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Heart Failure With Mid Range Ejection FractionEdit

Heart Failure With Mid Range Ejection Fraction (HFmrEF) is a clinical phenotype of heart failure characterized by a mid-range level of left ventricular ejection fraction. The ejection fraction (EF) is the percentage of blood pumped out of the left ventricle with each heartbeat, and it provides a global measure of systolic function. In most medical references, EF is used to distinguish three main categories: heart failure with reduced EF (HFrEF), usually defined as EF around 40% or less; heart failure with mid-range or mildly reduced EF (HFmrEF), commonly defined as EF in the 40–49% range; and heart failure with preserved EF (HFpEF), typically EF of 50% or higher. HFmrEF sits between the two more established groups, and patients in this category often share features of both HFrEF and HFpEF. Throughout the literature, definitions vary slightly (for example, some sources use 41–49% instead of 40–49%), but the mid-range label is widely accepted for discussion and treatment planning.

HFmrEF is not simply a temporary stage; EF can shift over time in either direction depending on underlying diseases and therapy. Some patients previously classified as HFrEF may improve into the mid-range, while others with HFpEF may see a decline into the mid-range. This dynamic nature has led clinicians to consider HFmrEF as a distinct clinical syndrome with its own patterns of risk, presentation, and response to treatment. For context, see Heart failure and its subtypes, as well as the concepts of Ejection fraction and Systolic dysfunction.

Definition and classification

  • Definition: HFmrEF refers to heart failure in which the left ventricular ejection fraction falls in the mid-range, most often cited as approximately 40–49% (with some guidelines using 41–49%). This places it between HFrEF (EF ≤40%) and HFpEF (EF ≥50%).
  • Relationship to other categories: HFmrEF is a bridge between HFrEF and HFpEF, sharing factors from both sides of the spectrum. The conditions that contribute to HFmrEF include ischemic heart disease, hypertension, valvular disease, cardiomyopathy, and systemic illnesses affecting the heart.
  • Guideline context: Clinical guidelines acknowledge HFmrEF as a recognizable phenotype and address it in the context of therapies that have proven benefit in HFrEF and, increasingly, in HFpEF and broader heart failure populations. See discussions of HFrEF and HFpEF for comparison.

Presentation, evaluation, and diagnosis

  • Symptoms: Patients typically report breathlessness with exertion, fatigue, and reduced exercise tolerance. They may also have edema, orthopnea, or paroxysmal nocturnal dyspnea, though the exact presentation can vary with the underlying cause and comorbidities.
  • Physical findings: Elevated jugular venous pressure, crackles on lung examination, peripheral edema, and signs of reduced cardiac output may be present in more advanced cases.
  • Diagnostic workup:
    • Echocardiography: The key test to determine EF and to assess chamber size, wall motion, valvular disease, and other structural problems.
    • Biomarkers: Natriuretic peptides such as BNP or NT-proBNP support the diagnosis and help gauge severity and prognosis.
    • ECG and imaging: Electrocardiography is used to detect rhythm disturbances or ischemia; cardiac MRI can be helpful in complex cases to characterize myocardium and scar.
    • Etiology assessment: Identification of contributing conditions such as ischemic heart disease, hypertension, valvular disease, or infiltrative disorders guides management strategies.
  • Terminology and links: See Ejection fraction for the measurement concept, Cardiomyopathy for diseases that affect the heart muscle, and Ischemic heart disease as a common underlying cause.

Epidemiology and prognosis

  • Prevalence: HFmrEF accounts for a meaningful minority of patients with heart failure, reflecting an overlap of risk factors and disease processes seen in HFrEF and HFpEF.
  • Risk profile: Patients with HFmrEF frequently have comorbidities such as hypertension, diabetes, obesity, chronic kidney disease, and atrial fibrillation, all of which influence outcomes.
  • Outcomes: Mortality and hospitalization risk in HFmrEF are influenced by the underlying etiology and by the presence of other heart and systemic diseases. The prognosis often falls somewhere between that of HFrEF and HFpEF, but precise risk varies by individual factors and therapy.

Pathophysiology and etiologies

  • Mechanistic themes: HFmrEF reflects a mixture of systolic and diastolic dysfunction, myocardial remodeling, and neurohormonal activation that can arise from ischemia, pressure or volume overload, and cardiomyopathy. The mid-range EF suggests a heart that is impaired enough to cause symptoms but retains a substantial amount of contractile reserve.
  • Common etiologies:
    • Ischemic heart disease and prior myocardial infarction
    • Chronic hypertension leading to concentric remodeling
    • Valvular heart disease (aortic stenosis/regurgitation, mitral regurgitation)
    • Cardiomyopathies (dilated, hypertrophic, or other)
    • Arrhythmias, particularly atrial fibrillation
    • Renal and metabolic diseases that influence cardiac loading conditions
  • Term usage: See Heart failure for a broader discussion of the syndrome, and Aortic valve disease or Mitral valve disease for valvular contributors.

Management and treatment

  • General principles: Management centers on relieving symptoms, preventing hospitalizations, and addressing the root causes and comorbidities. This typically includes lifestyle measures (physical activity within tolerance, sodium balance, weight management), treatment of comorbid conditions (diabetes, hypertension, kidney disease), and regular follow-up.
  • Pharmacologic therapies:
    • RAAS inhibition: ACE inhibitors or ARBs, and in appropriate patients, ARNIs (sacubitril/valsartan) to reduce afterload and neurohormonal activation.
    • Beta-blockers: Beneficial in many patients with systolic dysfunction to reduce heart rate, myocardial oxygen demand, and arrhythmia risk.
    • Mineralocorticoid receptor antagonists: Spironolactone or eplerenone for selected patients to reduce fluid retention and adverse remodeling.
    • SGLT2 inhibitors: Agents such as dapagliflozin or empagliflozin have demonstrated benefits in a range of heart failure patients, including those with EF in the mid-range, by reducing hospitalization and improving outcomes.
    • Diuretics: For symptom relief in volume overload; not disease-modifying but essential for managing congestion.
  • Device and procedural considerations:
    • Revascularization: In patients with ischemic heart disease, addressing significant coronary artery disease can improve symptoms and outcomes.
    • Valvular intervention: Correcting severe valvular disease may improve cardiac function and symptoms.
    • Device therapy: Implantable cardioverter-defibrillators or cardiac resynchronization therapy decisions depend on EF, QRS duration, and symptom burden; applicability in HFmrEF requires individualized assessment.
  • Evidence considerations:
    • Much of the rigorous trial evidence for disease-modifying therapy comes from HFrEF populations; however, observational studies and subset analyses suggest potential benefit in HFmrEF for several therapies. The evolving literature supports a pragmatic approach: use guideline-directed therapies when the patient’s profile resembles HFrEF and when tolerability and comorbidity considerations permit.
  • See also: SGLT2 inhibitors, Sacubitril/valsartan, Beta-blockers, ACE inhibitors, ARBs for background on the individual drug classes.

Controversies and debates

  • Distinct entity or a transitional phase: Clinicians debate whether HFmrEF should be treated as its own distinct phenotype or managed primarily by adapting approaches from HFrEF and HFpEF based on individual risk and comorbidity profiles. The dynamic nature of EF over time means some patients move between categories, complicating long-term management decisions.
  • Therapeutic extrapolation: Because most major trials enrolled patients with HFrEF or HFpEF, the strength of evidence to support broad use of disease-modifying therapies in HFmrEF varies. Some guidelines endorse using GDMT in HFmrEF when the patient’s profile aligns with HFrEF physiology, particularly in ischemic disease or reduced functional capacity, while others emphasize individualized care and attention to comorbidity management.
  • ARNI and HFpEF data: The ARNI class (e.g., sacubitril/valsartan) has proven benefit in HFrEF and mixed results in HFpEF. Post-hoc and subgroup analyses have suggested potential benefits in patients with EF in the mid-range, but definitive trial results specific to HFmrEF are limited, making decisions in this group nuanced.
  • Role of SGLT2 inhibitors: Growing evidence supports SGLT2 inhibitors for heart failure across EF spectrums, including HFmrEF. The precise magnitude of benefit and the patient subsets most likely to respond best continue to be refined by ongoing research.
  • Resource and cost considerations: Given the chronic nature of heart failure and the cost of newer therapies, clinicians weigh cost-effectiveness, patient adherence, and potential adverse effects when deciding on therapy, especially in patients with multiple comorbidities or limited access to care.

See also