Heart failure with reduced ejection fraction

Article written and reviewed by Dr Luca Moretti

Heart failure with reduced ejection fraction, or HFrEF, is the phenotype in which symptoms or signs of heart failure are associated with a left ventricular ejection fraction below 50%, underpinned by a consistent structural or functional abnormality. The threshold identifies the population in which randomized trials have demonstrated the greatest reduction in mortality and hospitalizations, but it does not represent an absolute biological boundary or directly measure contractility. Ejection fraction is the ratio of ejected volume to end-diastolic volume; it depends on preload, afterload, geometry, rhythm, and technique. A dilated ventricle may maintain a reasonable stroke volume despite a low percentage, while a small ventricle may eject a relatively high percentage but an insufficient absolute amount. For this reason, volumes and cardiac output, right heart function, valves, and pressures complete phenotyping; HFrEF is an etiologically heterogeneous syndrome: ischemia, genetic or inflammatory cardiomyopathies, toxicity, valvular disease, tachycardia, and overload converge in remodeling and neurohormonal activation. Modern therapy must therefore combine the four pharmacological pillars with identification and correction of the cause, devices when indicated, and control of congestion.

The course is not necessarily irreversible. Removal of the insult and early treatment may produce reverse remodeling, reduced volumes, and increased ejection fraction; the patient then transitions to the improved ejection fraction phenotype, but retains a history of HFrEF and susceptibility to relapse. Prognosis is highly variable. Tolerated blood pressure, kidney function, potassium, and heart rate determine the ability to implement therapy; scar, genotype, right heart dysfunction, valvular regurgitation, arrhythmias, and residual hospitalizations identify risk not captured by ejection fraction alone. Management requires speed without rigidity: introducing complementary classes early produces more benefit than slowly maximizing a single drug. Trial target doses remain the goal when tolerated, but even subtarget doses of multiple pillars may offer greater protection than an incomplete sequence.

Etiology, pathogenesis, and pathophysiology

Ischemic cardiomyopathy results from infarct necrosis, recurrent ischemia, hibernating myocardium, and remodeling. Scar distribution, aneurysm, ischemic mitral regurgitation, and arrhythmias influence the phenotype; coexisting coronary artery disease does not prove that all dysfunction is ischemic, and revascularization must address anatomical and clinical indications. Chronic hypertension may progress from concentric hypertrophy to dilation and reduced ejection fraction, particularly with ischemia, valvular disease, or predisposition. Aortic stenosis and aortic and mitral regurgitation produce overload and loss of reserve; secondary valvular dysfunction may become an independent amplifier; nonischemic dilated cardiomyopathies include genetic, post-myocarditis, peripartum, alcohol-related, anthracycline-induced, endocrine, nutritional, and idiopathic forms. An etiological diagnosis modifies family screening, arrhythmic risk, prognosis, and treatment of the cause.

TTN variants are frequent in dilated forms, while LMNA, FLNC, DSP, RBM20, and PLN may confer arrhythmic risk disproportionate to ejection fraction. Incomplete penetrance and interaction with alcohol, pregnancy, infections, or arrhythmias explain different phenotypes within the same family; a negative family history does not exclude a de novo or unrecognized variant. Lymphocytic, eosinophilic, giant-cell, or sarcoidosis-associated myocarditis may produce HFrEF, conduction blocks, and arrhythmias. Magnetic resonance imaging and biopsy have distinct roles; immunosuppression is reserved for defined forms and is not inferred from the presence of edema alone. Persistent tachycardia, a high ectopic beat burden, rapid atrial fibrillation, and right ventricular pacing may cause reversible dysfunction; recovery after rhythm control or correction of dyssynchrony retrospectively confirms the contribution, but does not always eliminate the substrate.

Myocyte loss and altered calcium handling reduce force and beta-adrenergic reserve. Dilation and spherical geometry increase wall stress, worsen oxygen consumption and mitral and tricuspid regurgitation; replacement and interstitial fibrosis alter conduction and mechanics. Dysfunction is not solely systolic. Elevated filling pressures, slowed relaxation, stiffness, and atrial dilation contribute to congestion; a low ejection fraction may coexist with normal pressure in euvolemia or with severe overload during worsening. Electrical dyssynchrony, particularly with left bundle branch block, produces early septal contraction, late lateral wall work, and inefficiency; resynchronization may transform this mechanism into reverse remodeling in responders.

Reduced effective cardiac output activates the renin-angiotensin-aldosterone system, the sympathetic nervous system, and vasopressin. Angiotensin II increases vasoconstriction and growth, aldosterone promotes sodium retention and fibrosis, and norepinephrine increases arrhythmias and cell death; these systems initially support blood pressure but become maladaptive over time. ARNI combines AT1 receptor blockade and neprilysin inhibition, enhancing natriuretic peptides without leaving angiotensin II uncontrolled. Beta-blockers reduce catecholamine toxicity; mineralocorticoid receptor antagonists limit aldosterone effects; the combined effect interrupts complementary components of remodeling; SGLT2 inhibitors rapidly reduce events through hemodynamic, renal, metabolic, and cellular mechanisms. Benefit in patients with and without diabetes demonstrates that they are not merely glucose-lowering agents.

Congestion results from sodium retention and venous redistribution; increased left-sided pressures cause pulmonary edema and postcapillary hypertension; increased right-sided pressures cause edema, ascites, and organ damage. Ventricular interdependence means that right ventricular dilation and an altered septum further reduce left ventricular filling; elevated renal venous pressure, more than low cardiac output alone, contributes to deterioration in filtration. Tubular activation and chronic diuretic exposure produce distal adaptation, explaining resistance in congested phases. Reduced cardiac output induces peripheral vasoconstriction and shifts flow toward the heart and brain. Muscle, kidneys, and intestine receive less oxygen; skeletal myopathy and deconditioning become independent determinants of exercise intolerance.

Recovery of ejection fraction may reflect true biological regression, a change in loading conditions, or measurement error. Reverse remodeling is favored by a reversible etiology, short disease duration, absence of extensive scar, treated bundle branch block, and early drug implementation; genotype and fibrosis limit its completeness. Arrhythmic risk does not necessarily disappear with recovery, particularly in scar-related or genetic cardiomyopathies; device decisions must consider the history of arrhythmias, scar, and cause, not only the latest ejection fraction. Treatment withdrawal in recovered dilated cardiomyopathies led to relapses in TRED-HF; normalization is therefore interpreted as remission in many patients, with continuation of disease-modifying treatments.

Clinical manifestations

Dyspnea, orthopnea, and paroxysmal nocturnal dyspnea result from pulmonary pressure, reduced compliance, effusions, and the ventilatory response. Exertional dyspnea may precede clinical congestion because capillary pressure rises during exercise; crackles are often absent in the chronic state. Fatigability and weakness reflect low cardiac output reserve, vasoconstriction, myopathy, anemia, and iron deficiency; the symptom may persist after euvolemia and does not automatically justify more diuretic. Edema, weight gain, jugular venous distention, ascites, hepatomegaly, and early satiety indicate systemic congestion; jugular venous pressure and hepatojugular reflux are more specific than isolated peripheral edema.

Low cardiac output may cause a narrowed pulse pressure, cold extremities, oliguria, mental slowing, and intolerance of minimal exertion. Low systolic blood pressure has prognostic value, but an asymptomatic patient with habitually low values differs from one with new hypotension with hypoperfusion; a third heart sound, displaced apex beat, and murmurs of mitral or tricuspid regurgitation reflect dilation and pressures. An accentuated pulmonary component of the second heart sound and a parasternal heave suggest pulmonary hypertension and right heart involvement. Palpitations, presyncope, and syncope may result from tachyarrhythmias, bradycardia, obstruction, or low cardiac output and require immediate assessment; syncope in HFrEF must not be automatically attributed to medications.

NYHA class, although subjective, stratifies symptoms and prognosis. The six-minute walk test quantifies submaximal capacity; cardiopulmonary exercise testing measures peak VO2 and VE/VCO2 and supports advanced assessment, distinguishing cardiac, ventilatory, and peripheral limitations. Quality of life can be measured with KCCQ, which responds to treatment and has prognostic value. Patient-reported improvements are relevant outcomes even when ejection fraction changes little. Sarcopenia, frailty, and cachexia appear with advanced disease and increase the risk of falls, infections, and intolerance; unintentional weight loss must be distinguished from edema reduction.

Acute decompensations manifest as increasing congestion, a need for diuretics, an urgent visit, or hospitalization. Every episode identifies residual risk even if ejection fraction remains unchanged; recent hospitalization changes priorities for titration, follow-up, and consideration of vericiguat or advanced therapies. Hypertensive pulmonary edema may also occur in HFrEF, while shock develops when cardiac output and vascular compensatory mechanisms cannot maintain perfusion; the warm/cold and wet/dry profile guides stabilization. Death may be sudden from arrhythmia or progressive from pump failure; the balance between these modes changes with therapy, age, comorbidities, and devices.

Investigations and diagnosis

Echocardiography confirms an ejection fraction <50%, measures volumes, and describes geometry, right heart function, atria, valves, pulmonary pressure, and the pericardium; the biplane Simpson method is preferable when images permit; contrast or three-dimensional imaging improves border definition in selected cases. Reproducibility is essential before basing device decisions on minimal differences. Stroke volume, velocity-time integral, global longitudinal strain, and TAPSE add mechanical and prognostic information; the E/e’ ratio and other diastolic indices estimate pressures but are not infallible in valvular disease, pacing, or fibrillation. A repeat echocardiogram is indicated after sufficient optimization when the result changes ICD or CRT decisions, after clinical changes, or after procedures. Frequent repetitions without a clinical question do not replace clinical assessment.

ECG assesses pathological Q waves, bundle branch block, QRS duration, fibrillation, and arrhythmias. QRS duration and morphology determine eligibility for resynchronization; Holter or device monitoring quantifies tachycardias, ectopic beats, and bradycardias. BNP or NT-proBNP supports diagnosis, establishes risk, and may provide a baseline; obesity lowers levels and kidney disease increases them; BNP rises with neprilysin inhibition, while NT-proBNP is not a direct substrate. Chronically elevated troponin indicates injury and risk but does not prove acute ischemia. Complete blood count, kidney function, sodium, potassium, bicarbonate, liver function, TSH, ferritin, and transferrin saturation identify causes, comorbidities, and treatment safety.

Ischemic assessment is selected according to probability, symptoms, anatomy, and the possibility of revascularization. Coronary CT is useful at selected levels of probability; functional tests assess ischemia and viability; coronary angiography is indicated when the result can change strategy. Magnetic resonance imaging identifies subendocardial or transmural ischemic scar patterns and midwall, subepicardial, or diffuse nonischemic patterns. Late enhancement and mapping point toward myocarditis, sarcoidosis, amyloidosis, or iron deposition and contribute to arrhythmic stratification. Endomyocardial biopsy is reserved for presentations in which histological diagnosis urgently changes therapy, such as suspected giant-cell, eosinophilic, or checkpoint inhibitor-associated myocarditis. Indiscriminate use adds risk without benefit.

Genetic testing is indicated in cardiomyopathies with a family history, early onset, conduction disorders, arrhythmias, or syndromic phenotypes and may also be appropriate in apparently sporadic forms. Testing must be accompanied by genetic counseling; variants of uncertain significance must not be used for predictive diagnosis in relatives; family screening includes history, ECG, and echocardiography, adapted to the gene, age, and phenotype. A pathogenic variant allows targeted surveillance, but variable penetrance prevents certain individual predictions. Alcohol, cocaine, methamphetamines, anthracyclines, and other exposures must be quantified; cardio-oncology integrates dose, biomarkers, and imaging, avoiding both ignoring toxicity and unnecessarily interrupting cancer treatment.

Cardiopulmonary exercise testing is central when symptoms are disproportionate and in selection for transplantation or mechanical support. Peak VO2, percent predicted, VE/VCO2, blood pressure, and rhythm are interpreted in light of achieved effort, beta-blockade, sex, age, and obesity; no isolated threshold determines eligibility. Right heart catheterization clarifies pressures, cardiac output, and vascular resistance in shock, refractory congestion, discordant findings, and advanced assessment; the cardiac index must be interpreted alongside oxygen saturations, hemoglobin, and the calculation method; an invalid wedge pressure may distort the entire profile. Implantable pulmonary pressure monitoring may reduce hospitalizations in selected patients with recurrent events if a team capable of intervening is available. It does not replace optimized therapy or education.

The differential diagnosis includes primary valvular disease, constriction, tachycardia-mediated cardiomyopathy, congenital heart disease, high-output states, and transient dysfunction from Takotsubo syndrome or myocarditis; a reversible cause must be sought before defining the cardiomyopathy as idiopathic. Classification documents HFrEF, the ejection fraction value and date, etiology, NYHA class, stage, rhythm, QRS, right heart function, valves, and congestion. The maximum tolerated therapy and objective reasons for failure to titrate must also be recorded. An ejection fraction that, after previous HFrEF, increases by at least 10 percentage points to >40% meets the criteria for HFimpEF; it does not equate to de novo HFpEF. The history prevents withdrawal errors and maintains attention to arrhythmic and etiological risk.

Treatment and prognosis

Sacubitril/valsartan is preferred when tolerated in symptomatic patients, replacing an ACE inhibitor or ARB. It reduces cardiovascular death and hospitalization compared with enalapril in PARADIGM-HF; it requires a 36-hour interval after an ACE inhibitor, monitoring of blood pressure, kidney function, and potassium, and attention to angioedema. When ARNI is not possible, ACE inhibitors or ARBs retain benefit; asymptomatic hypotension does not automatically require withdrawal; volume status, nitrates, calcium channel blockers, and other drugs without prognostic benefit are reassessed first. Titration of renin-angiotensin blockade must distinguish expected hemodynamic changes from progressive injury. Bilateral renal artery stenosis, pregnancy, angioedema, and severe hyperkalemia affect the choice.

Beta-blockers with supporting evidence are carvedilol, bisoprolol, and metoprolol succinate; nebivolol has data in older adults. They are started during stability and euvolemia, with slow increases; symptomatic bradycardia, conduction block, and hypoperfusion require caution, whereas an initially low heart rate does not always preclude minimal doses. The mineralocorticoid receptor antagonists spironolactone and eplerenone reduce death and hospitalizations. Potassium and eGFR must meet safety criteria; review of supplements, NSAIDs, and diet and selective use of binders may facilitate continuation. Dapagliflozin and empagliflozin reduce worsening events and cardiovascular death even without diabetes, with a modest blood pressure effect; the initial eGFR dip is hemodynamic; the risk of euglycemic ketoacidosis requires withholding during fasting, procedures, or significant acute illness.

The four pillars should be introduced within a few weeks, choosing the sequence according to physiology. Low blood pressure favors drugs with minimal blood pressure effects; tachycardia favors beta-blockade; hyperkalemia affects MRA use; congestion requires volume control first; the goal is early completeness, not a universal sequence. Diuretics relieve congestion but do not replace prognosis-modifying therapy; the dose is reduced after remodeling and euvolemia, maintaining an adjustment plan; thiazides or acetazolamide are reserved for resistance with monitoring. Management of hypotension includes orthostatic confirmation, investigation for dehydration or infection, and reduction of nonessential drugs. In kidney dysfunction, simultaneous withdrawal of multiple pillars is avoided without distinguishing cause and severity.

Ivabradine reduces hospitalizations in patients in sinus rhythm with an ejection fraction ≤35%, a heart rate ≥70/min, and symptoms despite maximally tolerated beta-blockade. It does not act in atrial fibrillation; an elevated heart rate may signal congestion or anemia that requires correction. Hydralazine and isosorbide dinitrate are indicated in specific symptomatic Black populations in addition to therapy and as an alternative when RAASi cannot be used. Headache, hypotension, and a complex regimen limit adherence. Digoxin may reduce hospitalizations and assist rate control without a mortality benefit; low concentrations, kidney function, and interactions are crucial. Vericiguat is considered after recent worsening in high-risk patients, not in a stable patient without a recent event.

An ICD for primary prevention is considered after at least three months of optimized therapy in appropriate patients with persistently reduced ejection fraction and meaningful life expectancy. Benefit decreases when nonarrhythmic death, frailty, or comorbidities predominate; genetic cardiomyopathies may require additional criteria. CRT offers the greatest benefit with left bundle branch block and a very wide QRS, but indications include selected subgroups; the percentage of biventricular pacing should be close to 100%; atrial fibrillation, ectopic beats, and lead malposition reduce response. Conduction system pacing is an emerging option or alternative in selected settings, but experience, anatomy, and long-term data must be considered. Device programming and remote monitoring prevent inappropriate shocks.

Revascularization and anti-ischemic therapy follow coronary artery disease, anatomy, and symptoms. CABG has prognostic benefit in selected patients with ischemic dysfunction and suitable anatomy; PCI is not extended as an automatic solution for stable cardiomyopathy without specific indications. Transcatheter mitral repair reduces hospitalizations and mortality in selected patients with severe disproportionate secondary regurgitation who remain symptomatic despite therapy and CRT if indicated. Selection requires a Heart Team and comparison of regurgitation severity, ventricular dimensions, and pulmonary pressure. Atrial fibrillation ablation may improve symptoms and, in selected HFrEF populations, outcomes; rhythm control is particularly important in tachycardia-mediated cardiomyopathy. Anticoagulation follows thromboembolic risk.

Physical activity and rehabilitation improve capacity and quality of life; training combines aerobic, resistance, and respiratory exercise, adapted to blood pressure, arrhythmias, and devices; physical inactivity accelerates myopathy and frailty. Intravenous iron improves symptoms and capacity in patients with deficiency and may reduce events in selected settings; erythropoiesis-stimulating agents are not a general treatment. Vaccinations, smoking cessation, treatment of obstructive sleep apnea, and nutrition complete care. NSAIDs, thiazolidinediones, and nondihydropyridine calcium channel blockers may worsen the phenotype. Adaptive servo-ventilation is not recommended in HFrEF with predominantly central sleep apnea; it may instead be considered when sleep-disordered breathing is predominantly obstructive, to improve sleep quality, quality of life, and symptoms.

After hospitalization, the patient requires rapid titration and follow-up. Every visit checks symptoms, volume status, blood pressure, heart rate, kidney function, potassium, and adherence; the target dose is pursued without sacrificing the presence of the fundamental classes. Recurrent hospitalizations, inotropes, hypotension, organ dysfunction, and refractory congestion require referral for LVAD or transplantation. Cardiopulmonary exercise testing, hemodynamics, frailty, support, and contraindications form the selection assessment; prognosis improves with reverse remodeling, but scar and genotype maintain risk. Palliative care, symptom control, and advance care planning must be integrated before the terminal phase.

Complications

Acute worsening may manifest as congestion, pulmonary edema, or shock; residual congestion after treatment predicts readmission; a moderate creatinine change during an effective response does not automatically equate to tubular injury. Cardiorenal syndrome combines venous pressure, low perfusion, and kidney disease; hyperkalemia and kidney failure often lead to treatment reduction. Addressing NSAIDs, supplements, and dehydration and providing monitoring help avoid unnecessary permanent withdrawals. Hyponatremia, hypokalemia, hypomagnesemia, and alkalosis result from disease and diuretics and promote arrhythmias, weakness, and confusion; correction must target the mechanism and be gradual.

Ventricular tachycardia and ventricular fibrillation cause sudden death; bradycardia, conduction blocks, and atrial fibrillation worsen cardiac output. Scar, ischemia, genetics, and adrenergic activation determine risk, which is only partly represented by ejection fraction. Appropriate ICD shocks save lives but signal progression; repeated shocks require correction of causes, drugs, and ablation. Inappropriate shocks worsen quality of life and are reduced through programming and control of supraventricular tachycardias. Ventricular thrombi and atrial fibrillation increase embolism; anticoagulation is not indicated in HFrEF in sinus rhythm without another reason. Contrast imaging or magnetic resonance imaging clarifies suspected apical thrombi.

Secondary mitral regurgitation increases atrial volume and pressure, while tricuspid regurgitation reflects and amplifies right-sided congestion; right ventricular dysfunction is a strong prognostic sign and limits tolerance of ventilation, LVAD, and preload changes. Postcapillary pulmonary hypertension may acquire a precapillary component, increasing right ventricular afterload. Specific pulmonary vasodilators are not routine therapy for hypertension due to left heart disease and may aggravate edema; splanchnic congestion and intestinal edema promote malabsorption; hepatic congestion causes cholestasis and, in advanced stages, coagulopathy. Hypoxic hepatitis occurs in shock and indicates extreme severity.

Iron deficiency, anemia, sarcopenia, and cachexia reduce capacity, immunity, and eligibility for treatment. Cachexia is not corrected by simple caloric supplementation if congestion and inflammation remain active; it requires treatment of the disease, nutrition, and compatible activity. Frailty, depression, and cognitive decline reduce adherence and independence. Polypharmacy and orthostatic hypotension increase falls, making review of drugs without prognostic benefit necessary before removing effective ones. Sexual dysfunction and work limitations are relevant outcomes that are often ignored; rehabilitation and explicit communication improve quality of life and participation.

Transition to HFimpEF is a favorable outcome but not a guaranteed cure; relapse may follow drug withdrawal, pregnancy, alcohol, arrhythmias, or new ischemia; monitoring and therapy must continue. Progression to advanced heart failure manifests as hospitalizations, increasing diuretic requirements, hypotension, low cardiac output, and multiorgan damage; delayed referral reduces options and increases inotrope dependence. Death from pump failure, arrhythmia, or noncardiovascular causes must be considered when assessing the proportionality of ICD, procedures, and therapies. Shared decisions and advance care planning keep care aligned with goals.