What is the workup for causes of heart failure with reduced ejection fraction (HFrEF)?

Workup for Causes of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with newly diagnosed HFrEF require a systematic evaluation to distinguish ischemic from nonischemic etiologies and identify specific treatable cardiomyopathies, as this fundamentally alters management and prognosis. 1

Initial Laboratory Assessment

The following blood tests should be obtained at presentation in all HFrEF patients 1:

• Natriuretic peptides (BNP >100 pg/mL or NT-proBNP >300 pg/mL supports diagnosis) 1
• Cardiac troponin (elevated in acute coronary syndromes, myocarditis, or cardiac amyloidosis) 1
• Complete metabolic panel: creatinine, BUN, sodium, potassium 1
• Liver function tests (abnormal in congestive hepatopathy or infiltrative disease) 1
• Hemoglobin A1c (diabetes screening) 1
• Thyroid-stimulating hormone (TSH) in all newly diagnosed cases 1
• Lipid panel 1

Specialized Laboratory Testing for Specific Cardiomyopathies

Based on clinical suspicion, obtain 1:

• Serum and urine protein electrophoresis with immunofixation plus serum free light chains if increased LV wall thickness, neuropathy, or carpal tunnel syndrome suggest cardiac amyloidosis 1
• Ferritin and transferrin saturation if family history of hemochromatosis or frequent transfusions 1
• Serum alpha-galactosidase level (in men) if angiokeratomas or sensory neuropathy suggest Fabry disease 1
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) if inflammatory/autoimmune disease suspected 1
• HIV and hepatitis C serology in appropriate clinical contexts 1

Cardiac Imaging

Transthoracic Echocardiography (First-Line)

Resting transthoracic echocardiography is the initial imaging modality of choice for all patients with suspected or confirmed HFrEF 1. This should assess 1:

• Left ventricular ejection fraction (HFrEF defined as LVEF ≤40%) 1, 2
• LV dimensions and wall thickness (increased thickness suggests infiltrative disease, hypertrophic cardiomyopathy, or hypertension) 1
• Regional wall motion abnormalities (suggest ischemic etiology) 1
• Valvular structure and function (primary valve disease can cause or contribute to HF) 1
• Right ventricular function and pulmonary pressures 1
• Pericardial disease 1

Cardiac Magnetic Resonance Imaging (CMR)

CMR should be considered when echocardiography is non-diagnostic or when specific cardiomyopathies are suspected 1. CMR is particularly valuable for 1:

• Myocardial characterization with late gadolinium enhancement (identifies fibrosis patterns specific to ischemic vs. nonischemic etiologies, infiltrative diseases, sarcoidosis, myocarditis) 1
• Precise volumetric assessment when echocardiography is technically limited 1
• T2-weighted imaging for myocardial edema in suspected myocarditis 1
• T2 imaging* for iron overload in hemochromatosis 1

Distinguishing Ischemic from Nonischemic Etiology

Coronary Artery Assessment

Coronary evaluation is essential in all HFrEF patients to distinguish ischemic from nonischemic cardiomyopathy 1:

For patients with high pretest probability or symptoms of coronary disease 1:

• Coronary angiography (invasive) is usually appropriate 1
• Coronary CT angiography is an alternative if lower pretest probability 1

For myocardial perfusion assessment 1:

• Rest/vasodilator stress SPECT/CT or PET/CT 1
• Rest/vasodilator stress cardiac MRI 1

For myocardial viability and contraction assessment 1:

• Rest/exercise or dobutamine stress echocardiography 1

Additional Imaging Studies

Chest Radiography

Chest X-ray should be obtained in all patients to assess 1:

• Cardiomegaly 1
• Pulmonary vascular congestion and edema 1
• Pleural effusions 1
• Alternative pulmonary diagnoses 1

Nuclear Imaging for Cardiac Amyloidosis

Technetium pyrophosphate (99mTc-PYP) scan should be performed when cardiac amyloidosis is suspected (increased LV wall thickness, neuropathy, carpal tunnel syndrome) and the monoclonal protein screen is negative 1. This distinguishes transthyretin (ATTR) amyloidosis from light chain (AL) amyloidosis 1.

FDG-PET Scan for Cardiac Sarcoidosis

18F-fluorodeoxyglucose PET imaging is indicated when cardiac sarcoidosis is suspected (extracardiac sarcoidosis, high-degree AV block in patients <60 years, ventricular arrhythmias) 1.

Invasive Hemodynamic Assessment

Right heart catheterization should be considered 1:

• To confirm diagnosis when noninvasive testing is inconclusive 1
• As part of advanced HF evaluation for device therapy or transplantation 1
• To assess for pulmonary hypertension 1

Endomyocardial Biopsy

Endomyocardial biopsy should be considered when a specific diagnosis would alter therapy, such as 1:

• Suspected myocarditis (particularly giant cell or eosinophilic) 1
• Suspected cardiac amyloidosis with positive monoclonal protein screen 1
• Suspected cardiac sarcoidosis when other testing is inconclusive 1
• Suspected restrictive cardiomyopathy of unclear etiology 1

Genetic Testing and Counseling

Genetic counseling and testing should be offered when an inherited cardiomyopathy is suspected based on 1:

• Family history of cardiomyopathy or sudden cardiac death 1
• Unexplained LV hypertrophy suggesting hypertrophic cardiomyopathy 1
• Clinical features suggesting specific genetic conditions (e.g., Fabry disease, hemochromatosis with HFE gene testing) 1

Critical Diagnostic Pitfalls

Do not assume all HFrEF is either simply "ischemic" or "nonischemic"—specific treatable etiologies must be actively excluded 1. Cardiac amyloidosis has a median survival of only 4 months once HF symptoms develop if untreated, but disease-specific therapies now exist 1.

Natriuretic peptides can be falsely low in flash pulmonary edema, right-sided HF, or end-stage decompensated HF 1. Obesity also reduces natriuretic peptide levels 1.

Increased LV wall thickness in HFrEF is not simply "hypertensive heart disease"—this finding mandates evaluation for infiltrative cardiomyopathies, particularly cardiac amyloidosis 1.