What is the definition of heart failure, how is it classified by ejection fraction and clinical stage, what are the key diagnostic tests including the sensitivity and specificity of elevated B‑type natriuretic peptide and N‑terminal pro‑B‑type natriuretic peptide and imaging modalities, and what are the current guideline‑directed treatment recommendations for each phenotype?

Heart Failure: Definition, Classification, Diagnostic Testing, and Treatment

Definition

Heart failure is a clinical syndrome characterized by symptoms and/or signs caused by structural and/or functional cardiac abnormality, corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. 1

The diagnosis requires three components 2:

• Typical symptoms: breathlessness at rest or on exertion, fatigue, ankle swelling 2
• Typical signs: tachycardia, pulmonary rales, pleural effusion, elevated jugular venous pressure, peripheral edema, hepatomegaly 2
• Objective cardiac abnormality: structural or functional abnormality on echocardiography, elevated natriuretic peptides, or evidence of congestion 2, 1

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Classification

By Ejection Fraction (EF)

The universal classification divides heart failure into four phenotypes based on left ventricular ejection fraction 2, 1:

Category	LVEF Range	Definition
HFrEF (reduced EF)	≤40%	Symptomatic HF with reduced ejection fraction [2,1]
HFmrEF (mildly reduced EF)	41–49%	Symptomatic HF with mildly reduced ejection fraction [2,1]
HFpEF (preserved EF)	≥50%	Symptomatic HF with preserved ejection fraction [2,1]
HFimpEF (improved EF)	Baseline ≤40%, now >40%	≥10-point increase from baseline LVEF ≤40% to >40% [2,1]

By Clinical Stage

The ACC/AHA staging system classifies patients by disease progression 2, 1:

• Stage A (At Risk): Risk factors present (hypertension, diabetes, coronary disease) but no structural heart disease or symptoms 1
• Stage B (Pre-HF): Structural heart disease present but no symptoms 1
• Stage C (Symptomatic HF): Structural heart disease with current or prior symptoms 1
• Stage D (Advanced HF): Refractory symptoms despite maximal medical therapy, requiring advanced interventions 1

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Diagnostic Laboratory Testing

Natriuretic Peptides: Sensitivity and Specificity

BNP and NT-proBNP are primarily valuable for ruling out heart failure rather than confirming it, with excellent negative predictive value but only moderate specificity. 2, 3

Non-Acute (Ambulatory) Thresholds

Test	Rule-Out Threshold	Sensitivity	NPV	Specificity	PPV
BNP	<35 pg/mL	90–97% [2,3]	94–98% [2,3]	60–76% [2,3]	44–57% [2]
NT-proBNP	<125 pg/mL	99% [2,3]	98–99% [2,3]	60–76% [2,3]	44–57% [2]

Acute (Emergency Department) Thresholds

Test	Rule-Out Threshold	Sensitivity	NPV	Rule-In Threshold
BNP	<100 pg/mL	90% [2,3]	94% [2,3]	>400 pg/mL [3]
NT-proBNP	<300 pg/mL	99% [2,3]	98% [2,3]	Age-adjusted (see below) [2,3]

Age-Adjusted NT-proBNP Thresholds (ESC)

Age	Rule-Out	Rule-In
<50 years	<300 pg/mL [2,3]	>450 pg/mL [2,3]
50–75 years	<300 pg/mL [2,3]	>900 pg/mL [2,3]
>75 years	<300 pg/mL [2,3]	>1,800 pg/mL [2,3]

Critical Adjustments for Special Populations

Obesity significantly reduces BNP/NT-proBNP levels, with each BMI unit decrease correlating with lower natriuretic peptide concentrations; severe obesity (BMI >35 kg/m²) reduces sensitivity for detecting heart failure. 3, 4

Chronic kidney disease elevates natriuretic peptides independent of cardiac status; when GFR <60 mL/min/1.73 m², raise BNP rule-out threshold to 200–225 pg/mL and NT-proBNP to 1,200 pg/mL. 3

Atrial fibrillation raises BNP by approximately 20–30% independent of heart failure; standard thresholds are unreliable and higher cut-offs must be applied (NT-proBNP >1,500 pg/mL suggests possible structural disease; >3,000 pg/mL strongly suggests heart failure). 3

Important Limitations

BNP cannot distinguish between HFrEF and HFpEF, though values tend to be lower in HFpEF; approximately 29% of symptomatic HFpEF patients have BNP ≤100 pg/mL despite elevated filling pressures. 5, 6

False-positive elevations occur with acute coronary syndrome, pulmonary embolism, sepsis, severe COPD, and renal failure; confirmatory echocardiography is mandatory for positive results. 2, 3

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Imaging: Echocardiography

Transthoracic echocardiography is the primary imaging modality for diagnosing heart failure, determining ejection fraction phenotype, and identifying structural abnormalities. 2

Essential Echocardiographic Parameters

For HFpEF diagnosis, the following structural and functional criteria must be assessed 2:

Structural Criteria

• Left atrial volume index (LAVI) >34 mL/m² 2
• Left ventricular mass index (LVMI): ≥115 g/m² (males), ≥95 g/m² (females) 2

Functional Criteria

• E/e′ ratio ≥13 indicates elevated filling pressures 2
• Mean e′ velocity (septal and lateral) <9 cm/s 2
• Tricuspid regurgitation velocity >2.8 m/s 2

The E/e′ ratio has a pooled correlation coefficient of 0.56 with invasively measured filling pressures in HFpEF, demonstrating only modest correlation; no single parameter is sufficient for diagnosis. 2

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Treatment Guidelines by Phenotype

HFrEF (LVEF ≤40%): Quadruple Therapy

Immediate initiation of four-drug guideline-directed medical therapy (GDMT) is a Class I recommendation for all patients with HFrEF 2:

1. ARNI (sacubitril-valsartan) or ACE-inhibitor/ARB 2
2. Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) 2
3. Mineralocorticoid receptor antagonist (spironolactone or eplerenone) 2
4. SGLT2 inhibitor (empagliflozin or dapagliflozin) 2, 4

Loop diuretics should be titrated to relieve congestion; therapy should begin in the emergency department without delay, as early intervention improves outcomes. 2

HFpEF (LVEF ≥50%): Disease-Modifying Therapy

SGLT2 inhibitors (empagliflozin or dapagliflozin) are first-line disease-modifying therapy for HFpEF and should be initiated in all patients to reduce cardiovascular death and heart failure hospitalizations. 2, 4

Additional therapies for HFpEF include 2, 4:

• Mineralocorticoid receptor antagonists to reduce morbidity and mortality 4
• Angiotensin receptor-neprilysin inhibitors may be considered for selected patients, though evidence shows smaller reductions in HF hospitalizations compared to HFrEF 4
• Loop diuretics used judiciously as needed to reduce congestion, not as disease-modifying therapy 4

Beta-blockers are not routinely recommended for HFpEF unless specific indications exist (prior MI, angina, atrial fibrillation). 4

HFmrEF (LVEF 41–49%)

Patients with HFmrEF should be treated similarly to HFrEF with quadruple GDMT, as this phenotype represents a transitional state. 2

Critical Management Principles

Aggressive management of comorbidities is mandatory in HFpEF, as hypertension, diabetes, obesity, atrial fibrillation, coronary disease, and chronic kidney disease directly contribute to symptoms and prognosis. 4

Before confirming HFpEF diagnosis, systematically exclude mimics requiring different treatment: cardiac amyloidosis, hypertrophic cardiomyopathy, cardiac sarcoidosis, hemochromatosis, Fabry disease, high-output heart failure, and pericardial disease. 4, 7

BNP-guided titration of GDMT is associated with higher medication doses and improved clinical outcomes; a reduction >30–50% signals adequate therapeutic response. 3, 8