# Heart Failure with Reduced Ejection Fraction

## Definition and Classification

### Current Definitions (2022 AHA/ACC/HFSA)

The 2022 AHA/ACC/HFSA guidelines establish a refined classification system for heart failure based on left ventricular ejection fraction. Heart failure with reduced ejection fraction is defined as an LVEF of 40% or less. Heart failure with mildly reduced ejection fraction occupies the intermediate zone with an LVEF between 41% and 49%, while heart failure with preserved ejection fraction is characterized by an LVEF of 50% or greater. An important contemporary addition is the category of heart failure with improved ejection fraction, which applies to patients whose LVEF was previously 40% or less but has since risen above 40% on reassessment.

| Classification | LVEF | Abbreviation |
|---|---|---|
| HF with Reduced EF | <= 40% | HFrEF |
| HF with Mildly Reduced EF | 41% - 49% | HFmrEF |
| HF with Preserved EF | >= 50% | HFpEF |
| HF with Improved EF | Previously <= 40%, now > 40% | HFimpEF  |  Critically, guideline-directed medical therapy should be continued in these patients because neurohormonal activation may recur if treatment is discontinued, leading to recurrent ventricular dysfunction. |

The New York Heart Association functional classification provides a complementary framework based on symptom burden. Class I denotes no limitation of physical activity, with ordinary activity causing no symptoms. Class II indicates slight limitation, where symptoms arise with ordinary physical activity. Class III reflects marked limitation, with symptoms occurring during less-than-ordinary activity. Class IV represents the most severe functional impairment, with symptoms present even at rest.

| NYHA Class | Symptom Description | Functional Limitation |
|---|---|---|
| I | No symptoms with ordinary activity | None |
| II | Symptoms with ordinary activity | Slight |
| III | Symptoms with less-than-ordinary activity | Marked |
| IV | Symptoms at rest | Severe |

### ACC/AHA Stages

The ACC/AHA staging system captures the progressive nature of heart failure from risk factor exposure through end-stage disease. Stage A identifies patients at risk for heart failure due to conditions such as hypertension, diabetes mellitus, coronary artery disease, obesity, cardiotoxin exposure, or a family history of cardiomyopathy, but who have not yet developed structural heart disease or symptoms. Stage B encompasses patients with structural heart disease, including reduced ejection fraction, left ventricular hypertrophy, chamber enlargement, wall motion abnormalities, or valvular disease, but who remain asymptomatic. Stage C represents the transition to clinical heart failure, defined by structural heart disease accompanied by current or prior heart failure symptoms. Stage D designates advanced heart failure with refractory symptoms that require specialized interventions such as mechanical circulatory support, heart transplantation, or palliative care.

| ACC/AHA Stage | Description | Key Features |
|---|---|---|
| A | At risk | HTN, DM, CAD, obesity, cardiotoxin exposure, family history; no structural disease or symptoms |
| B | Pre-heart failure | Structural disease (reduced EF, LVH, WMA, valvular disease); no symptoms |
| C | Symptomatic HF | Structural disease with current or prior HF symptoms |
| D | Advanced HF | Refractory symptoms; requires MCS, transplant, or palliative care |

## Etiology and Pathophysiology

### Common Etiologies

Ischemic cardiomyopathy stands as the most common cause of heart failure with reduced ejection fraction, accounting for approximately 60 to 70% of cases. It manifests with regional wall motion abnormalities that correspond to specific coronary territories, and the extent of scar burden is a critical determinant of myocardial viability and recovery potential following revascularization.

Idiopathic dilated cardiomyopathy is a diagnosis of exclusion, made after ischemic, valvular, hypertensive, and other secondary causes have been systematically ruled out. Notably, approximately 30 to 50% of cases previously deemed idiopathic are now recognized to have a genetic basis. Valvular etiologies include severe aortic stenosis or regurgitation and severe mitral regurgitation, which produces progressive volume overload of the left ventricle. Hypertensive cardiomyopathy results from long-standing uncontrolled hypertension, beginning with concentric left ventricular hypertrophy and eventually progressing to eccentric remodeling with cavity dilation.

Toxic cardiomyopathies encompass several injurious exposures. Alcohol-related cardiomyopathy typically develops with consumption exceeding 7 to 8 drinks per day for more than 5 years. Cocaine and methamphetamine exert direct myocardial toxicity through catecholamine-mediated injury. Chemotherapy-related cardiomyopathy includes anthracycline toxicity, which is dose-dependent and often irreversible, and trastuzumab cardiotoxicity, which is generally reversible upon drug discontinuation.

Peripartum cardiomyopathy presents during the last month of pregnancy through 5 months postpartum, with recovery of ventricular function occurring in approximately 50% of patients. However, subsequent pregnancies carry a relapse risk of roughly 20% if ejection fraction has not fully recovered. Tachycardia-mediated cardiomyopathy represents a reversible form of ventricular dysfunction caused by sustained tachycardia, including uncontrolled atrial fibrillation, atrial tachycardia, or frequent premature ventricular contractions exceeding a 15 to 20% burden. Infiltrative diseases such as amyloidosis, sarcoidosis, and hemochromatosis represent important and increasingly recognized etiologies. Metabolic and endocrine causes include thyroid disease, acromegaly, pheochromocytoma, and beriberi from thiamine deficiency. Among genetic causes, titin truncating variants are the most common in familial dilated cardiomyopathy, occurring in approximately 25% of cases, while lamin A/C mutations carry a particularly ominous prognosis with associated conduction disease and sudden cardiac death risk.

### Neurohormonal Activation

The pathophysiology of heart failure with reduced ejection fraction centers on maladaptive neurohormonal activation. The renin-angiotensin-aldosterone system drives disease progression through multiple deleterious pathways. Angiotensin II causes vasoconstriction, sodium retention, myocardial fibrosis, and adverse ventricular remodeling. Aldosterone compounds these effects by promoting fibrosis, endothelial dysfunction, and potassium and magnesium wasting.

The sympathetic nervous system becomes chronically overactivated in heart failure, leading to elevated catecholamine levels that produce tachycardia, vasoconstriction, myocyte apoptosis, and beta-receptor downregulation. While acutely compensatory, this sustained sympathetic drive is chronically maladaptive and contributes to progressive ventricular dysfunction.

Natriuretic peptides, including BNP and NT-proBNP, are released in response to myocardial wall stress and represent a counterregulatory system. They promote natriuresis, vasodilation, and anti-fibrotic effects, opposing the detrimental actions of the RAAS and sympathetic nervous system. Neprilysin, an endopeptidase that degrades natriuretic peptides along with bradykinin and adrenomedullin, represents a therapeutic target. Its inhibition by sacubitril augments these beneficial counterregulatory pathways, forming the pharmacologic rationale for combined neprilysin and RAAS inhibition.

<image>
A detailed pathophysiology diagram of the neurohormonal cascade in heart failure. Central illustration of a failing heart with reduced EF. Three main pathways radiating outward: (1) RAAS pathway (shown in red): renin from JGA → angiotensinogen → angiotensin I (ACE step) → angiotensin II → effects (vasoconstriction, aldosterone release from adrenal gland, myocardial fibrosis, sodium retention), with drug intervention points marked (ACEi, ARB, MRA). (2) Sympathetic pathway (shown in orange): baroreceptor activation → increased NE from sympathetic nerves → effects (tachycardia, vasoconstriction, myocyte toxicity, beta-receptor downregulation), with beta-blocker intervention point marked. (3) Natriuretic peptide pathway (shown in green): wall stress → BNP/ANP release → effects (natriuresis, vasodilation, anti-fibrosis), with neprilysin degradation pathway and sacubitril inhibition point marked. Include SGLT2i mechanism shown in blue affecting kidney tubule. All drug intervention points shown as red X marks with drug class names.
</image>

## Guideline-Directed Medical Therapy (GDMT)

### The Four Pillars of HFrEF Therapy

#### Pillar 1: RAAS Inhibition

Inhibition of the renin-angiotensin-aldosterone system forms the first pillar of heart failure therapy. ACE inhibitors, including enalapril, ramipril, and lisinopril, have a robust evidence base established by landmark trials such as CONSENSUS and SOLVD. Target doses include enalapril 10 to 20 mg twice daily, lisinopril 20 to 40 mg daily, and ramipril 5 mg twice daily. Angiotensin receptor blockers serve as alternatives for patients intolerant of ACE inhibitors, typically due to cough. Valsartan at a target dose of 160 mg twice daily was studied in Val-HeFT, and candesartan at 32 mg daily was evaluated in the CHARM program. Importantly, the combination of an ACE inhibitor with an ARB is not recommended, as demonstrated in the ONTARGET trial, which showed increased adverse events without meaningful benefit.

The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan represents the preferred agent in this class. The PARADIGM-HF trial demonstrated a 20% reduction in cardiovascular death and heart failure hospitalization compared with enalapril, establishing its superiority. The target dose is 97/103 mg twice daily, and a mandatory 36-hour washout from ACE inhibitors is required before initiation to mitigate the risk of angioedema. Current guidelines favor sacubitril/valsartan over ACE inhibitors or ARBs in NYHA Class II to III patients who tolerate these agents, and it may be used as first-line therapy without requiring a prior trial of ACE inhibitor or ARB.

| RAAS Inhibitor | Target Dose | Key Trial | Key Result |
|---|---|---|---|
| Enalapril | 10-20 mg BID | CONSENSUS, SOLVD | Mortality reduction |
| Lisinopril | 20-40 mg daily | ATLAS | Higher dose superior |
| Ramipril | 5 mg BID | HOPE | CV event reduction |
| Valsartan (ARB) | 160 mg BID | Val-HeFT | Alternative if ACEi intolerant |
| Candesartan (ARB) | 32 mg daily | CHARM | Alternative if ACEi intolerant |
| Sacubitril/Valsartan (ARNI) | 97/103 mg BID | PARADIGM-HF | 20% reduction in CV death/HF hospitalization vs enalapril |

#### Pillar 2: Beta-Blockers

Only three beta-blockers have demonstrated mortality benefit in heart failure with reduced ejection fraction: carvedilol, metoprolol succinate (the extended-release formulation), and bisoprolol. The MERIT-HF trial showed a 34% mortality reduction with metoprolol succinate at a target dose of 200 mg daily. The COPERNICUS trial demonstrated a 35% mortality reduction with carvedilol, even in patients with severe NYHA Class IV symptoms, with a target dose of 25 mg twice daily or 50 mg twice daily for patients weighing more than 85 kilograms. CIBIS-II established a 34% mortality reduction with bisoprolol at a target dose of 10 mg daily.

| Beta-Blocker | Target Dose | Key Trial | Mortality Reduction |
|---|---|---|---|
| Carvedilol | 25 mg BID (50 mg BID if > 85 kg) | COPERNICUS | 35% |
| Metoprolol Succinate (XL) | 200 mg daily | MERIT-HF | 34% |
| Bisoprolol | 10 mg daily | CIBIS-II | 34% |

Beta-blockers should be initiated at low doses when the patient is euvolemic and hemodynamically stable, with gradual up-titration every two weeks as tolerated. They should not be started during acute decompensation. It is essential to recognize that metoprolol tartrate, atenolol, and other beta-blockers are not interchangeable with the three evidence-based agents, as they lack the mortality data required to support their use in this population.

#### Pillar 3: Mineralocorticoid Receptor Antagonists (MRA)

Spironolactone was evaluated in the RALES trial, which showed a 30% mortality reduction in patients with NYHA Class III to IV symptoms. The target dose is 25 to 50 mg daily. Eplerenone was studied in the EMPHASIS-HF trial, demonstrating a 37% reduction in cardiovascular death and heart failure hospitalization in NYHA Class II patients. The target dose is 50 mg daily, and eplerenone carries fewer anti-androgenic side effects than spironolactone, making it the preferred alternative when gynecomastia develops, which occurs in approximately 10% of patients on spironolactone.

Monitoring is critical with MRA therapy. Potassium and creatinine should be checked within one week of initiation, at one month, and then every three months thereafter. These agents are contraindicated when potassium exceeds 5.0 mEq/L or the estimated glomerular filtration rate falls below 30 mL/min/1.73 m squared.

#### Pillar 4: SGLT2 Inhibitors

The SGLT2 inhibitors represent the most recent addition to the foundational therapy of heart failure with reduced ejection fraction. Dapagliflozin was studied in the DAPA-HF trial, which demonstrated a 26% reduction in worsening heart failure and cardiovascular death compared with placebo, irrespective of diabetes status. Empagliflozin was evaluated in EMPEROR-Reduced, showing a 25% reduction in cardiovascular death and heart failure hospitalization. Both agents are dosed at 10 mg daily with no titration required.

The mechanisms of benefit extend beyond glycemic control and include osmotic diuresis, natriuresis, improved cardiac energetics, and anti-fibrotic and anti-inflammatory effects. The benefits have been demonstrated across the ejection fraction spectrum, with EMPEROR-Preserved and DELIVER extending the evidence to HFpEF. Common side effects include genital mycotic infections in 3 to 6% of patients, volume depletion, and rarely euglycemic diabetic ketoacidosis, predominantly in patients with type 1 diabetes.

### Simultaneous vs. Sequential Initiation

The traditional approach of sequential up-titration of one drug class at a time over several months has been challenged by contemporary evidence. The STRONG-HF trial supports a strategy of rapid initiation of all four pillars simultaneously or within 2 to 4 weeks at low doses, followed by up-titration. This accelerated approach is associated with more rapid ejection fraction recovery and symptom improvement. When prioritizing based on clinical profile, patients who are volume overloaded benefit from early initiation of an SGLT2 inhibitor combined with a diuretic. In patients with hypotension, SGLT2 inhibitors and low-dose beta-blockers may be started first. For patients with hyperkalemia, sacubitril/valsartan and SGLT2 inhibitors are advantageous choices, as both agents tend to lower potassium.

### Additional Therapies

The combination of hydralazine and isosorbide dinitrate has a specific evidence base in self-identified Black patients with NYHA Class III to IV symptoms already on optimal therapy. The A-HeFT trial demonstrated a 43% mortality reduction in this population, with target doses of hydralazine 75 mg three times daily and isosorbide dinitrate 40 mg three times daily.

Ivabradine was evaluated in the SHIFT trial and reduces heart failure hospitalization without conferring a mortality benefit. It is indicated in patients in sinus rhythm with a heart rate of 70 bpm or greater despite maximally tolerated beta-blocker therapy. The dosing is 5 to 7.5 mg twice daily, and it is contraindicated in atrial fibrillation.

Vericiguat, a soluble guanylate cyclase stimulator, was studied in the VICTORIA trial and showed a modest 10% reduction in cardiovascular death and heart failure hospitalization in patients with recently decompensated heart failure with reduced ejection fraction. The target dose is 10 mg daily.

### Diuretics

Loop diuretics, including furosemide, bumetanide, and torsemide, remain essential for volume management and symptom relief in heart failure, although they do not confer a mortality benefit. Furosemide has highly variable oral bioavailability ranging from 10 to 80%, whereas torsemide demonstrates more reliable absorption in the range of 80 to 100% with a longer duration of action.

Diuretic resistance is a common clinical challenge and can be addressed through several strategies: increasing the diuretic dose, switching to intravenous administration, adding a thiazide diuretic such as metolazone 2.5 to 5 mg given 30 minutes before the loop diuretic to achieve sequential nephron blockade, or considering acetazolamide, which was studied in the ADVOR trial at 500 mg intravenously daily and showed improved decongestion. The clinical target is euvolemia, assessed through daily weights, jugular venous pressure examination, and the absence of orthopnea, peripheral edema, and pulmonary rales.

<image>
A clinical algorithm flowchart for GDMT initiation and uptitration in HFrEF. Start with "New Diagnosis HFrEF (EF <= 40%)" at top. Four parallel columns representing the four pillars, each starting simultaneously: Column 1 (red): ARNI - start sacubitril/valsartan 24/26 mg BID → titrate to 49/51 mg BID → target 97/103 mg BID (if unable, use ACEi or ARB). Column 2 (blue): Beta-blocker - start carvedilol 3.125 mg BID or metoprolol succinate 12.5-25 mg daily → double dose every 2 weeks → target carvedilol 25 mg BID or metoprolol 200 mg daily. Column 3 (green): MRA - start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily → target spironolactone 25-50 mg or eplerenone 50 mg (monitor K+ and Cr). Column 4 (purple): SGLT2i - start dapagliflozin 10 mg or empagliflozin 10 mg (no titration needed). Bottom box: "Additional therapies if still symptomatic: hydralazine/ISDN (Black patients), ivabradine (HR >= 70, sinus rhythm), vericiguat (recent decompensation)." Include timeline markers at 2-week intervals along each column.
</image>

## Device Therapy

### ICD for Primary Prevention

Implantable cardioverter-defibrillator therapy for primary prevention is indicated in patients with an LVEF of 35% or less despite at least 3 months of optimal guideline-directed medical therapy, NYHA Class II to III functional status, a life expectancy exceeding 1 year, and reasonable functional status. For ischemic cardiomyopathy, ICD implantation should be deferred until at least 40 days after myocardial infarction, as the DINAMIT and IRIS trials demonstrated no benefit from early ICD placement in the immediate post-infarction period. For non-ischemic cardiomyopathy, a waiting period of 3 to 9 months on guideline-directed medical therapy is appropriate before making the ICD decision, as significant ejection fraction improvement is possible during this optimization period.

The evidence supporting ICD therapy in ischemic cardiomyopathy is well established. MADIT-II demonstrated a 31% mortality reduction in patients with ischemic cardiomyopathy and an ejection fraction of 30% or less. SCD-HeFT showed a 23% mortality reduction in patients with NYHA Class II to III heart failure, encompassing both ischemic and non-ischemic etiologies, with an ejection fraction of 35% or less. The DANISH trial, conducted exclusively in non-ischemic cardiomyopathy, did not show a reduction in all-cause mortality with ICD therapy, although it did reduce sudden cardiac death. Subgroup analysis suggested that younger patients, particularly those under 68 years of age, appeared to derive benefit. The subcutaneous ICD represents an appropriate alternative for patients without a pacing indication or need for antitachycardia pacing, offering the advantage of avoiding transvenous lead complications.

### CRT Indications (see dedicated lecture)

Cardiac resynchronization therapy carries its strongest indication in patients with an LVEF of 35% or less, left bundle branch block with a QRS duration of 150 ms or greater, and NYHA Class II to IV symptoms despite optimal guideline-directed medical therapy. The benefits of CRT include improved ejection fraction with an average gain of 10 to 15 percentage points, reverse ventricular remodeling, reduced heart failure hospitalization, and a mortality benefit.

## Monitoring and Follow-Up

### Biomarkers

NT-proBNP and BNP serve as valuable tools for monitoring treatment response, with a target reduction of more than 30% from baseline. Persistent elevation despite therapy optimization is associated with worse outcomes. For acute heart failure presentations, an NT-proBNP below 300 pg/mL makes heart failure unlikely. For chronic heart failure evaluation, a threshold below 125 pg/mL argues against the diagnosis. Age-adjusted cutoffs apply for acute heart failure: 450 pg/mL for patients under 50, 900 pg/mL for those aged 50 to 75, and 1800 pg/mL for patients over 75. Serial troponin elevation suggests ongoing myocardial injury and portends a worse prognosis.

### Remote Monitoring

The CardioMEMS system, evaluated in the CHAMPION trial, is an implantable pulmonary artery pressure sensor that enables daily monitoring of pulmonary artery pressures. It demonstrated a 28% reduction in heart failure hospitalization in NYHA Class III patients and is used to guide individualized adjustment of diuretic and vasodilator therapy. Device-based monitoring parameters, including intrathoracic impedance, heart rate variability, activity levels, and atrial arrhythmia burden, provide additional data to support clinical decision-making.

### Prognosis and Risk Scores

Several validated tools exist for prognostic assessment in heart failure. The Seattle Heart Failure Model predicts 1- to 5-year survival using clinical, laboratory, medication, and device variables. The MAGGIC score is a meta-analysis-derived risk model applicable to chronic heart failure. Key prognostic markers that indicate poor outcomes include persistent NYHA Class III to IV status, low systolic blood pressure below 100 mmHg, hyponatremia below 135 mEq/L, elevated blood urea nitrogen and creatinine, anemia, and persistent QRS widening.

## Key Clinical Pearls

- All four pillars of GDMT should be initiated as quickly as possible -- waiting to up-titrate one drug before starting another delays benefit and increases mortality
- Mild creatinine rise (up to 30%) after RAAS inhibitor initiation is expected and acceptable; do not reflexively discontinue unless hyperkalemia or symptomatic hypotension
- Beta-blockers should NOT be initiated during acute decompensation but should be continued (at reduced dose if needed) in patients already on them unless cardiogenic shock or severe hemodynamic compromise
- SGLT2 inhibitors are the easiest pillar to initiate: single dose, no titration, minimal hemodynamic effect, and kidney-protective -- consider starting first in many patients
- Always assess and treat reversible causes: revascularization for ischemic CM with viable myocardium, thyroid replacement, alcohol cessation, rate control for tachycardia-mediated CM, correction of severe valvular disease
- Reassess EF at 3-6 months after GDMT optimization; if EF has improved to > 40%, continue all GDMT (HFimpEF) -- withdrawal risks relapse

## References

- Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145:e895-e1032.
- McMurray JJV, et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure (PARADIGM-HF). NEJM. 2014;371:993-1004.
- McMurray JJV, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF). NEJM. 2019;381:1995-2008.
- Packer M, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced). NEJM. 2020;383:1413-1424.
- Bardy GH, et al. Amiodarone or an Implantable Cardioverter-Defibrillator for Congestive Heart Failure (SCD-HeFT). NEJM. 2005;352:225-237.