Heart failure with mildly reduced ejection fraction

Article written and reviewed by Dr Luca Moretti

Heart failure with a left ventricular ejection fraction between 41% and 49% falls within HFrEF according to the ESC 2026 classification, in the context of symptoms or signs and a cardiac abnormality capable of explaining the syndrome. The category does not indicate “mild” disease: congestion, right heart dysfunction, functional limitation, hospitalizations, and mortality may be substantial even when ejection fraction is only moderately below normal. HFrEF with an LVEF of 41-49% occupies the higher-ejection-fraction portion of the HFrEF spectrum, in biological continuity with HFpEF. Toward the lower limit, dilation, ischemia, and response to the neurohormonal therapies typical of HFrEF are more frequent; toward the upper limit, age, hypertension, obesity, atrial fibrillation, and multisystem phenotypes increase. A single threshold does not capture this heterogeneity; classification must always include the trajectory. A patient who has moved from 30% to 45% has HF with improved ejection fraction and retains the indication to maintain HFrEF therapy; someone declining from 60% to 45% may have ischemic, valvular, or myocardial progression. Both measure 45%, but mechanism, risk, and treatment do not coincide.

Ejection fraction shows inter- and intraobserver variability and depends on loading conditions. Values around 40% or 50% require review of images, method, volumes, and previous measurements, avoiding a change in the entire strategy for a difference of a few points that is not biologically certain. Therapeutic evidence has grown with trials enrolling the entire spectrum above 40%; SGLT2 inhibitors have robust benefit; finerenone reduced worsening events at ejection fractions of at least 40%. ARNI or an ACE inhibitor/ARB, mineralocorticoid receptor antagonists, and beta-blockers are part of foundational HFrEF therapy even in the LVEF range of 41-49%; treatment remains guided by congestion, etiology, and comorbidities, not ejection fraction alone. Ischemia, hypertension, valvular disease, arrhythmias, kidney disease, obesity, iron deficiency, and inactivity must be addressed with the same precision devoted to the specific drug.

The designation HFmrEF replaced the previous term “mid-range,” clarifying that it does not identify a mere residual group but a range with its own evidence. Recommendations have evolved from post hoc extrapolations to prospective trials extending to ejection fractions above 40%, although they remain less numerous than for HFrEF. Proximity to the threshold modifies the probability of response to some classes but does not allow prediction of benefit in the individual patient. Sex, rhythm, etiology, and previous ejection fraction interact with the value, and subgroup analyses generate hypotheses rather than rigid therapeutic boundaries. A monograph on the phenotype must therefore avoid two opposite errors: treating every patient as having “nearly normal” HFrEF or as having undifferentiated HFpEF. The correct strategy uses therapies with direct evidence, maintains those that produced recovery, and adds interventions targeting the cause.

Etiology, pathogenesis, and pathophysiology

An LVEF of 41-49% in a patient with heart failure may represent an early phase of systolic dysfunction, an improving phase of previous HFrEF with a lower ejection fraction, or deterioration of previous HFpEF. The direction of change is prognostic: improvement after therapy is generally associated with better outcomes than a new reduction, but risk remains higher than in people without a history of heart failure. Ischemic heart disease is frequent, particularly in the phenotype close to HFrEF. Limited infarctions, recurrent ischemia, mitral regurgitation, and remodeling may reduce ejection fraction into the 41-49% range; scar and viability must be defined when they can change revascularization or arrhythmic risk. Hypertension and arterial stiffness increase afterload, hypertrophy, and fibrosis; an initially concentric ventricle may develop longitudinal contractile failure and then reduced ejection fraction, particularly with diabetes, kidney disease, or ischemia.

Aortic and mitral valvular diseases may produce HFrEF with an LVEF of 41-49% before or after an intervention. In mitral regurgitation, ejection fraction overestimates myocardial function because part of the stroke volume is ejected into the atrium; a “mildly reduced” ejection fraction may therefore represent advanced dysfunction in that context. Genetic cardiomyopathies, myocarditis, cancer therapy-related toxicity, peripartum cardiomyopathy, and tachycardia may temporarily remain in this range during recovery or progression. Magnetic resonance imaging, family history, and the time course identify the substrate. Atrial fibrillation is both cause and consequence. Loss of atrial systole and a rapid response increase pressures, while atrial dilation and fibrosis promote the arrhythmia; rhythm control may improve ejection fraction when a tachycardia-mediated component exists.

Contractility is reduced to a variable degree, and ejection fraction does not describe stroke volume. A dilated ventricle with 45% may have adequate resting cardiac output but poor reserve; a small, stiff ventricle with the same value may have a low ejected volume and elevated pressures. Volumes, deformation, and exercise reserve distinguish these phenotypes. Diastolic and systolic dysfunction coexist. Slowed relaxation, fibrosis, and stiffness increase atrial pressure; reduced longitudinal contraction and inefficient ventricular-arterial coupling limit the increase in cardiac output; right heart function may deteriorate because of postcapillary pulmonary hypertension, ischemia, or tricuspid regurgitation. Systemic congestion and central venous pressure determine kidney function, liver function, and prognosis independently of the left ventricular value.

Neurohormonal activation in HFrEF with an LVEF of 41-49% is intermediate but not uniform. Patients with previous HFrEF retain a biology sensitive to renin-angiotensin blockade, beta-blockade, and mineralocorticoid receptor antagonism; inflammation, stiffness, and microvascular dysfunction predominate in adipose and hypertensive phenotypes. SGLT2 inhibitors act across the entire spectrum, with an early reduction in worsening; the continuity of the effect supports the idea that ejection fraction is a quantitative modifier rather than a clear pathological divide. Finerenone blocks the mineralocorticoid receptor with a nonsteroidal profile and reduced total worsening events and cardiovascular death in FINEARTS-HF, mainly through heart failure events. Potassium and kidney function remain safety determinants.

Congestion may depend on gradual retention or venous redistribution. In stiff, hypertensive phenotypes, small volume changes cause large pressure increases; in dilated phenotypes, increased total body sodium and functional valvular regurgitation predominate. The kidney responds to venous pressure and tubular activation; diuretic resistance is no less important because ejection fraction is above 40%. Insufficient decongestion increases readmission, while excessive diuresis limits therapy and perfusion. Obesity, diabetes, iron deficiency, and skeletal myopathy reduce functional capacity; exercise intolerance therefore arises from the heart, vessels, lungs, muscle, and oxygen transport.

Age and sex influence the distribution of causes: women and older adults more often have hypertension, concentric geometry, and fibrillation, while coronary artery disease and scar are frequent in men, without absolute divisions. Microvascular disease may impair coronary reserve and relaxation even without epicardial stenoses; atrial function is crucial. Dilation and fibrosis reduce reservoir function and contraction, promote atrial functional mitral regurgitation, and make filling more dependent on heart rate and rhythm; transition to fibrillation may therefore cause an abrupt loss of function. Postcapillary pulmonary hypertension and vascular remodeling increase right ventricular load; progression to right heart dysfunction changes the presentation from predominantly left-sided dyspnea to systemic congestion, ascites, and low cardiac output.

Clinical manifestations

Dyspnea and reduced exercise tolerance are the main manifestations. The patient may have symptoms only during activity because filling pressure rises dynamically; orthopnea and nocturnal dyspnea indicate more overt congestion. Fatigability may result from reduced cardiac output reserve, chronotropic incompetence, beta-blockade, anemia, iron deficiency, and deconditioning; the distinction is important because increasing the diuretic does not correct a peripheral limitation. Edema, weight gain, jugular venous distention, ascites, and early satiety reflect systemic venous pressure; right-sided congestion may predominate despite only mildly reduced left ventricular ejection fraction.

Presentation varies with the phenotype. The ischemic patient may report angina and have scar; the hypertensive patient develops pulmonary edema with elevated blood pressure; the patient with atrial fibrillation presents with palpitations or worsening after loss of rhythm. A valvular murmur, third heart sound, displaced apex beat, or accentuated pulmonary component of the second heart sound points toward the mechanism, but examination may reveal few findings in obesity or a compensated state. NYHA class describes limitation but does not separate phenotypes. KCCQ, the six-minute walk test, and cardiopulmonary exercise testing quantify impact and response more precisely.

Worsening may be treated with an increase in oral diuretic therapy, intravenous treatment, or hospitalization; the need for intensification identifies worsening heart failure even outside the hospital and must trigger investigation of the precipitant and treatment review. Infection, ischemia, arrhythmia, hypertension, edema-inducing drugs, and renal progression are frequent causes; a single precipitant may not be identifiable, and the event may reflect progression of heart disease. Blood pressure is useful for distinguishing congestion with vascular reserve from low cardiac output. Cold extremities, oliguria, and altered mental status indicate hypoperfusion and must not be minimized because ejection fraction exceeds 40%.

The history of previous values may reveal HFimpEF. A patient improving from 25% to 45% may be asymptomatic, but treatment withdrawal promotes relapse; one declining from 60% to 45% requires investigation for a new cause. Measurement variability may artificially move the patient between categories. Symptoms, volumes, and trajectory prevent the creation of unreal diagnostic changes with every echocardiogram. Frailty, depression, obesity, and pulmonary disease modify symptom perception; diagnosis must not attribute everything to ejection fraction or deny heart failure because comorbidities exist.

Quality of life may be profoundly impaired even with few physical signs; the KCCQ documents symptom frequency, limitations, self-efficacy, and quality of life, making changes not captured by ejection fraction and biomarkers visible. The six-minute walk test is influenced by motivation, osteoarthritis, and obesity but measures daily function; cardiopulmonary exercise testing separates the chronotropic response, ventilation, cardiac output, and peripheral component. Discordance between testing and NYHA class requires interpretation, not exclusion of one of the findings. Hospitalizations and urgent visits must be reconstructed, including events treated with outpatient intravenous diuretics; the worsening trajectory is a risk indicator and may justify intensification even if the echocardiographic value does not change.

Investigations and diagnosis

Diagnosis requires clinical manifestations and demonstration of the cardiac abnormality. BNP or NT-proBNP, ECG, and echocardiography are cornerstones; low peptides reduce probability, but obesity may suppress them, and treatment or a euvolemic state may reduce their magnitude. Echocardiography must confirm the 41-49% value with a robust method and describe volumes, strain, right heart function, valves, atria, and pressures. If quality is poor, contrast, three-dimensional imaging, or magnetic resonance imaging avoids classification based on an endocardial border that is not visualized; the value is compared with previous studies. An absolute change of a few points within measurement variability does not demonstrate progression or recovery; large changes concordant with volumes and clinical findings are more credible.

ECG assesses infarction, hypertrophy, conduction blocks, and arrhythmias. A wide QRS may indicate dyssynchrony, but standard CRT indications mainly concern lower ejection fractions; frequent pacing may contribute to dysfunction and requires specialist assessment. Complete blood count, kidney function, electrolytes, liver function, glucose, HbA1c, TSH, ferritin, and transferrin saturation identify causes and comorbidities; the albumin/creatinine ratio improves cardiorenal stratification. Troponin may be chronically elevated because of stress, ischemia, kidney disease, or infiltration; an acute change requires an acute coronary syndrome pathway, without confusing myocardial injury with primary myocardial infarction.

Cardiac magnetic resonance imaging measures ejection fraction and volumes and identifies ischemic scar, myocarditis, sarcoidosis, amyloidosis, and iron deposition; late enhancement may indicate arrhythmic risk even when ejection fraction does not reach standard ICD thresholds. Coronary assessment depends on probability, symptoms, and the possibility of changing therapy. In patients with a new reduction, ischemia must be considered; the presence of calcification alone does not demonstrate causality. Genetic testing and family screening are indicated in suspected cardiomyopathies. Conduction disorders, a family history of sudden death, and muscular or cutaneous phenotypes increase suspicion.

In a patient with dyspnea and discordant findings, true heart failure with an LVEF of 41-49%, now classified as HFrEF, must be distinguished from pulmonary disease, anemia, obesity, and deconditioning. Cardiopulmonary exercise testing quantifies the mechanism; stress echocardiography or exercise catheterization demonstrates dynamic pressures when resting values are normal; right heart catheterization is reserved for uncertainty, severe symptoms, pulmonary hypertension, or advanced assessment. Pulmonary capillary wedge pressure, cardiac output, and vascular resistance distinguish postcapillary, precapillary, and combined forms; diagnosis must identify treatable phenocopies, including amyloidosis, hypertrophic cardiomyopathy, constriction, valvular disease, and high-output states.

Longitudinal assessment includes NYHA class, KCCQ, weight, blood pressure, rhythm, kidney function, potassium, and therapy; echocardiography is repeated when the result changes classification or management, not according to a rigid schedule. The clinical document should report HFrEF with an LVEF of 41-49%, the current value, previous values, etiology, congestion, right heart function, and comorbidities; this precision avoids automatically applying the same treatment to different trajectories. An ejection fraction of 40% generally belongs to HFrEF and 50% to HFpEF according to current classifications; however, therapeutic decisions use the continuity of evidence, not threshold formalism.

Quantification of ejection fraction must consider ectopy, fibrillation, and blood pressure changes. In an irregular rhythm, representative cycles are needed; during tachycardia or acute decompensation, the measurement may change after stabilization; end-diastolic volume distinguishes dilated from concentric geometry with the same ejection ratio. Longitudinal strain may be abnormal before ejection fraction declines and helps identify diffuse injury, but varies with loading conditions and software. An apical-sparing pattern suggests amyloidosis and must trigger the specific pathway, not replace diagnosis. When ejection fraction is close to decisive thresholds, review by an experienced laboratory or magnetic resonance imaging reduces spurious reclassification; treatment choice must not depend on a decimal value lacking reproducibility.

Treatment and prognosis

Diuretics are indicated for congestion and titrated to euvolemia. Dose and combination depend on kidney function and response, not on the ejection fraction category; effective decongestion improves symptoms and reduces residual risk. Dapagliflozin and empagliflozin reduce the risk of worsening across the LVEF range of 41-49%. DELIVER and EMPEROR-Preserved included patients above 40%, with consistent benefits even without diabetes and in patients whose ejection fraction had previously improved; SGLT2 inhibitors require education about genital infections, volume status, and euglycemic ketoacidosis. The initial eGFR dip does not necessarily indicate injury and must be distinguished from hypovolemia.

Finerenone reduced total worsening events and cardiovascular death at ejection fractions of at least 40% in FINEARTS-HF. The benefit was driven mainly by a reduction in heart failure events; hyperkalemia and kidney function require monitoring, and use must comply with current approvals and indications. Spironolactone has complex TOPCAT data because of regional heterogeneity; mineralocorticoid receptor antagonists are now recommended in symptomatic heart failure regardless of ejection fraction. Spironolactone is not routinely combined with another mineralocorticoid receptor antagonist. ARNI and ARB show signals of greater benefit at lower ejection fractions. In HFrEF with an LVEF of 41-49%, ARNI or an ACE inhibitor is part of foundational therapy in appropriate patients, with assessment of blood pressure, kidney function, and potassium.

Beta-blockers with evidence in heart failure are part of foundational HFrEF therapy even with an LVEF of 41-49%, regardless of the presence of coronary artery disease, atrial fibrillation, or hypertension. In atrial fibrillation, their main role is rate control and management of comorbidities, with individual targets. ACE inhibitors or ARBs, when used as an alternative to ARNI according to tolerability and indication, form part of renin-angiotensin system blockade in HFrEF therapy with an LVEF of 41-49%, in addition to any indications for hypertension, kidney disease, or ischemia. Neurohormonal therapy is not withdrawn in patients who meet HFimpEF criteria after previous HFrEF. Vericiguat, ivabradine, hydralazine-nitrate, and digoxin have no general indication based solely on an LVEF of 41-49%; they may be relevant because of an HFrEF history, rhythm, or another specific condition.

Hypertension must be controlled while avoiding orthostatic hypotension. Coronary artery disease and valvular diseases follow specific guidelines; a reduction in ejection fraction in mitral or aortic regurgitation may be a late sign and requires timely assessment. Atrial fibrillation is treated with anticoagulation according to risk and rate or rhythm control. In arrhythmia-mediated phenotypes, ablation may improve function; with simple coexistence, the decision considers symptoms, duration, and the atrium. Diabetes and kidney disease require cardiorenal strategies; obesity is addressed with nutrition, activity, and appropriate therapies. GLP-1 or dual agonists have direct data mainly in adipose HFpEF and must be individualized.

Physical activity, rehabilitation, and correction of iron deficiency improve capacity and quality of life. Excessive sodium or fluid restrictions are not universal; education must teach signs of recurrent congestion and diuretic management. ICD and CRT are generally not indicated with an ejection fraction of 41-49% for primary prevention on the threshold alone. Previous ventricular arrhythmia, a high-risk genotype, sarcoidosis, or a need for pacing may create independent indications. Pulmonary pressure monitoring and multidisciplinary programs may reduce events in selected patients with hospitalizations, regardless of ejection fraction, if integrated into a responsive care pathway.

Prognosis is intermediate in aggregate but depends on the trajectory. Patients recovering from HFrEF retain risk and benefit from continued therapy; those declining from preserved values may have active disease and an unfavorable prognosis. Hospitalizations, congestion, right heart dysfunction, kidney disease, hyponatremia, atrial fibrillation, and frailty predict events more than the category alone; serial reassessment is therefore part of treatment. Persistent symptoms and repeated worsening require investigation of the cause and possible advanced assessment; an ejection fraction above 40% does not exclude severe pump failure, pulmonary hypertension, or a need for palliative care.

After hospitalization, initiation of an SGLT2 inhibitor and optimization of other appropriate treatments must not be deferred without reason; early follow-up checks volume status, blood pressure, kidney function, and potassium and reconstructs treatment withheld during the acute phase. Multidisciplinary rehabilitation is particularly useful in older patients and those with cardiometabolic disease, in whom limitation arises from multiple organs. Resistance activity, balance training, and nutrition preserve lean mass alongside aerobic exercise; palliative care is not reserved for a very low ejection fraction. Refractory dyspnea, hospitalizations, and loss of independence justify symptom control and planning even in HFrEF with an LVEF of 41-49%, while continuing proportionate therapies.

Complications

Acute congestive decompensations are the most frequent complication and may present with pulmonary edema, systemic edema, or hypoperfusion; residual congestion increases readmission and requires verification of the oral dose and follow-up. Cardiorenal syndrome results from venous pressure, preexisting kidney disease, and drugs; creatinine and potassium affect MRA and RAASi use; a modest rise during decongestion or SGLT2 therapy must not be interpreted without volume status and urine output. Hyponatremia, hypokalemia or hyperkalemia, and alkalosis increase arrhythmias, weakness, and confusion. Monitoring is particularly important with diuretic combinations and mineralocorticoid receptor antagonists.

Atrial fibrillation is common and worsens pressures, symptoms, and thromboembolism. Ventricular tachycardia may occur in the presence of ischemic or nonischemic scar even without an ejection fraction ≤35%; syncope and palpitations require monitoring and imaging. Secondary mitral and tricuspid regurgitation amplify congestion and remodeling; right heart function may deteriorate because of pulmonary hypertension, modifying prognosis and treatment tolerance. Thromboembolism and stroke are mainly linked to fibrillation, thrombi, or another indication; HFrEF with an LVEF of 41-49% in sinus rhythm does not justify routine anticoagulation.

The kidneys, liver, and lungs may become target organs, and disease in them may act as a precipitant. Hepatic congestion produces cholestasis and ascites; severe hypoperfusion causes hypoxic injury and signals high risk. Iron deficiency, anemia, sarcopenia, and frailty reduce capacity and increase hospitalization; treatment must preserve muscle mass and independence, avoiding interpreting every weight loss as a diuretic benefit. Depression and cognitive impairment alter adherence; simplification and caregiver involvement are part of relapse prevention.

Full implementation of foundational therapy is already indicated in HFrEF with an LVEF of 41-49%; a further LVEF reduction represents progression and requires reassessment of ICD/CRT indications after therapy. Transition to an ejection fraction ≥50% may represent recovery or variability; the history prevents erroneous reclassification as de novo HFpEF; relapse after recovery is promoted by treatment withdrawal and persistence of genotype or scar. Control of rhythm, blood pressure, and the cause must continue even in the absence of symptoms. Repeated hospitalizations, hypotension, right heart dysfunction, and organ damage may lead to advanced disease; options are evaluated according to global physiology, not excluded by a value of 45%.

Functional and atrial mitral regurgitation may increase with dilation or fibrillation and aggravate pulmonary pressure; severity is reassessed after volume and blood pressure control because hemodynamic loading modifies the apparent degree of regurgitation. Renal progression may make diuresis and mineralocorticoid receptor antagonism more difficult; strategies to maintain therapies include addressing interfering drugs, close monitoring, and potassium management. Not every rise in creatinine equates to permanent toxicity; death is not exclusively cardiovascular: infections, tumors, frailty, and pulmonary disease contribute. Prevention and treatment of comorbidities are therefore integral to prognosis, not parallel activities.