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