HFrEF: Heart Failure with Reduced Ejection Fraction

2. What It Is

Heart failure is a clinical syndrome, not a single disease. The term describes a state in which the heart cannot pump enough blood to meet the body’s metabolic demands, or can only do so at the cost of abnormally raised filling pressures. That distinction matters, because it separates two fundamentally different types of heart failure with different mechanisms, different evidence bases, and different prognoses.

HFrEF is heart failure with a reduced ejection fraction. The ejection fraction (EF) is the percentage of blood in the left ventricle that is ejected with each heartbeat. A normal EF is 55-70%. In HFrEF, the EF is below 40% 5 / Solid .

The biology underlying HFrEF is systolic dysfunction: the left ventricle contracts weakly. The chambers dilate as the heart attempts to maintain forward output through the Frank-Starling mechanism, increasing preload to generate more stroke volume. Over time, this compensatory dilation itself becomes part of the pathology. The LV remodels into a spherical shape that is mechanically inefficient, worsening the dysfunction it was meant to compensate.

The causes of HFrEF include:

• Ischemic cardiomyopathy: prior myocardial infarctions scar the myocardium, replacing contractile tissue with fibrosis. This is the most common cause in the United States.
• Non-ischemic dilated cardiomyopathy (NICM): idiopathic in many cases; genetic in 20-35% (most commonly TTN gene mutations, followed by LMNA, SCN5A, and others).
• Tachycardia-induced cardiomyopathy: persistent rapid heart rates, most often from uncontrolled atrial fibrillation, causing reversible LV dysfunction.
• Alcohol-induced cardiomyopathy: dose-dependent myocardial toxicity; potentially reversible with abstinence.
• Chemotherapy-induced cardiomyopathy: anthracyclines (doxorubicin), trastuzumab, and tyrosine kinase inhibitors all carry cardiotoxicity risk.
• Peripartum cardiomyopathy: occurs in the last month of pregnancy or within five months of delivery; recovery rate approximately 30-50% at six months 4 / Promising .
• Inflammatory cardiomyopathy: myocarditis, giant cell myocarditis, sarcoidosis.
• Stress cardiomyopathy (Takotsubo): typically reversible.

The diagnosis of HFrEF requires two elements: symptoms of heart failure (dyspnea, fatigue, fluid retention) combined with objective evidence of reduced EF on imaging. Neither alone is sufficient.

Relevant staging: The AHA/ACC uses four stages. Stage A is risk without structural disease. Stage B is structural disease without symptoms. Stage C is structural disease with current or prior symptoms. Stage D is refractory heart failure requiring advanced therapies. The NYHA functional classification (I through IV) describes symptom severity at any given time and does not map one-to-one with stage.

3. The Mechanism

The story of HFrEF is the story of the neurohormonal hypothesis, and understanding that story explains why the modern treatment regimen looks the way it does.

The compensatory cascade

When the left ventricle’s output falls, the body’s first response is adaptive. The sympathetic nervous system activates: heart rate rises, contractility increases, peripheral arteries constrict to maintain blood pressure. The renin-angiotensin-aldosterone system (RAAS) activates: angiotensin II increases afterload and triggers aldosterone-driven sodium and water retention. These responses make evolutionary sense. In the setting of hemorrhage or acute dehydration, they maintain perfusion to vital organs.

In heart failure, these systems are not responding to a transient insult. They are chronically activated in response to a permanently impaired pump. Sustained sympathetic activation increases wall stress and oxygen demand. Sustained RAAS activation causes progressive volume overload and fibrosis. Angiotensin II directly promotes myocardial fibrosis and apoptosis. Aldosterone promotes interstitial fibrosis. Norepinephrine is directly toxic to cardiomyocytes at high concentrations 5 / Solid .

The result is a self-reinforcing cycle: reduced cardiac output triggers neurohormonal activation, which causes further myocardial damage and remodeling, which further reduces cardiac output. This is the pathological arc of untreated HFrEF.

The Frank-Starling mechanism and its limits

The heart uses preload to augment contractility. As ventricular filling increases, myofibrils are stretched and generate greater contractile force (Frank-Starling law). In the failing heart, this mechanism initially preserves stroke volume but at the cost of raised end-diastolic pressures. When LV end-diastolic pressure rises above 18-20 mmHg, it is transmitted backward into the pulmonary circulation, causing pulmonary capillary wedge pressure to rise, fluid to leak from the pulmonary capillaries, and alveolar edema to develop. The patient cannot lie flat because gravity redistributes this fluid toward the apices when supine, causing orthopnea and paroxysmal nocturnal dyspnea.

Chamber remodeling

Chronic volume and pressure overload cause the LV to enlarge and change shape. The normal LV is ellipsoidal. The failing LV becomes spherical. By the law of Laplace, wall stress is proportional to chamber radius. A larger, rounder chamber generates higher wall stress at any given pressure, requiring more energy to contract to the same degree. The geometry of remodeling is itself a cause of progressive dysfunction. Reverse remodeling, a reduction in LV volumes and a return toward more ellipsoidal geometry, is what occurs when guideline-directed medical therapy works.

The natriuretic peptide system

In response to raised wall stress, the heart secretes B-type natriuretic peptide (BNP) from the ventricles. BNP and its precursor NT-proBNP are the two clinically measured forms. They are vasodilatory, natriuretic, and antagonistic to the RAAS. They are imperfect compensatory signals: in advanced heart failure, they are markedly raised but functionally insufficient to overcome the dominant neurohormonal activation. Clinically, they are the most useful biomarkers for diagnosing heart failure (sensitivity 90%, specificity 76% for BNP >100 pg/mL; Solid; Maisel AS, et al. NEJM 2002; 10.1056/NEJMoa020233) and for tracking response to therapy.

4. How We Diagnose

The diagnosis of HFrEF begins with clinical suspicion and is confirmed with imaging and biomarkers. The workflow follows a logical sequence.

Symptom assessment

The cardinal symptoms are dyspnea on exertion, orthopnea (shortness of breath when lying flat), paroxysmal nocturnal dyspnea (waking from sleep short of breath), and fatigue. Lower extremity edema is common but non-specific. The Framingham criteria formally require two major criteria or one major plus two minor criteria. Clinically, the combination of exertional dyspnea, orthopnea, raised JVP, S3 gallop, and radiographic pulmonary edema is diagnostic without further testing.

Physical examination

Key findings: jugular venous distension (JVD) at greater than 3 cm above the sternal angle in the 45-degree position indicates raised right atrial pressure. Laterally displaced apical impulse indicates LV enlargement. S3 gallop (low-frequency sound in early diastole, filling into a dilated ventricle) carries a positive likelihood ratio of 11 for raised LV filling pressures 5 / Solid . Hepatojugular reflux (sustained JVD with sustained right upper quadrant compression) indicates raised venous pressures. Bi-basal crackles indicate pulmonary edema. Pitting edema.

Electrocardiogram

Non-specific but often abnormal: left bundle branch block (LBBB) is associated with dyssynchrony and is an indication for cardiac resynchronization therapy if EF remains below 35% on maximally tolerated guideline-directed therapy. Q waves suggest prior MI. Low voltage suggests pericardial effusion or amyloidosis.

BNP and NT-proBNP

BNP above 400 pg/mL or NT-proBNP above 1,800 pg/mL in the dyspneic outpatient is highly specific for decompensated heart failure. Values below 100 pg/mL effectively rule out acute heart failure 5 / Solid . Intermediate values (100-400 for BNP) require clinical correlation. In the BREATHE-2 era, BNP-guided therapy reduced all-cause mortality by 18% compared to symptom-guided therapy 4 / Promising 32057-5).

Echocardiography

The transthoracic echocardiogram (TTE) is the cornerstone imaging study. It provides EF (the key diagnostic criterion), LV dimensions and volumes, wall motion abnormalities (suggesting ischemic etiology), diastolic function parameters, valvular anatomy, right ventricular function, and an estimate of pulmonary artery pressure. Every patient with newly diagnosed heart failure should have a TTE. The LVEF should be re-assessed 3-6 months after initiation of guideline-directed medical therapy to determine response and to guide device decisions.

Cardiac MRI

CMR is the gold standard for LV volumes and EF when echocardiographic windows are poor. Late gadolinium enhancement (LGE) distinguishes ischemic from non-ischemic cardiomyopathy: subendocardial or transmural LGE in a coronary distribution indicates prior infarction; mid-wall LGE suggests non-ischemic fibrosis from myocarditis, sarcoidosis, or genetic cardiomyopathy. CMR also detects amyloid infiltration, iron overload, and Fabry disease when parametric mapping is included.

Coronary evaluation

All newly diagnosed HFrEF patients without a clear non-ischemic etiology should undergo coronary evaluation, because ischemic cardiomyopathy may be partially reversible with revascularization. Coronary angiography remains the definitive test. CT coronary angiography is an alternative in lower-risk patients with a good acoustic window for functional ischemia assessment via CT-FFR.

Genetic testing

The ACC/AHA 2022 guidelines recommend genetic testing for patients with non-ischemic dilated cardiomyopathy, particularly when there is a family history of heart failure, SCD, or conduction disease. LMNA mutations carry specific implications (high SCD risk, may warrant earlier ICD) separate from the EF threshold. TTN truncating mutations are the most common genetic cause overall.

5. The Evidence

No condition in cardiovascular medicine has a richer trial evidence base than HFrEF. The modern four-drug regimen exists because four separate pathways were shown in landmark randomized controlled trials to independently reduce mortality.

The ACE Inhibitor Era: CONSENSUS (1987)

The CONSENSUS trial enrolled 253 patients with NYHA Class IV heart failure and randomized them to enalapril versus placebo. At six months, enalapril reduced all-cause mortality by 40% (p = 0.002) 5 / Solid . This was the first mortality-reducing therapy ever demonstrated for heart failure. The SOLVD-Treatment trial extended the benefit to milder symptoms (EF below 35%, NYHA II-III): enalapril reduced mortality by 16% (HR 0.84, p = 0.0036) and hospitalization for heart failure by 26% 5 / Solid . ACE inhibitors became the foundation of therapy.

ARBs (candesartan, valsartan) were shown to be equivalent alternatives for patients intolerant of ACE inhibitors due to cough 5 / Solid 14461-9).

Beta-blockers: MERIT-HF (1999) and COPERNICUS (2001)

For most of the 1980s, beta-blockers were considered contraindicated in heart failure. The fear was that blocking the compensatory sympathetic activation would worsen the syndrome. The trials proved the opposite.

MERIT-HF enrolled 3,991 patients with symptomatic HFrEF (mean EF 28%) and randomized them to metoprolol succinate versus placebo. The trial was stopped early at 12 months: metoprolol reduced all-cause mortality by 34% (HR 0.66, 95% CI 0.53-0.81) 5 / Solid 01185-9). The benefit was seen across the spectrum of heart failure severity.

COPERNICUS enrolled 2,289 patients with severe HFrEF (EF below 25%, NYHA III-IV at rest): carvedilol reduced all-cause mortality by 35% (HR 0.65, p = 0.0014), also stopped early 5 / Solid . The CIBIS-II trial showed similar results for bisoprolol 5 / Solid 11181-9).

Three beta-blockers are approved for HFrEF mortality reduction: metoprolol succinate, carvedilol, and bisoprolol. Metoprolol tartrate (short-acting) is NOT one of them.

Mineralocorticoid Receptor Antagonists: RALES (1999) and EMPHASIS-HF (2011)

RALES enrolled 1,663 patients with severe HFrEF (EF below 35%, NYHA III-IV) already on ACE inhibitor and diuretic, and randomized them to spironolactone 25 mg daily versus placebo. The trial was stopped early: spironolactone reduced all-cause mortality by 30% (HR 0.70, 95% CI 0.60-0.82) 5 / Solid . The mechanism: aldosterone blockade reduces myocardial fibrosis and sudden cardiac death.

EMPHASIS-HF enrolled milder patients (NYHA II HFrEF with recent decompensation) and randomized them to eplerenone (a more selective MRA than spironolactone). Eplerenone reduced the composite of cardiovascular death or hospitalization for heart failure by 37% (HR 0.63) 5 / Solid . The indication for MRA therapy was extended to the NYHA II population.

ARNI: PARADIGM-HF (2014)

This is the trial that changed the ACE inhibitor era. PARADIGM-HF enrolled 8,442 patients with symptomatic HFrEF (EF below 40%, later tightened to below 35%) and randomized them to sacubitril-valsartan (Entresto) versus enalapril. The trial was stopped early at 27 months: sacubitril-valsartan reduced cardiovascular death or hospitalization for heart failure by 20% (HR 0.80, 95% CI 0.73-0.87), reduced all-cause mortality by 16% (HR 0.84), and reduced sudden cardiac death by 20% 5 / Solid . Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides, BNP, and bradykinin. Valsartan blocks the angiotensin receptor. Together, they amplify the heart’s natural protective peptide signaling while blocking RAAS-driven damage.

Sacubitril-valsartan has replaced ACE inhibitors/ARBs as the preferred RAAS blocker in patients who can tolerate it. The washout period (36 hours from last ACE inhibitor dose) before initiation is mandatory to prevent angioedema.

SGLT2 Inhibitors: DAPA-HF (2019) and EMPEROR-Reduced (2020)

These are the newest pillar and, arguably, the most surprising. SGLT2 inhibitors were developed as glucose-lowering drugs. DAPA-HF enrolled 4,744 patients with HFrEF (EF below 40%), including 42% without diabetes, and randomized them to dapagliflozin 10 mg daily versus placebo, on top of maximally tolerated background therapy. Dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 26% (HR 0.74, 95% CI 0.65-0.85) 5 / Solid . The benefit was identical in diabetics and non-diabetics.

EMPEROR-Reduced enrolled 3,730 HFrEF patients (EF below 40%) and randomized them to empagliflozin 10 mg versus placebo. Empagliflozin reduced cardiovascular death or hospitalization for worsening heart failure by 25% (HR 0.75, 95% CI 0.65-0.86) 5 / Solid .

The mechanism in heart failure is not glucosuria alone. SGLT2 inhibitors reduce preload and afterload through osmotic effects, attenuate myocardial inflammation, improve mitochondrial function, and possibly exert direct anti-fibrotic effects. They also reduce hospitalization for heart failure faster than any other class, with benefits apparent within 30 days.

The Four-Pillar Regimen

The 2022 AHA/ACC/HFSA guidelines now recommend four drug classes as simultaneous targets for all patients with HFrEF (EF below 40%) without contraindications:

These four pillars address four distinct pathological pathways: RAAS overactivation (ARNI), sympathetic overactivation (beta-blocker), aldosterone/fibrosis (MRA), and myocardial metabolic stress/volume (SGLT2i). The drugs are not interchangeable. Removing one pillar removes the mortality benefit of that pathway.

Device Therapy

ICD (Implantable Cardioverter-Defibrillator): For patients with HFrEF (EF below 35%) who have already received guideline-directed medical therapy for at least 90 days and whose EF remains below 35%, an ICD is recommended if life expectancy exceeds one year with good functional status 5 / Solid . ICD reduces sudden cardiac death. It does not improve symptoms or reverse remodeling. It is a safety net, not a treatment.

CRT (Cardiac Resynchronization Therapy): Approximately 30% of HFrEF patients have left bundle branch block (LBBB), causing the ventricles to contract out of synchrony. CRT paces both ventricles simultaneously, restoring synchronous contraction. The MADIT-CRT trial (EF below 30%, LBBB, NYHA I-II) showed 34% reduction in heart failure events with CRT-D versus ICD alone 5 / Solid . CRT reverse-remodels the LV, improving EF by 10-15 percentage points in responders. Responder rate is approximately 65-70%.

LVAD (Left Ventricular Assist Device): For Stage D HFrEF, the HeartMate III (Abbott) is FDA-approved under PMA for bridge-to-transplant and destination therapy. The MOMENTUM 3 trial showed the HeartMate III had superior freedom from disabling stroke or reoperation compared to HeartMate II (82.3% vs 76.9% at 2 years) 5 / Solid . LVAD as destination therapy in patients ineligible for transplant provides a median survival of 3.3 years, with some patients living beyond 5-7 years.

6. The Patient Experience

The person with newly diagnosed HFrEF typically receives a diagnosis after a hospitalization, or sometimes after an incidental echo performed for another reason shows a low EF. The emotional arc is specific: shock (the heart “failure” label carries weight), confusion (four new medications at discharge), and the disorientation of suddenly being a “heart patient.”

What the patient actually feels depends on their functional class. An NYHA Class II patient may have mild breathlessness going up stairs but lead a near-normal life. An NYHA Class III patient limits activity because breathlessness occurs with minimal exertion: walking to the mailbox, making the bed. An NYHA Class IV patient is symptomatic at rest. The same patient can traverse these classes in both directions depending on therapy adequacy.

Weight monitoring is the single most concrete self-management tool. A weight gain of more than 2 lbs in one day or 5 lbs in one week signals fluid accumulation and should trigger a call to the medical team before decompensation requires hospitalization. This is not a peripheral recommendation. The TELE-HF trial tested remote weight monitoring and the CHAMPION trial tested direct measurement of pulmonary artery pressure with the CardioMEMS device 5 / Solid : CardioMEMS-guided management reduced heart failure hospitalization by 28%.

Sodium restriction to less than 2,000-2,500 mg per day is recommended by most guidelines, though the SODIUM-HF trial (Ezekowitz JA, et al., Lancet 2022; 10.1016/S0140-6736(22)00369-5) showed no difference in clinical events with low-sodium diet vs usual care, complicating the picture 4 / Promising . The 2022 guidelines still recommend reducing sodium in symptomatic patients.

Exercise. The fear that exercise will harm the failing heart is understandable but wrong. The HF-ACTION trial enrolled 2,331 HFrEF patients in supervised exercise training versus usual care: exercise training reduced all-cause mortality or hospitalization by 11% (HR 0.89, p = 0.03) 5 / Solid . Cardiac rehabilitation programs are recommended for stable HFrEF patients. In Illinois, programs are available at Carle Foundation Hospital (Urbana), Northwestern Memorial (Chicago), NorthShore University HealthSystem (Evanston), and OSF HealthCare (Peoria).

Sexual activity: a common concern patients rarely raise. Stable NYHA Class I-II patients can resume sexual activity safely. For patients whose functional capacity falls below 5 METs on exercise testing, the sexual activity question requires individualized discussion.

Depression affects 20-40% of HFrEF patients 5 / Solid and is an independent predictor of worse outcomes, independent of EF. The SADHART-CHF trial tested sertraline in depressed heart failure patients and showed no improvement in outcomes (neither harm nor benefit from sertraline specifically), but depression screening and treatment remain important because untreated depression impairs medication adherence. The SSRI data does not justify withholding psychiatric treatment.

7. Decisions and Trade-Offs

Starting all four drugs

The instinct in practice is often to start one drug, see how the patient tolerates it, add a second at the next visit, and so on. This is not aligned with what the evidence supports. Every day a patient with HFrEF (EF below 35%) is on below-target therapy, there is ongoing neurohormonal myocardial damage. The STRONG-HF trial showed that rapid uptitration to full-dose GDMT (guideline-directed medical therapy) within two weeks of hospitalization reduced 180-day heart failure readmission and all-cause mortality by 34% versus usual care 5 / Solid 02076-1). The safety data in STRONG-HF was reassuring: rapid uptitration was not associated with excess adverse events when done with appropriate follow-up.

The DELIVER and EMPEROR-Reduced trials included patients already on sacubitril-valsartan, demonstrating additive benefit from SGLT2i on top of the best current RAAS blockade. The four-drug regimen is supported by trials designed in the context of the best available background therapy.

Blood pressure and heart rate: the titration tension

All four drugs lower blood pressure or heart rate. Starting at low doses and titrating to target doses requires sequential visits, but the target doses matter: in MERIT-HF, metoprolol was uptitrated to 200 mg/day. In PARADIGM-HF, sacubitril-valsartan was titrated to 97/103 mg twice daily. Many patients in real-world practice never reach target doses because providers accept partial doses as “adequate.”

A resting heart rate above 70 bpm in a patient with HFrEF and sinus rhythm despite beta-blocker therapy is an indication for consideration of ivabradine, which reduces heart rate through If channel inhibition in the sinoatrial node. The SHIFT trial showed ivabradine reduced the composite of cardiovascular death or hospitalization for worsening heart failure by 18% in patients with HFrEF, resting heart rate above 70, and sinus rhythm 5 / Solid 61198-1).

Device timing

The ICD decision: should a patient with a newly diagnosed EF of 25% get an ICD at first presentation? No. Three to six months of guideline-directed medical therapy may improve the EF above 35%, removing the ICD indication. The IRIS trial data and the 2022 guidelines recommend reassessing EF after at least 90 days of GDMT before implanting a primary prevention ICD.

The CRT decision: requires QRS duration above 150 ms with LBBB morphology for highest response rate. CRT with pacemaker-only function (CRT-P) is appropriate for patients who require pacing but do not have an ICD indication. CRT-D is appropriate for those who meet both criteria.

Wearable ICD (LifeVest)

For patients newly diagnosed with HFrEF who are still in the GDMT initiation window (waiting to see if EF recovers), and who have a history of non-sustained VT or a high SCD risk, a wearable cardioverter-defibrillator (LifeVest, Zoll Medical) provides temporary protection. ZOLL data shows detection sensitivity of 99% for VF. The VEST trial did not show mortality benefit in post-MI patients with low EF, but the wearable ICD remains an option during the 90-day bridge period when ICD implant is premature 3 / Early .

Advanced heart failure: the escalation ladder

Stage D HFrEF (refractory, recurrent hospitalizations, volume overload unresponsive to oral diuretics, NYHA Class IV at rest) requires a different framework. The INTERMACS scale (1-7) stratifies patients for timing of LVAD or transplant listing. An INTERMACS 1 patient (cardiogenic shock on maximal inotropes) needs a bridge to a bridge. An INTERMACS 3-4 patient (stable on inotropes) is the best-positioned candidate for LVAD implant. The Columbia Protocol at Columbia University and the approach used at Northwestern Medicine in Chicago involve multidisciplinary shock team assessment, hemodynamic profiling with right heart catheterization, and staged escalation before LVAD or transplant listing.

Clinical Synthesis

HFrEF is the paradigm case for what preventive cardiology exists to prevent and to manage. The story begins upstream, with the risk factors that cause ischemic cardiomyopathy in the first place: hypertension, diabetes, hyperlipidemia, smoking, obesity. A structured cardiovascular assessment at age 40-50 that catches a patient with an EF trending down, or a genetic cardiomyopathy marker, or a missed prior MI on a stress test, changes the trajectory before the 3 a.m. ambulance call.

Once HFrEF is diagnosed, the gap between what the evidence supports and what patients actually receive is the primary modifiable variable. Multiple studies document that fewer than 25% of HFrEF patients in the United States are on all four guideline-recommended drug classes at target doses 5 / Solid . This is not a patient compliance problem. It is a system problem: inadequate follow-up intervals, inadequate medication uptitration, and inadequate access to cardiologists who manage high-volume heart failure practices.

Structured remote monitoring is the program tier appropriate for patients with established HFrEF. Regular biomarker monitoring (BNP or NT-proBNP), body weight tracking, medication uptitration tracking, and access to the cardiology team between standard quarterly visits. For patients approaching Stage D, or for patients with HFrEF requiring LVAD or transplant evaluation, comprehensive preventive cardiology provides direct facilitation of access to advanced heart failure centers.

In Illinois, advanced heart failure centers include the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital (Chicago), the University of Chicago Comer/UC Heart and Vascular Center (Chicago), and Carle Foundation Hospital (Urbana) for regional referral coordination. Rural patients in central and southern Illinois may face extended transport times to these centres; coordinated referral pathways, including telemedicine bridge appointments, address that access barrier directly.

The contractor from Champaign started four drugs and a cardiac rehabilitation program. His EF improved to 40%, the ICD decision was deferred when his EF crossed above 35% at month nine, and he has not been readmitted in two years. His wife checks his weight every morning. The 3 a.m. calls have stopped.

That outcome is available to the majority of patients with HFrEF. The biology has been mapped. The trials have been done. The drugs exist. The access has to be built.