, so the beta-1 mediated increase in contractility to adrenaline and noradrenaline is impaired.
9. Cardiac output rises to about 300%, heart rate to about 180 per minute, stroke volume to about 100 ml, end-diastolic volume rises a little, end-systolic volume falls, and ejection fraction rises to about 80%.
10. Cardiac output normal-ish, heart rate normal or high, stroke volume normal-ish, end-diastolic volume high, end-systolic volume a little high, ejection fraction decreased.
11. Peripheral vasoconstriction raises total peripheral resistance and so maintains mean arterial pressure (MAP = CO x TPR), which is otherwise hard to maintain because of the low cardiac output. Venoconstriction also increases venous return and hence end-diastolic volume and stroke volume, within limits. The mediators are increased sympathetic nerve activation, elevated plasma angiotensin II and elevated plasma endothelin-1.
12. Preserved: heart (coronary), brain (cerebral) and skeletal muscle. Reduced: kidney (renal), skin (cutaneous) and gut (splanchnic). Cardiac output falls from 5.8 to 4.4 l/min in the example.
13. An acute fall of plasma volume or blood pressure stimulates renin release; renin cleaves angiotensinogen to angiotensin I (10 residues); converting enzyme cleaves angiotensin I to angiotensin II (8 residues, His-Leu removed); angiotensin II drives salt and water retention and increased salt and water uptake; plasma volume and blood pressure are restored, which inhibits further renin release (negative feedback).
14. Increased appetite for salt, increased thirst, reduced GFR and renal blood flow, stimulation of aldosterone secretion, and systemic vasoconstriction.
15. Reduced cardiac function plus increased plasma volume elevates venous pressure, which raises capillary pressure, which disturbs Starling’s equilibrium, which increases interstitial fluid volume and produces oedema. If net filtration exceeds lymph flow, fluid accumulates.
16. Arteriolar end: net hydrostatic gradient 34 minus colloid osmotic gradient 25 gives 9 favouring ultrafiltration. Venular end: 17 minus 25 gives 8 favouring reabsorption. A rise in venous pressure raises venular capillary hydrostatic pressure from 15 to 30 mmHg, so the venular hydrostatic gradient becomes 28 and the net balance changes from 8 favouring reabsorption to 3, shifting the balance toward filtration.
17. About 4 to 5 litres of excess fluid.
18. Increased end-diastolic volume, then increased end-diastolic pressure, then a decreased left atrial to left ventricular pressure gradient, then increased left atrial volume and pressure, then increased pulmonary venous pressure, then increased pulmonary capillary pressure, shifting fluid into the lung interstitium. Interstitial congestion reduces lung compliance (stiffer lungs), reducing ventilation and causing dyspnoea; fluid may eventually flood the alveolar spaces and impair oxygen transport.
19. Lying supine distributes blood centrally, which exacerbates the failure, increases pulmonary venous congestion, increases filtration out of the capillaries and increases oedema and therefore shortness of breath. The distribution of fluid within the lungs when lying down is also more harmful than when upright. This is paroxysmal nocturnal dyspnoea.
20. Oedema at the ankles in ambulant patients and over the sacrum in bed-bound patients, an elevated jugular venous pulse, and an enlarged liver, with bilateral pitting oedema of the lower legs and feet.
21. T = Pr/w, so wall tension is proportional to transmural pressure and radius and inversely proportional to wall thickness. Dilation increases r and thins w, so wall tension rises for any given intraventricular pressure.
22. Increased tension increases myocardial oxygen demand; reduced active tension development on the length-tension curve makes contraction of the dilated heart less efficient; increased cardiac work is needed to maintain arterial blood pressure; and in the greatly dilated heart the atrioventricular valves may become leaky, reducing effective ejection fraction and so stroke volume, cardiac output and mean arterial pressure.
23. Reduce cardiac work; reduce the excessive plasma volume and cardiac dilation; improve myocardial contractility. The caution is that treatment must not undermine the compensatory mechanisms, for example the raised end-diastolic volume, so it must be done gently.
24. Stroke volume may fall. The near-normal stroke volume in mild compensated failure depends on the compensatory rise in end-diastolic volume and pressure moving the ventricle along its depressed Starling curve; removing plasma volume lowers end-diastolic volume and slides the ventricle back down that curve. Because the failing curve is depressed, the fall in stroke volume at the lower filling pressure is substantial, and the sympathetic reserve that would normally offset it is blunted by ${\beta }_1$-adrenoceptor down-regulation.