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Heart failure is when the heart is unable to
pump effectively, called systolic heart failure;
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or unable to fill properly, called diastolic heart
failure. In both cases, blood output is reduced.
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Ejection fraction is reduced
in systolic heart failure,
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but typically preserved in
diastolic heart failure.
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The pathophysiology of heart failure involves a
vicious cycle in which reduced cardiac output,
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as a compensatory response, activates the
renin-angiotensin-aldosterone system (RAAS) and
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sympathetic system. However, these systems cause
vasoconstriction, increase heart rate and blood
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pressure, making it even harder for the heart to
pump. Increased aldosterone level also promotes
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ventricular remodeling, myocardial scarring,
and vascular injury, worsening the disease.
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On the other hand, the natriuretic peptide system
is also activated. This system is protective to
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the heart. It promotes vasodilation, sodium and
water excretion, and inhibits cardiac remodeling.
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Most drugs used in heart failure therapy aim
to inhibit RAAS and sympathetic activities,
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and/or promote the natriuretic system. Other drugs
increase ventricular contractility or reduce water
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retention – a major heart failure symptom.
First-line therapy for patients with reduced
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ejection fraction typically includes
an angiotensin-converting enzyme
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(ACE) inhibitor, and a beta-blocker.
- ACE inhibitors block the conversion
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of angiotensin-I to angiotensin-II in
RAAS, thereby inhibiting RAAS activity.
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Common side effects include dry cough, headache,
and hypotension. Rarely, ACE inhibitors may
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cause a swelling reaction known as angioedema.
- Angiotensin receptor blockers (ARBs) inhibit
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the effects of angiotensin-II. Their mechanism
of action is similar to that of ACE inhibitors,
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but they do not usually cause a cough. However,
they are less effective and are typically used
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in patients who cannot tolerate ACE inhibitors.
- Beta-blockers decrease heart rate by binding to
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β1-adrenergic receptor in the heart and blocking
the sympathetic influences that act through these
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receptors. Common side effects are those of
hypotension. Rarer but more severe adverse
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events include bradycardia and AV blocks.
- Vasodilators reduce blood pressure and are
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usually used for patients who cannot tolerate ACE
inhibitors or ARBs. Side effects include nausea,
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palpitations, joint pain, and rash.
- Diuretics are often prescribed to
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relieve fluid retention. Loop diuretics are most
powerful and typically used for most patients.
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Thiazides are less effective, but they also have
a vasodilation effect, and are thus preferred for
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patients with hypertension but only mild fluid
retention. Major side effects include electrolyte
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imbalances, metabolic alkalosis, and hypovolemia.
- Aldosterone receptor antagonists block the
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action of aldosterone. Because aldosterone’s
primary function is to promote sodium and water
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retention, and potassium excretion; aldosterone
antagonists act as potassium-sparing diuretics.
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However, their effect in heart failure treatment
is also attributed to the inhibition of
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aldosterone’s damaging impact on the heart and
blood vessels. Major adverse effects include
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hyperkalemia and impaired kidney function.
- Digoxin increases cardiac contractility
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by inhibiting the sodium-potassium pump,
causing intracellular sodium concentration
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to rise. This then leads to higher levels
of intracellular calcium via the action of
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sodium-calcium exchanger. Higher calcium
results in increased muscle contraction.
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Digoxin also decreases sympathetic
activities, slowing down heart rate. However,
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due to its many adverse effects, it is
normally used only for patients who do
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not improve with other medications.
- Ivabradine slows the heart rate by
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inhibiting the “funny” channel responsible
for spontaneous firing of the SA node.
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Adverse effects include bradycardia,
atrial fibrillation, and vision problems.
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Ivabradine should be avoided in patients
with a low resting heart rate, low blood
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pressure, and certain heart conditions.
- ARNIs are a new class of medications.
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ARNI therapy consists of a neprilysin inhibitor
and an ARB. Neprilysin is an enzyme that breaks
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down a number of peptides, among which are
natriuretic peptides. Inhibition of neprilysin
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promotes the natriuretic system. However,
neprilysin also cleaves angiotensin II,
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so inhibition of neprilysin would activate RAAS.
Thus, an ARB is added to prevent RAAS activation.
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Major reactions include hypotension,
hyperkalemia, and renal failure.
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ARNIs are used in patients who do not
respond to ACE inhibitors and beta-blockers.
