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PubMed This is a summary of 21 peer-reviewed journal articles Updated
Cardiology · Heart Failure with Reduced Ejection Fraction

The Biology of HFrEF: How Your Heart and Body Respond

At a Glance

In HFrEF, or systolic heart failure, the heart cannot pump strongly enough to meet the body’s needs. The body’s short-term stress responses may worsen heart enlargement and weakness when they stay active, while echocardiography, blood tests, and imaging help identify the cause.

A diagnosis of Heart Failure with reduced Ejection Fraction (HFrEF) means that the heart’s biology has shifted from a healthy, efficient pump to one that is struggling to meet the body’s demands. Understanding this shift is the first step in reversing the cycle and protecting your heart muscle.

The Vicious Cycle: Why Heart Failure Progresses

HFrEF usually begins with an “insult” to the heart muscle—such as a heart attack, a viral infection, or long-term high blood pressure—that weakens its ability to contract [1]. When the heart’s output falls, the body tries to “fix” the problem by activating two major survival systems [2]:

  1. The Sympathetic Nervous System (SNS): This is your “fight or flight” response. It releases adrenaline to make the heart beat faster and more forcefully [3].
  2. The Renin-Angiotensin-Aldosterone System (RAAS): This system tells your kidneys to hold onto salt and water to increase blood volume and maintain blood pressure [4].

While these responses help in a short-term emergency, when they stay “turned on” for weeks or months, they become toxic to the heart. The constant adrenaline and high pressure cause adverse remodeling—a process where the heart’s chambers stretch out (dilation), the walls thicken or scar, and the heart becomes even less efficient [5][6]. This creates a “vicious cycle” where the body’s attempts to help actually cause more damage [7].

The Diagnostic Toolkit

To break this cycle, your doctors must first map out exactly what is happening inside your heart using physical history, examination, and a combination of tests.

The Echocardiogram (Echo)

This ultrasound of the heart is a central test for HFrEF. On your report, you will see several key terms:

  • LVEF (Left Ventricular Ejection Fraction): The percentage of blood pumped out with each beat. In HFrEF, this is 40% or lower [8].
  • LV Dilation: A sign that the heart has stretched out to try to hold more blood [6].
  • GLS (Global Longitudinal Strain): A supplemental, load-dependent measure of how well the heart muscle fibers are shortening [9].
  • Filling Pressures (E/e’): An estimate that helps calculate the pressure inside your heart. High pressures often mean fluid is “backing up” into your lungs [10].

BNP and NT-proBNP

These are “stress signals” released by the heart muscle when it is stretched or under pressure [11]. While these blood tests help evaluate and support a diagnosis of heart failure, they do not confirm it alone. Your doctor will interpret these numbers alongside your Echo results, as things like age, kidney function, atrial fibrillation, and weight can alter the levels [12][13].

Finding the “Why”: Etiology

Identifying the root cause (etiology) of your heart failure is vital because it determines your treatment path. Common causes include:

  • Ischemic: Damage from coronary artery disease or a previous heart attack [14].
  • Non-Ischemic: This broad category includes genetic factors, viral infections (myocarditis), heart valve disease, or “cardiotoxins” like certain chemotherapy drugs or excessive alcohol [15][16][17].

If the cause isn’t clear from an Echo, you may need advanced imaging. A Cardiac MRI (CMR) can look for specific patterns of scarring or inflammation that point to the cause [18][19]. Alternatively, a cardiac catheterization may be selected to look for blocked arteries or to directly measure the pressures inside your heart and lungs [20][21].

Information Your Team May Collect

Before finishing your initial workup, your care team may collect these important data points to guide treatment:

Data Point Why It Matters
LVEF % Defines your specific heart failure “phenotype.”
Etiology Identifies if the cause is ischemic, genetic, or toxic.
NT-proBNP/BNP Provides a baseline “stress level” for your heart, though not always required.
QRS Duration A measurement from your ECG that helps determine if you need a special pacemaker.
Kidney Function Determines which life-saving medications are safe for you to start.

Common questions in this guide

What does an ejection fraction of 40% or less mean?
An ejection fraction of 40% or less is consistent with HFrEF, meaning the left ventricle pumps out a reduced proportion of blood with each beat. Doctors interpret this measurement together with your symptoms, examination, and other test results rather than using the number alone.
Why can the body’s response to HFrEF make heart failure worse?
When the heart’s output falls, the sympathetic nervous system and the renin-angiotensin-aldosterone system try to maintain circulation by increasing heart activity and retaining salt and water. If these responses remain active for a long time, they can increase pressure, stretch the heart, and contribute to scarring and weaker pumping.
What do BNP and NT-proBNP results tell me?
BNP and NT-proBNP are stress signals released when the heart is stretched or under pressure. They can support the evaluation of heart failure and provide a baseline for follow-up, but they do not confirm the diagnosis by themselves. Age, kidney function, atrial fibrillation, and body weight can affect the levels.
How do doctors determine what caused HFrEF?
Doctors may investigate ischemic causes, such as coronary artery disease or a previous heart attack, and non-ischemic causes, such as genetic factors, viral inflammation, valve disease, certain chemotherapy drugs, or heavy alcohol use. The history, examination, echocardiogram, and additional testing are considered together to identify the most likely cause.
When might I need a cardiac MRI or heart catheterization?
These tests may be considered when an echocardiogram and medical history do not fully explain the heart failure. Cardiac MRI can look for patterns of scarring or inflammation, while catheterization can assess blocked arteries and directly measure pressures in the heart and lungs. Your cardiology team decides whether either test is appropriate for you.
What personal information should I share during an HFrEF evaluation?
Tell your care team about chest pain or pressure, family members with early heart failure or an enlarged heart, and exposure to chemotherapy drugs, heavy alcohol, or stimulants. Also describe patterns of weight gain, ankle swelling, and shortness of breath, because these details may help the team understand your condition and fluid status.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What was my specific ejection fraction (LVEF) on my echocardiogram, and what does it tell you about my heart function?
  2. 2.What is my BNP or NT-proBNP level, and how will we use this number to monitor my progress?
  3. 3.Based on my tests, do you believe my heart failure is ischemic (caused by artery blockages) or non-ischemic?
  4. 4.Do we need to perform a Cardiac MRI (CMR) or a cardiac catheterization to better understand the cause of my HFrEF?
  5. 5.Does my echocardiogram show any issues with my heart valves or the right side of my heart?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (21)
  1. 1

    Heart failure with reduced ejection fraction.

    Bloom MW, Greenberg B, Jaarsma T, et al.

    Nature reviews. Disease primers 2017; (3()):17058 doi:10.1038/nrdp.2017.58.

    PMID: 28836616
  2. 2

    Neurohormonal activation in heart failure with reduced ejection fraction.

    Hartupee J, Mann DL

    Nature reviews. Cardiology 2017; (14(1)):30-38 doi:10.1038/nrcardio.2016.163.

    PMID: 27708278
  3. 3

    Heart failure management with β-blockers: can we do better?

    de Oliveira MT, Baptista R, Chavez-Leal SA, Bonatto MG

    Current medical research and opinion 2024; (40(sup1)):43-54 doi:10.1080/03007995.2024.2318002.

    PMID: 38597068
  4. 4

    Unraveling the complex pathophysiology of heart failure: insights into the role of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS).

    Maryam , Varghese TP, B T

    Current problems in cardiology 2024; (49(4)):102411 doi:10.1016/j.cpcardiol.2024.102411.

    PMID: 38246316
  5. 5

    Hormonal crossroads of the heart: from classic endocrine regulation to cardiac hormone secretion: an updated review.

    Iglesias P, Iglesias I

    Journal of endocrinological investigation 2026; (49(4)):747-761 doi:10.1007/s40618-025-02767-2.

    PMID: 41335196
  6. 6

    Contemporary Pillars of Heart Failure with Reduced Ejection Fraction Medical Therapy.

    Rahamim E, Nachman D, Yagel O, et al.

    Journal of clinical medicine 2021; (10(19)) doi:10.3390/jcm10194409.

    PMID: 34640427
  7. 7

    Edema formation in congestive heart failure and the underlying mechanisms.

    Abassi Z, Khoury EE, Karram T, Aronson D

    Frontiers in cardiovascular medicine 2022; (9()):933215 doi:10.3389/fcvm.2022.933215.

    PMID: 36237903
  8. 8

    Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association.

    Bozkurt B, Coats AJS, Tsutsui H, et al.

    European journal of heart failure 2021; (23(3)):352-380 doi:10.1002/ejhf.2115.

    PMID: 33605000
  9. 9

    Echo and heart failure: when do people need an echo, and when do they need natriuretic peptides?

    Modin D, Andersen DM, Biering-Sørensen T

    Echo research and practice 2018; (5(2)):R65-R79.

    PMID: 29691224
  10. 10

    Longitudinal NT-proBNP: Associations With Echocardiographic Changes and Outcomes in Heart Failure.

    Teramoto K, Tay WT, Tromp J, et al.

    Journal of the American Heart Association 2024; (13(9)):e032254 doi:10.1161/JAHA.123.032254.

    PMID: 38639333
  11. 11

    N‑Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) as a Biomarker in Heart Failure With Preserved Ejection Fraction (HFpEF) Versus Heart Failure With Reduced Ejection Fraction (HFrEF): The Way Forward in the Age of Proteomics.

    Kanyal S, Das A, Bashir AMD, et al.

    Cureus 2025; (17(10)):e94162 doi:10.7759/cureus.94162.

    PMID: 41209853
  12. 12

    Comparison of BNP and NT-proBNP in Patients With Heart Failure and Reduced Ejection Fraction.

    Rørth R, Jhund PS, Yilmaz MB, et al.

    Circulation. Heart failure 2020; (13(2)):e006541 doi:10.1161/CIRCHEARTFAILURE.119.006541.

    PMID: 32065760
  13. 13

    Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

    Ibrahim NE, Piña IL, Camacho A, et al.

    European journal of heart failure 2020; (22(11)):2018-2025 doi:10.1002/ejhf.2005.

    PMID: 32946164
  14. 14

    Clinical profile and one-year survival of patients with heart failure with reduced ejection fraction: The largest report from India.

    Chopra VK, Mittal S, Bansal M, et al.

    Indian heart journal 2019; (71(3)):242-248 doi:10.1016/j.ihj.2019.07.008.

    PMID: 31543197
  15. 15

    Longitudinal evaluation of ventricular ejection fraction and NT-proBNP across heart failure subgroups.

    Martinsson A, Oest P, Wiborg MB, et al.

    Scandinavian cardiovascular journal : SCJ 2018; (52(4)):205-210 doi:10.1080/14017431.2018.1461920.

    PMID: 29656687
  16. 16

    A case series about the favorable effects of sacubitril/valsartan on anthracycline cardiomyopathy.

    De Vecchis R, Paccone A

    SAGE open medical case reports 2020; (8()):2050313X20952189 doi:10.1177/2050313X20952189.

    PMID: 32974024
  17. 17

    Excess Mortality Associated With Functional Tricuspid Regurgitation Complicating Heart Failure With Reduced Ejection Fraction.

    Benfari G, Antoine C, Miller WL, et al.

    Circulation 2019; (140(3)):196-206 doi:10.1161/CIRCULATIONAHA.118.038946.

    PMID: 31117814
  18. 18

    Diagnostic Accuracy of Cardiac Magnetic Resonance Imaging in the Evaluation of Newly Diagnosed Heart Failure With Reduced Left Ventricular Ejection Fraction.

    Won E, Donnino R, Srichai MB, et al.

    The American journal of cardiology 2015; (116(7)):1082-7.

    PMID: 26251006
  19. 19

    [Cardiovascular magnetic resonance imaging: routine use in cardiology and unique strengths].

    Schulz A, Reiter T

    Innere Medizin (Heidelberg, Germany) 2026; doi:10.1007/s00108-026-02152-y.

    PMID: 42420516
  20. 20

    State-of-the-art management of ischemic cardiomyopathy: integrating diagnostic pathways, revascularization strategies, and guideline-directed therapy.

    Busti M, Melenovsky V, Savarese G, et al.

    Heart failure reviews 2026; (31(1)).

    PMID: 42209870
  21. 21

    Natriuretic Peptides as Predictors for the Diagnosis of Pulmonary Hypertension Secondary to Left Heart Disease and for the Assessment of Its Severity.

    Sawczak F, Kukfisz A, Soloch A, et al.

    International journal of molecular sciences 2026; (27(17)) doi:10.3390/ijms27177776.

    PMID: 42737672

This page explains HFrEF biology and diagnostic testing for informational purposes only and does not constitute medical advice. Your cardiology team should interpret your results and decide whether additional testing is appropriate.

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