Heart failure

Heart failure

Heart failure (HF) is caused by the heart’s inability to pump enough blood to meet the body’s needs. In response, the body activates compensatory mechanisms, such as the sympathetic nervous system which leads to tachycardia, sodium and water retention, vasoconstriction, and over time, ventricular hypertrophy, all geared towards increasing cardiac output. Leading causes of HF are coronary artery disease and hypertension.

Neurohormonal signaling by angiotensin II, norepinephrine, aldosterone, and others drive cardiac remodeling. These hormones promote disease progression, making them ideal targets for pharmacologic therapy. On the other hand, some other medications may exacerbate HF through negative inotropic effects, direct cardiotoxicity, or increased sodium and water retention.

Heart failure with reduced ejection fraction (HFrEF) (Systolic heart failure) is characterized by a reduced (≤40%) left ventricular ejection fraction (LVEF). It is caused by the heart’s impaired ability to contract. Myocardial infarction, dilated cardiomyopathies, and ventricular hypertrophy can lead to HFrEF. Heart failure with reduced ejection fraction is amenable to the medical therapies described below.

Heart failure with preserved ejection fraction (HFpEF) (Diastolic heart failure) is characterized by impaired ventricular relaxation and increased diastolic stiffness. In HFpEF, the LVEF is preserved (≥50%). Ventricular stiffness, ventricular hypertrophy, myocardial ischemia and myocardial infarction, mitral or tricuspid valve stenosis, and pericardial disease can lead to HFpEF. There is no standard treatment regimen for patients with HFpEF. Management consists of optimal treatment of the underlying diseases, such as hypertension, diabetes, and obesity.


The following classes of drugs have been shown to reduce mortality in patients with HFrEF:

1) Angiotensin Converting Enzyme Inhibitors (ACEIs) decrease angiotensin II and aldosterone, reducing ventricular remodeling, vasoconstriction, and sodium and water retention. These drugs inhibited the conversion of angiotensin I to angiotensin II by inhibiting ACE. All patients with HFrEF should receive an ACEI unless contraindicated. Patients who do not yet have HF symptoms but already have structural heart disease should receive an ACEI to prevent HF development. Drugs in this class include captopril, lisinopril, enalapril and others. ACEIs also inhibit the inactivation of bradykinin which contributes to dry cough in patients taking an ACEI.

2) Angiotensin Receptor Blockers (ARBs) such as valsartan are similar to ACEIs in their blockade of the harmful effects of angiotensin II. Drugs in this class are highly selective, competitive receptor antagonists at the AT1 receptor, which mediates the effects of angiotensin II. They are recommended for patients unable to tolerate ACEIs, usually due to dry cough. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs.

Doses of ACEIs/ARBs should start low and be titrated to the target dose every 2 weeks as tolerated. Monitor renal function and potassium at baseline and 1 to 2 weeks after initiation.

3) Angiotensin Receptor/Neprilysin Inhibitors (ARNI) include the combination valsartan and sacubitril. Natriuretic peptides may produce beneficial effects in patients with heart failure including promotion of diuresis and natriuresis, vasodilation, and inhibition of sympathetic nervous system by reduced catecholamine secretion and inhibition of renin-angiotensin-aldosterone system. Natriuretic peptides are catabolized and inactivated by the enzyme neprilysin. Sacubitril inhibits neprilysin thereby maintaining levels of natriuretic peptides. Neprilysin also breaks down angiotensin II, necessitating the combination of the sacubitril with valsartan.

Patients with HFrEF that remain symptomatic while taking an ACEI or ARB can be transitioned to an ARNI. Patients taking an ARB can switch immediately; however, patients taking an ACEI require a 36-hour washout period due to the risk of angioedema.

4) Aldosterone Receptor Antagonists (ARAs) such as spironolactone block the aldosterone (mineralocorticoid) receptor, thereby inhibiting oxidative stress, sodium reabsorption, potassium excretion, and cardiac remodeling.

ARAs are recommended for patients with a LVEF <35%. HF patients with mild symptoms should only be considered for ARAs if they have a history of prior cardiovascular hospitalization or elevated BNP levels. ARAs are also recommended in patients who develop symptoms of HF or with a history of diabetes mellitus following an acute-MI and a LVEF <40%. ARAs are contraindicated in patients with an eGFR <30 mL/min/1.73 m2 or a potassium level >5 mEq/L.

5) Beta-blockers reduce heart rate, cardiac oxygen consumption, remodeling due to cardiac hypertrophy, and stimulation of the renin-angiotensin-aldosterone system by antagonizing the sympathetic nervous system.

Only bisoprolol, carvedilol, and metoprolol succinate have shown mortality benefits and are recommended for all patients with HFrEF. Doses should start low and be titrated to the target dose every two weeks as tolerated. Beta-blockers can be initiated while optimizing the dose of ACEI/ARBs but should not be started in patients with volume overload.

The following classes of drugs decrease symptoms associated with HFrEF and improve quality of life. However, they have not been shown to reduce mortality.

6) Diuretics, in addition to dietary sodium restriction, are recommended for patients with clinical signs of volume overload. Loop diuretics such as furosemide are typically required. However, patients with mild fluid retention may benefit from a less potent thiazide class diuretic like hydrochlorothiazide.

7) Nitrates and hydralazine: The combination of hydralazine and nitrates (isosorbide dinitrate) decreases cardiac remodeling by promoting vasodilation. The combination is recommended to reduce morbidity and mortality in symptomatic patients self-described as African American already receiving ACEI/ARB, an ARA, and evidence-based beta blockers. They are also recommended in patients who cannot tolerate an ACEI or an ARB.

8) Ivabradine inhibits the “funny” current in the SA node, decreasing heart rate. The funny current is responsible for a steady increase in resting membrane potential through sodium and potassium ionic currents. Inhibition of this current prolongs diastolic depolarization, slowing firing in the SA node, and ultimately reducing heart rate. Ivabradine reduces hospitalizations in HF patients on a target dose of ACEI/ARB and beta-blocker. Patients must be in sinus rhythm and have a heart rate over 70 bpm.

9) Digoxin inhibits the Na/K ATPase pump, resulting in increased intracellular sodium. This promotes an influx of calcium via the Na/Ca exchange pump which increases contractility of the heart. Because the heart can pump with greater contractility, sympathetic tone is reduced and vagal tone predominates, suppressing AV node conduction and slowing the heart rate. It is recommended in patients experiencing symptoms despite taking the target doses of ACEI/ARBs and beta-blockers.

Abigail Elmes
Kelly Karpa

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