Heart failure: mechanisms and the combined drug regimen

Why a weak heart gets worse over time, and how a set of drugs taken together slows that down and helps people live longer.

Updated Nov 12, 2026

Heart failure means the heart cannot pump or fill well enough to meet the body's needs. The body answers with hormonal and nervous responses that help at first but damage the heart in the long run. Modern treatment blocks those responses with several drugs at once, relieves congestion with diuretics, and avoids drugs that whip the heart harder, which proved harmful.

Key points

Two main types: reduced ejection fraction (HFrEF, a weak, dilated ventricle) and preserved ejection fraction (HFpEF, a stiff ventricle that fills poorly).
A failing heart triggers the sympathetic system, the renin–angiotensin–aldosterone system and vasopressin; these keep up pressure short term but cause salt and water retention, remodelling and fibrosis.
In HFrEF four drug groups prolong life when used together: an ARNI (or ACE inhibitor/ARB), an evidence-based beta blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor.
Diuretics relieve congestion and symptoms but are not shown to prolong life.
Long-term positive inotropes (PDE3 inhibitors, catecholamines and others) increased mortality in trials; they are kept for short-term rescue.
In Latin America, chronic Chagas disease is an added cause of heart failure and arrhythmia.

What fails: HFrEF and HFpEF

In HFrEF the left ventricle contracts weakly and dilates, often after a heart attack or in a cardiomyopathy. In HFpEF the ventricle squeezes normally but is stiff, so filling pressures rise; it is more common in older people with hypertension, diabetes, obesity and atrial fibrillation, and its mechanisms are much less well understood. Both cause breathlessness, fatigue and fluid build-up. Common causes are coronary disease, hypertension, cardiomyopathies, valve disease and arrhythmias. In the 21 continental Latin American countries where Chagas disease is endemic, some infected people develop heart damage decades later, with arrhythmias and progressive heart failure.

Neurohumoral activation: the vicious circle

When output falls, the body acts as if it were bleeding. Sympathetic nerves speed and strengthen the heart and narrow arteries; the kidneys release renin, so angiotensin II and aldosterone rise; vasopressin rises too. Pressure and perfusion of the brain and heart are protected, but at a price: salt and water are retained, afterload rises, and angiotensin II, aldosterone and noradrenaline drive hypertrophy, fibrosis and myocyte death (remodelling). The natriuretic peptides ANP and BNP push the other way, promoting salt loss and vasodilation, but they are overwhelmed. This explains why drugs that block these systems slow progression and why measuring BNP helps diagnosis.

Staging

The American College of Cardiology and American Heart Association describe stages: A, at risk (for example hypertension or diabetes) without structural disease; B, structural disease without symptoms; C, structural disease with current or past symptoms; D, advanced disease despite treatment. Symptom severity is also graded with the New York Heart Association classes I to IV. Staging shows that prevention starts with treating risk factors long before symptoms appear.

The combined regimen in HFrEF

Each drug group below blocks a different part of the vicious circle, and their benefits add up. Guidelines start them early and together rather than one after another over many months, then raise doses as tolerated.

ARNI (sacubitril–valsartan), or an ACE inhibitor or ARB if an ARNI is not used: less angiotensin II effect, and more natriuretic peptide effect with sacubitril.
Beta blocker proven in heart failure (bisoprolol, carvedilol or metoprolol succinate): started low and raised slowly because it can worsen symptoms at first.
Mineralocorticoid receptor antagonist (spironolactone or eplerenone): blocks aldosterone's fibrotic effects; potassium and kidney function are watched.
SGLT2 inhibitor (dapagliflozin or empagliflozin): benefit also in people without diabetes.
Add-ons in selected patients: ivabradine when heart rate stays high in sinus rhythm, hydralazine with isosorbide dinitrate, digoxin for symptoms, vericiguat; plus devices such as resynchronisation pacing and defibrillators.

Congestion and HFpEF

Loop diuretics such as furosemide relieve fluid overload quickly and are used at the lowest dose that keeps the patient free of congestion. In HFpEF, diuretics for congestion and treatment of the causes (hypertension, atrial fibrillation, obesity, diabetes) are the core; SGLT2 inhibitors have reduced hospitalisation, while many drugs that work in HFrEF have not clearly helped.

Lessons from failed drugs

In the 1980s and 1990s, drugs that made the heart contract harder seemed logical. Oral PDE3 inhibitors such as milrinone, beta agonists, calcium sensitisers and mixed agents such as vesnarinone improved haemodynamics but increased deaths, mainly from arrhythmias and faster myocyte loss. Partial beta agonists that raise night-time heart rate also raised mortality. The lesson changed the field: unload the heart and block neurohumoral activation instead of stimulating it. Today intravenous inotropes such as dobutamine or milrinone are used only briefly for low output and shock, or as a bridge. Digoxin, a weak inotrope, reduced hospital admissions in the DIG trial without lowering mortality. Some drugs also worsen heart failure and are avoided: NSAIDs, non-dihydropyridine calcium channel blockers in HFrEF, and thiazolidinediones.

Test yourself

Think of the answer, then tap the question to see it.

Which three neurohumoral systems are activated in heart failure?

The sympathetic nervous system, the renin–angiotensin–aldosterone system and vasopressin (antidiuretic hormone) release.

What are the four drug groups that together prolong life in HFrEF?

An ARNI (or ACE inhibitor/ARB), a heart-failure beta blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor.

Why are oral positive inotropes not used for chronic heart failure?

Trials of PDE3 inhibitors, beta agonists and similar drugs showed more deaths, mainly arrhythmic, despite better short-term haemodynamics.

Do loop diuretics prolong survival in heart failure?

They are not shown to; they relieve congestion and symptoms, so the lowest dose that keeps the patient free of fluid overload is used.

What is the difference between HFrEF and HFpEF?

In HFrEF the ventricle contracts weakly and dilates; in HFpEF it contracts normally but is stiff and fills poorly. Neurohumoral blockers help clearly only in HFrEF.

Add to my cards (5)

Example drugs

Connections

← All of pharmacology

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Heart Failure - What Is Heart Failure? | NHLBI, NIH (National Heart, Lung, and Blood Institute, 2026); Heart Failure - Treatment | NHLBI, NIH (National Heart, Lung, and Blood Institute, 2026); Chagas disease (also known as American trypanosomiasis) (World Health Organization, 2026).

Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake

Representative model, for educational purposes only.