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Heart failure involves structural and/or functional changes to the heart1,2

Complex mechanism of disease

Heart failure is a complex, progressive syndrome. Causes may include2,3:

  • Ischemic cardiomyopathy caused by conditions such as coronary artery disease4

  • Nonischemic cardiomyopathy caused by conditions such as high blood pressure, infections, metabolic disorders, or genetic predisposition4

The sympathetic nervous system and the renin-angiotensin-aldosterone system activate to compensate for these pathologies to help maintain circulatory homeostasis.2,3 Prolonged activation of these systems becomes harmful, contributing to the HF disease process.2,3

The natriuretic peptide system is also activated as a counter-regulatory mechanism.

Morphological changes by HF classification

LVEF is used to help classify patients with HF and inform prognosis and potential treatments.1 Each classification of heart failure is characterized by different types of structural and/or functional cardiac abnormalities.4,5 These characteristics are what contribute to the reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.6

HFrEF heart

HFrEF heart

LVEF ≤40%1

Systolic dysfunction (impaired LV contraction)5,7

Eccentric remodeling7

  • Low LV mass to volume ratio7 

  • LV dilatation (enlargement) and normal wall thickness5

Often preceded by cardiomyocyte loss due to ischemia, genetic mutation, myocarditis, or valvular disease5



HFpEF Heart

HFpEF* heart

LVEF ≥50%1

Diastolic dysfunction (impaired LV filling)6,7

Concentric LV hypertrophy (remodeling)7-9

  • High LV mass to volume ratio7

  • Thickened LV wall5

LV stiffness5 and/or enlarged left atrium (indicative of increased LV filling pressures)2,6

Often patients have chronic comorbidities (eg, hypertension, T2DM, obesity, renal insufficiency)

*In PARAGON-HF, defined as LVEF ≥45% with structural heart disease (LAE or LVH); median LVEF was 57%. LVEF is a variable measure and the normal range can vary.13

Important Safety Information


  • When pregnancy is detected, discontinue ENTRESTO as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

ENTRESTO is contraindicated in patients with hypersensitivity to any component...


ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat.


LAE, left atrial enlargement; LVH, left ventricular hypertrophy.

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
2. Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond). 2016;130(2):57-77. doi:10.1042/CS20150469
3. Menendez JT. The mechanism of action of LCZ696. Card Fail Rev. 2016;2(1):40-46. doi:10.15420/cfr.2016:1:1
4. Howell EH, Cameron SJ. Neprilysin inhibition: a brief review of past pharmacological strategies for heart failure treatment and future directions. Cardiol J. 2016;23(6):591-598. doi:10.5603/CJ.a2016.0063
5. Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and molecular differences between HFpEF and HFrEF: a step ahead in an improved pathological understanding. Cells. 2020;9(1):242. doi:10.3390/cells9010242
6. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. doi:10.1002/ejhf.592
7. Toth PP, Gauthier D. Heart failure with preserved ejection fraction: disease burden for patients, caregivers, and the health-care system. Postgrad Med. 2021;133(2):140-145. doi:10.1080/00325481.2020.1842621
8. Røe ÅT, Sjaastad I, Louch WE. Heart failure with preserved ejection fraction. Tidsskr Nor Laegeforen. 2017;137(18). English, Norwegian. doi:10.4045/tidsskr.16.1068
9. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271. doi:10.1016/j.jacc.2013.02.092
10. Sabbah HN. Silent disease progression in clinically stable heart failure. Euro J Heart Fail. 2017;19:469-478. doi:10.1002/ejhf.7054
11. Gheorghiade N, De Luca L, Fonarow GC, et al. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol. 2005;96(suppl):11G-17G. doi:10.1016/j.amjcard.2005.07.016
12. Mesquita ET, Jorge AJL, Rabelo LM, Souza CV. Understanding hospitalization in patients with heart failure. Int J Cardio Sci. 2017;30(1):81-90. doi:10.5935/2359-4802.2016006
13. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.