PHAY2003: Biological Systems and Therapeutics 2

Heart Failure - Summary

Dr Rebecca Lever

Definitions of Heart Failure

Heart failure can be defined as ‘A clinical syndrome that can result from any structural or functional

cardiac disorder that impairs the ability of the ventricle to fill with or eject blood’ (AHA/ACC HF

Guidelines 2001) or, alternatively, ‘An abnormality of cardiac structure or function leading to failure of

the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing

tissues, despite normal filling pressures (or only at the expense of increased filling pressures)’. (ESC HF

Guidelines 2008).

Taken together, these definitions capture very well the most important points about heart failure, that

any cardiovascular disorder may ultimately lead to ventricular failure, that the failing heart may initially

compensate in order to retain adequate perfusion of organs and tissues and that ultimately the problem

is a failure of the heart to generate a cardiac output sufficient to support a normal level of function.

This latter point is illustrated very well by the increasing level of disability that occurs as heart failure

progresses; the New York Heart Association (NYHA) classification system being commonly used to

‘define’ levels of disease, although it can be seen that clear overlap between classes exists (e.g. II to III or

III to IV), as the descriptions are somewhat subjective.

NYHA Classification

(Adapted from McMurray et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. European Heart Journal 2012; 33: 1787-1847).

‘Asymptomatic’

‘Mild’

‘Moderate’

‘Severe’

Signs and Symptoms of Heart Failure

The typical signs and symptoms of heart failure can broadly be listed as attributable to left or right

ventricular failure. However, it should be noted that whilst the right ventricle can fail in isolation, as a

result of chronic disease of the lungs and/or pulmonary circulation, right ventricular failure in the vast

majority of cases is as a result of left ventricular failure. These signs and symptoms, with their origins,

are outlined in the diagram on the next page.

Left ventricular failure leads to fatigue and breathlessness, particularly upon exertion, due to

insufficient perfusion and hence oxygenation of skeletal muscles as the pumping efficiency of the

ventricle declines. Orthopnoea (difficulty in breathing when lying flat) and paroxysmal nocturnal

dyspnoea, whereby the patient wakes suddenly, gasping for air, occur due to the presence of

pulmonary oedema, again as a result of left ventricular failure. When the left ventricle fails as a pump,

it is unable to process its preload effectively, i.e. pump blood that enters during a cardiac cycle into the

systemic arterial system. This leads to an increase in pressure in the left side of the heart that is

transmitted back into the pulmonary veins that feed into the left atrium, and hence the pulmonary

circulation in general. This leads to leakage of fluid out of pulmonary capillaries into the airspaces and

surrounding tissues of the lung, which reduces the efficiency of gas exchange and increases the work of

breathing. The effects are worsened when the patient lies flat because the redistribution of fluid due to

gravity increases the central venous pressure which further increases the preload that the failing heart

cannot process. It is common for patients with poorly managed heart failure to sleep propped up by

pillows to avoid this effect. Signs of left ventricular failure, which tend not to be apparent until function

is significantly impaired, may include cardiac murmurs due to valve dysfunction (e.g. mitral

regurgitation, whereby some blood is ejected back through the mitral valve to the left atrium during

ventricular systole, as a result of pressure overload in the ventricle), or chaotic movement of blood

during ventricular filling (a third heart sound, sometimes called a gallop rhythm). An echocardiogram

may reveal an increased ventricular mass (hypertrophy, initially a compensatory mechanism) or in the

later stages ventricular dilatation due to chronic pressure overload. The heart rate may be increased in

an attempt to increase cardiac output (discussed later). Pulmonary crepitations (known as rales) may be

heard on auscultation of the lungs (listening through a stethoscope), as a result of pulmonary oedema

(fluid-filled alveoli snapping open when breathing in), and pulmonary oedema may also be seen on a

chest X-ray.

Ongoing increased pressure in the pulmonary circulation increases the afterload of the right ventricle

and will eventually lead to its failure (just as the left ventricle may fail as a result of chronic, unmanaged,

systemic hypertension). The right ventricle is particularly susceptible to damage in this way because it is

not used to pumping into a high pressure system (normal mean pulmonary arterial pressure is in the

order of 15 mmHg). Failure of the right ventricle to process its preload will lead to increased pressure

that will transmit back into the vena cava and the systemic venous circulation in general. Signs will arise

that are secondary to venous congestion and include increased jugular venous pressure (JVP), which

may present as a visible distension of the jugular vein in the neck of the patient, hepatomegaly (increase

in the size of the liver), hepatojugular reflux (pressing over the liver causes a prolonged distension of

the jugular vein, due to redistribution of venous overload) and peripheral oedema. The

Ph

ysic

al s

ign

s:ju

gula

r (v

eno

us)

dis

ten

tio

nd

epen

den

t (p

itti

ng)

oe

de

ma

accu

mu

lati

on

of

abd

om

inal

flu

id (

asci

tes)

hep

ato

meg

aly

hep

ato

jugu

lar

refl

ux

Ph

ysic

al s

ign

s:(n

ot

pro

min

ent

un

til l

ater

sta

ges)

enla

rgem

ent

of

the

hea

rtm

itra

l reg

urg

itat

ion

pu

lmo

nar

y o

ed

em

a

Ch

ron

ic lu

ng

dis

eas

ele

adin

g to

incr

ease

dp

ulm

on

ary

resi

stan

ce

Biv

entr

icu

lar

(co

nge

stiv

e)h

eart

fai

lure

Sym

pto

ms:

fati

gue

exer

tio

nal

dys

pn

oe

ao

rth

op

no

ea

no

ctu

rnal

dys

pn

oea

Sym

pto

ms:

fati

gue

bre

ath

less

nes

ssw

olle

n a

nkl

es

Isch

aem

icC

hro

nic

hea

rtsy

stem

icd

ise

ase

hyp

erte

nsi

on

Left

ven

tric

ula

rfa

ilure

Oth

erC

VS

pat

ho

logy

Rig

ht

ven

tric

ula

rfa

ilure

incr

ease

dp

ulm

on

ary

resi

stan

ce

Ori

gin

s o

f th

e K

ey S

ign

s a

nd

Sym

pto

ms

of

Hea

rt F

ail

ure

latter will commonly present as dependent, or ‘pitting’ oedema (if it is pressed with e.g. a finger, an

indentation will be apparent after the pressure is removed) of the ankles and wrists in a patient who is

mobile, or the sacral area in a patient who is bed-bound. Ascites (accumulation of fluid in the peritoneal

cavity, leading to the appearance of abdominal distension) can also sometimes occur.

Biventricular heart failure, i.e. failure of the right ventricle secondary to failure of the left ventricle, is

commonly known as congestive heart failure – it is due to congestion of the normal movement of blood

through the cardiovascular system.

Heart failure is sometimes referred to as being systolic or diastolic in nature. Broadly speaking, these

definitions are used to indicate whether the main problem is with emptying (systolic) or filling (diastolic)

of the ventricle but have been replaced with more precise definitions that reference the ejection

fraction. The ejection fraction is simply the stroke volume divided by the end diastolic volume and

gives an indication of the ability of the ventricle to work as a pump, i.e. to eject the blood that enters

during diastole. In a healthy individual at rest, the ejection fraction is around 70%. However, in ‘systolic

failure’ this would be below 35% and correlates inversely with prognosis. This type of heart failure is

now referred to as heart failure with reduced ejection fraction (HFrEF). Conversely, ‘diastolic failure’ is

now referred to as heart failure with preserved ejection fraction (HFpEF), whereby the ejection fraction

would be greater than 35-55% (precise figure varies) and is often associated with left ventricular wall

thickening (hypertrophy). In practice, most patients with HFpEF can be demonstrated to have at least

mild systolic dysfunction as well and treatment approaches are the same.

Pathophysiology

Over time, a number of physical changes occur within the failing myocardium, many of which are

initially protective or compensatory mechanisms in response to the increases in pressure and/or cardiac

workload, but which are ultimately detrimental. Structural changes to cardiac myocytes include

hypertrophy, changes in energy utilisation, alterations in the relationship between action potential and

contraction, and ultimately cell death. However, structural changes also involve the blood vessels and

interstitium of the heart, which also contribute to the loss of function of the myocardium as an effective

pump.

However, a key feature in the progression of heart failure, which is also the major target of

pharmacological therapy, is activation of the renin-angiotensin-aldosterone system (RAAS) and

sympathetic nervous system, collectively referred to as neurohormonal activation. As the heart fails,

renal perfusion will be compromised as a result of the declining cardiac output and the RAAS will be

activated as though the blood volume had dropped. Hence, sodium and water will be retained and

peripheral resistance will increase, which only worsen the situation by increasing both preload and

afterload. Peripheral vascular resistance will further increase and heart rate will tend to increase as a

result of increased sympathetic activity; the limited cardiac output is ‘allocated’ in favour of e.g. the

central nervous system by a reduction in the perfusion of less vital organs such as the skin and skeletal

muscle, leading to symptoms of fatigue and exercise intolerance. However, this also worsens the

situation as ventricular workload increases as a result of enhanced 1 receptor stimulation by

catecholamines and the increased afterload due to widespread vasoconstriction of small arteries in e.g.

skin and muscle. This vicious cycle continues and the heart becomes progressively less able to

compensate.

Pharmacological Treatment of Heart Failure

The aims of treatment are to 1) increase survival, through reduction of neurohormonal changes and

progression of the disease (remodelling) and 2) improve quality of life by increasing exercise capacity

and reducing symptoms. All patients, unless there are clear contraindications, should be treated with an

ACE inhibitor and a beta blocker licensed for heart failure and the majority will also require treatment

with a diuretic. Additional therapeutic agents may be added, which include digoxin, aldosterone

receptor antagonists, angiotensin receptor antagonists and other agents such as ivabradine,

hydralazine with isosorbide dinitrate and anticoagulants in selected patients.

Diuretics

Diuretics are indicated in all stages of symptomatic heart failure where there are signs of fluid retention

(e.g. peripheral oedema, dyspnoea and/or lung rales associated with pulmonary oedema, jugular venous

distension, hepatomegaly). Diuretics are essential for the control of symptoms secondary to fluid

retention and symptomatic benefits are achieved quickly, within hours or days as opposed to weeks or

months for other therapies used in heart failure. Whilst diuretics themselves have no direct effect on

survival, their appropriate use influences the success of other therapies that do improve survival (e.g.

beta blockers cannot be started if signs of fluid overload are present).

Thiazide diuretics such as bendroflumethiazide act in the proximal portion of the distal convoluted

tubule and inhibit the Na+/Cl- symporter. Less than 10% of filtered sodium is reabsorbed here (i.e. the

vast majority of that originally filtered at the glomerulus has already been reabsorbed), hence these

agents contribute only a moderate degree of diuresis. They also possess some direct vasodilator

activity (probably due to activation of large conductance calcium-activated potassium channels (BKCa) in

vascular smooth muscle). Loop agents such as furosemide are more potent diuretics than thiazides and

lead to secretion of up to 25% of the sodium filtered at the glomerulus. These agents act in the thick

ascending limb of the loop of Henle, where the Na+/K+/2Cl- symporter in the apical membrane is

inhibited. This reduces the accumulation of ions in the medullary interstitium. As the thick ascending

loop is water impermeable, concentration of ions in the interstitium in the absence of water increases

osmotic pressure which drives the reabsorption of water from the collecting duct (under the influence

of vasopressin). Loop diuretics hence reduce this reabsorption, causing diuresis. They have an indirect

vasodilator effect and are particularly useful in reducing the symptoms associated with pulmonary

oedema. Thiazide and loop diuretics both have the potential to cause hypokalaemia and the potassium-

sparing diuretic amiloride is sometimes given alongside drugs such as bendroflumethiazide or

furosemide, if they are used e.g. in the treatment of hypertension, to prevent this. However, patients

being treated for heart failure will almost certainly be receiving at least one other drug that promotes

potassium retention (e.g. ACE inhibitor, angiotensin receptor antagonist, aldosterone receptor

antagonist) so additional measures are not usually required. However, the monitoring of potassium

levels in patients undergoing treatment for heart failure, especially in the initial stages, is sensible.

ACE Inhibitors

ACE inhibitors such as enalapril, lisinopril, ramipril are extremely useful in the management of heart

failure because, like diuretics, they improve symptoms but, unlike diuretics, they also prolong survival

and reduce the rate of progression of the disease. They are indicated in all stages of symptomatic heart

failure, although benefit has also been demonstrated in early, asymptomatic disease. The benefits of

ACE inhibitors in terms of disease progression and survival are at least in part due to their ability to

delay further remodelling of the myocardium and possibly induce a degree of ‘reverse remodelling’, i.e.

repair of changes that have already occurred. ACE inhibitors break the cycle of inappropriate and

detrimental activation of the RAAS, which leads to an improvement in symptoms and an increase in

cardiac output as salt and water retention and vasoconstriction are reduced. Effects on remodelling are

due to inhibition of negative effects of angiotensin II on cardiac myocytes (proliferation, fibrosis,

oxidative stress) and also to indirect inhibition of the negative effects of aldosterone on the heart (see

later). The patient would be started on a low dose of drug which would be increased gradually towards

a maintenance dose. Angiotensin receptor antagonists such as losartan and valsartan may be used as

an alternative in patients who cannot tolerate ACE inhibitors e.g. due to dry cough. An angiotensin

receptor antagonist may also be added on as second line therapy in patients already receiving optimum

therapy with a beta blocker and an ACE inhibitor in whom symptoms are not fully controlled. However,

ACE inhibitors are preferred as first-line agents because their positive effects on survival are better

documented.

Beta Blockers

Beta receptor antagonists should be offered to all patients with left ventricular systolic dysfunction. The

patient must be stable before starting treatment, with no physical evidence of fluid retention. For this

reason, most patients will already be on a diuretic and it is conventional to start and stabilise patients on

an ACE inhibitor first also. The only absolute contraindications for the use of beta blockers in heart

failure are reactive airways disease (i.e. asthma) and atrio-ventricular block. Over the long term, beta

blockers lead to an improvement in symptoms, and also prolong survival, although patients will initially

feel worse due to the negative inotropic effects of the drug. For this reason, a very low dose is used to

begin with which is titrated up towards a target dose, as far as the patient may tolerate the increases.

Beta blockers slow disease progression, reduce further remodelling and, like ACE inhibitors, may to an

extent reverse some of the remodelling that has already occurred. The specific agents that are licensed

in the UK for heart failure are bisoprolol, carvedilol and nebivolol, the latter for use in patients of 70

years or older. The positive effects of beta blockers are due in part to their anti-ischaemic, anti-

hypertensive and anti-arrhythmic properties, which tie in with their uses in other indications, but also

are due to anti-oxidant and anti-proliferative properties that reduce cardiac damage and remodelling.

Furthermore, in heart failure there are detrimental changes to the expression profile of cardiac beta-

adrenoceptors and long-term use of beta blockers can help to correct this.

Digoxin

Digoxin is added to therapy as a second line treatment in patients who remain symptomatic despite

optimum treatment with diuretics, ACE inhibitors and beta blockers. Digoxin is a positive inotrope,

which works by indirectly increasing intracellular [Ca2+] through inhibition of the Na+/K+-ATPase. It

improves symptoms but does not have any effect on survival or disease progression. Digoxin also

promotes a degree of sodium excretion and tends to improve neurohormonal control.

Aldosterone receptor antagonists

Aldosterone receptor antagonists have a significant positive effect on survival. They are added to

therapy as second line treatment in patients who remain symptomatic despite optimum treatment with

diuretics, ACE inhibitors and beta blockers. Spironolactone is the most commonly used example and

eplerenone is a newer and more selective agent that lacks the effects of spironolactone at other

hormone receptors and thus causes fewer side-effects. Aldosterone causes a range of detrimental

effects that promote disease progression in heart failure, including myocardial fibrosis, endothelial cell

dysfunction and baroreceptor dysfunction, which these drugs inhibit. Spironolactone is traditionally

known as a potassium-sparing diuretic. However, it is a very weak diuretic and is not used in this

setting for that specific property, not least because the majority of patients will already be treated with

a stronger loop or thiazide agent. However, the potassium-sparing effects of aldosterone receptor

antagonists should be borne in mind in relation to all other drugs that the patient is taking that might

also affect potassium levels; i.e. diuretics (promote loss), ACE inhibitors (promote retention) and

angiotensin receptor antagonists (promote retention). Importantly, both aldosterone receptor

antagonists and angiotensin receptor antagonists can be used as add-on therapy in patients who are

receiving an ACE inhibitor, but not both at the same time for this reason.