Diagnosing Heart Failure with Preserved Ejection Fraction (HFpEF)

Initial Diagnostic Assessment

• The European Society of Cardiology recommends a stepwise approach for diagnosing HFpEF, including assessment of symptoms and signs of heart failure, preserved ejection fraction (≥50%), elevated natriuretic peptides, and objective evidence of cardiac dysfunction, with careful exclusion of HFpEF mimics and noncardiac causes 1, 2
• The American College of Cardiology suggests applying the Universal Definition of Heart Failure, which requires symptoms/signs of HF caused by structural/functional cardiac abnormalities AND at least one of: 1) elevated natriuretic peptides or 2) objective evidence of cardiogenic pulmonary or systemic congestion 3
• Evaluate for symptoms and signs of heart failure, including major criteria: orthopnea, jugular venous distension, hepatojugular reflux, rales, S3 gallop rhythm, acute pulmonary edema, cardiomegaly, and minor criteria: dyspnea on exertion, nocturnal cough, ankle edema, tachycardia, hepatomegaly, pleural effusion 3
• Assess for typical clinical demographics and risk factors, including hypertension, obesity, diabetes mellitus, advanced age, and atrial fibrillation 1, 3
• Perform basic diagnostic tests, such as ECG, which may show LV hypertrophy, atrial fibrillation, repolarization abnormalities 2, and echocardiography to confirm preserved EF (≥50%) 1, 2
• Measure natriuretic peptide levels, with ambulatory thresholds of BNP >35 pg/mL or NT-proBNP >125 pg/mL 1, 3, and hospitalized thresholds of BNP >100 pg/mL or NT-proBNP >300 pg/mL 3

Echocardiographic Assessment

• Evaluate for structural and functional cardiac abnormalities, including left atrial enlargement, LV hypertrophy, diastolic dysfunction, and elevated pulmonary artery pressure 1

Exclusion of HFpEF Mimics

• Rule out noncardiac causes of symptoms, such as kidney failure, liver failure, and chronic venous insufficiency 4, 5
• Exclude cardiac mimics that may present with preserved EF, including infiltrative/restrictive cardiomyopathies, hypertrophic cardiomyopathy, valvular heart disease, pericardial disease, and high-output heart failure 4, 5, 6
• Consider specific testing for HFpEF mimics based on clinical suspicion, such as cardiac amyloidosis, hypertrophic cardiomyopathy, cardiac sarcoidosis, hemochromatosis, and pericardial disease 6, 7

Advanced Diagnostic Testing

• If diagnosis remains uncertain after initial assessment, consider cardiac MRI to evaluate for infiltrative disease, fibrosis, or pericardial abnormalities 8
• Perform functional testing with echocardiographic or invasive hemodynamic exercise stress tests to unmask elevated filling pressures 1
• Invasive hemodynamic assessment may be needed in selected cases to confirm elevated LV filling pressures 4, 5

Common Pitfalls and Caveats

• Normal natriuretic peptide levels do not exclude HFpEF, especially in obese patients who may have lower values despite elevated filling pressures 3
• Not all patients with dyspnea, preserved EF, and comorbidities have HFpEF; careful exclusion of alternative diagnoses is essential 4, 5
• Avoid over-reliance on a single parameter; the diagnosis requires integration of clinical, laboratory, and imaging findings 1
• HFpEF is often a diagnosis of exclusion after ruling out specific cardiac and non-cardiac causes of symptoms 4, 5
• Not every patient requires exhaustive testing to exclude all HFpEF mimics; testing should be guided by clinical suspicion 4

Reconciling Favorable Nuclear Test Results with Low SVI and Clinical Decompensation in Heart Failure with Preserved Ejection Fraction (HFpEF)

Understanding the Apparent Discordance

• The American College of Radiology notes that nuclear myocardial perfusion imaging (MPI) primarily evaluates myocardial ischemia, infarction, and global LVEF, but does not directly assess diastolic function, filling pressures, or stroke volume index that are critical in HFpEF 9, 10
• The European Heart Journal states that resting nuclear ventriculography can evaluate LVEF and ventricular volumes, but provides limited information about the hemodynamic derangements characteristic of HFpEF, such as elevated left ventricular end-diastolic pressure or impaired ventricular-arterial coupling 9
• Comments like "excellent heart function" from nuclear studies typically refer to preserved LVEF and absence of large perfusion defects, which does not exclude HFpEF, as defined by the European Heart Journal 11, 12

Clinical Implications and Urgent Actions

• The European Society of Cardiology recommends reassessment by specialists for patients with worsening heart failure symptoms or important cardiovascular events, which applies to patients with decompensation, as stated in the European Heart Journal 11
• The European Heart Journal suggests that patients with severely reduced SVI, declining LVEF trajectory, CKD stage 3a with declining eGFR, and clinical decompensation with edema meet multiple high-risk criteria warranting specialist evaluation 11
• The European Heart Journal recommends optimizing volume status with diuretics to address systemic congestion, which is fundamental to HFpEF management 11, 13

Limitations of Nuclear Cardiology in HFpEF

• The American College of Radiology notes that nuclear imaging provides limited information about diastolic dysfunction, which is the fundamental abnormality in HFpEF, and cannot assess E/e' ratios, left atrial enlargement, or elevated filling pressures 9, 10
• The ACR Appropriateness Criteria note limited evidence for nuclear imaging as follow-up in known heart failure, emphasizing that echocardiography remains the primary modality for assessing cardiac structure and function, as stated in the Journal of the American College of Radiology 9

Diagnostic Criteria and Evaluation of Heart Failure with Preserved Ejection Fraction (HFpEF)

Core Diagnostic Requirements

• Diagnose HFpEF when all three of the following are present: typical heart‑failure symptoms or signs, left‑ventricular ejection fraction (LVEF) ≥ 50 %, and either elevated natriuretic peptide levels or objective evidence of elevated filling pressures, after excluding cardiac and non‑cardiac mimics. 14

Natriuretic Peptide Thresholds

• Outpatient setting: BNP > 35 pg/mL or NT‑proBNP > 125 pg/mL supports HFpEF. 14
• Atrial fibrillation: higher cut‑offs are required—BNP > 105 pg/mL or NT‑proBNP > 365 pg/mL. 15
• Obesity effect: Natriuretic peptide concentrations are markedly lower in obese individuals; consider reducing the diagnostic cut‑off by ~50 % or proceed directly to advanced testing if clinical suspicion remains high. 15

Echocardiographic Confirmation of Preserved EF and Structural Findings

• LVEF criterion: LVEF ≥ 50 % is mandatory for HFpEF; LVEF 41‑49 % defines HFmrEF, and LVEF < 40 % defines HFrEF. 14
• Left‑ventricular hypertrophy: wall thickness ≥ 12 mm or LV mass index > 115 g/m² (men) / > 95 g/m² (women). [14][15]
• Left‑atrial enlargement: left‑atrial volume index > 34 mL/m². [14][15]
• Mitral annular calcification and aortic sclerosis are supportive structural markers. [16][17]
• Diastolic function:
  
  • E/e′ > 15 → major criterion for elevated filling pressures. [14][15]
  • E/e′ 9‑15 → intermediate; requires additional supporting evidence. [14][15]
  • Estimated pulmonary‑artery systolic pressure > 35 mm Hg also supports elevated filling pressures. [14][15]

Clinical Scoring When Diagnosis Is Uncertain (H₂FPEF Score)

• Scoring components (0‑9 points):
  
  • BMI > 30 kg/m² (2 points) [14][18]15
  • Use of ≥2 antihypertensive agents (1 point) [14][18]
  • Presence of atrial fibrillation (3 points) [14][18]
  • Pulmonary‑artery systolic pressure > 35 mm Hg on echo (1 point) [14][18]
  • Age > 60 years (1 point) [14][18]
  • Echo‑derived E/e′ > 9 (1 point) [14][18]
• Interpretation:
  
  • Score ≥ 6 → high likelihood of HFpEF (>95 % probability). 14
  • Score 2‑5 → intermediate probability; proceed to functional testing. 14
  • Score < 2 → low likelihood of HFpEF. 14
• Utility in obesity: The H₂FPEF score does not rely on natriuretic peptides, making it especially useful when peptide levels are falsely low due to obesity. 15

Exclusion of Cardiac Mimics

• Infiltrative cardiomyopathy (e.g., cardiac amyloidosis): obtain serum and urine protein electrophoresis with immunofixation and consider technetium‑pyrophosphate (PYP) scintigraphy when suspicion exists. [18][19]
• Hypertrophic cardiomyopathy: diagnosis suggested by asymmetric septal hypertrophy > 15 mm and systolic anterior motion of the mitral valve. [16][17]19
• Valvular heart disease: exclude severe aortic stenosis (mean gradient > 40 mm Hg or valve area < 1.0 cm²) and severe mitral regurgitation. [16][17]

Exclusion of Non‑Cardiac Mimics

• Renal disease: screen with urinalysis for proteinuria and assess eGFR/creatinine. [18][19]
• Liver disease/cirrhosis: evaluate with abdominal ultrasound and liver‑function tests. [18][19]
• Chronic venous insufficiency: clinical examination for varicose veins and stasis changes. 19
• Primary pulmonary disease: chest imaging, spirometry, and arterial blood gases. [18][19]
• Pulmonary hypertension of vascular origin: right‑heart catheterisation if indicated. [16][17]

Functional Testing for Uncertain Cases

• Exercise stress echocardiography: measure E/e′ during/after exercise; an exercise‑induced E/e′ > 15 confirms elevated filling pressures. 14
• Invasive hemodynamic exercise testing (gold standard):
  
  • Pulmonary‑capillary wedge pressure > 25 mm Hg with exercise confirms HFpEF. 14
  • Pulmonary‑capillary wedge pressure > 15 mm Hg at rest also confirms HFpEF. 14

Typical Risk‑Factor Profile Enhancing Pre‑Test Probability

• Hypertension: present in the vast majority of HFpEF patients. [16][17]20
• Obesity: > 80 % of HFpEF patients have BMI > 30 kg/m². [14][18]
• Diabetes mellitus: affects 25‑50 % of HFpEF patients. [16][17]20
• Atrial fibrillation: common comorbidity that worsens diastolic filling. [14][16][17][20]
• Chronic kidney disease: frequently co‑exists with HFpEF. 18
• Advanced age (≥ 65 years): aging impairs ventricular relaxation and increases arterial stiffness. [16][17]20
• Female sex: HFpEF is more prevalent in elderly women than men. [16][17]20

Pathophysiologic Rationale (Supporting Evidence)

• Aging reduces elastic properties of the heart and great vessels, raising systolic blood pressure and myocardial stiffness; chronic hypertension induces concentric LV hypertrophy; fibrotic remodeling and impaired relaxation decrease ventricular filling rates. [16][17]20

Key Diagnostic Pitfalls (Cited)

• Obesity‑related peptide suppression: Do not dismiss HFpEF in obese patients with normal natriuretic peptide levels; obesity can lower peptide concentrations despite elevated filling pressures. 15
• Missed cardiac amyloidosis: In patients with carpal‑tunnel syndrome, lumbar spinal stenosis, or unexplained neuropathy plus HFpEF features, obtain monoclonal protein screening and consider a PYP scan. [18][19]