What biomarkers are used for the diagnosis and prognosis of Peripheral Artery Disease (PAD)?

Diagnostic and Prognostic Biomarkers for Peripheral Artery Disease (PAD)

The ankle-brachial index (ABI) is the most established and recommended first-line diagnostic biomarker for PAD, with values ≤0.90 confirming the diagnosis, while toe-brachial index (TBI), transcutaneous oxygen pressure (TcPO₂), and inflammatory markers provide additional diagnostic and prognostic information. 1

Primary Diagnostic Biomarkers

Hemodynamic/Vascular Assessment

• Ankle-Brachial Index (ABI):

  • First-line diagnostic test recommended by both European and American guidelines 1
  • Interpretation:
    • ≤0.90: Confirms PAD diagnosis
    • 0.91-0.99: Borderline (requires additional testing)
    • 1.00-1.40: Normal

    • 1.40: Non-compressible arteries (requires alternative testing) 1

• Toe-Brachial Index (TBI):

  • Essential when ABI >1.40 due to arterial calcification
  • Values ≤0.70 are considered abnormal
  • Particularly valuable in diabetic patients 1

• Transcutaneous Oxygen Pressure (TcPO₂):

  • Values <30 mmHg indicate critical limb perfusion
  • Strong predictor of wound healing potential 1

Prognostic Biomarkers

Critical Limb Perfusion Indicators

• Ankle Pressure: <50 mmHg indicates severe ischemia and poor prognosis 1
• Toe Pressure: <30 mmHg indicates critical limb-threatening ischemia (CLTI) 1
• TcPO₂: <25 mmHg indicates poor healing potential 1

Healing Potential Predictors

Any of the following findings increases wound healing probability by at least 25% 1:

• Skin perfusion pressure ≥40 mmHg
• Toe pressure ≥30 mmHg
• TcPO₂ ≥25 mmHg

Inflammatory Biomarkers

Recent evidence suggests several inflammatory markers have diagnostic and prognostic value in PAD:

• C-reactive protein (CRP):

  • Elevated levels associated with PAD diagnosis and progression
  • Included in biomarker panels for PAD risk assessment 2, 3

• Interleukins:

  • Pro-inflammatory ILs (IL-1β, IL-2, IL-5, IL-6, IL-8): Positively correlated with PAD diagnosis and progression
  • Anti-inflammatory ILs (IL-4, IL-10): Protective against PAD diagnosis and adverse limb events
  • IL-6 and IL-8 show strongest association with PAD 4, 3

• Novel Biomarker Panel:

  • Combination of β2-microglobulin, cystatin C, hsCRP, and glucose
  • Significantly associated with PAD status (OR = 7.3 after adjusting for traditional risk factors)
  • May help identify patients requiring further vascular testing 2

Clinical Application Algorithm

1. Initial Screening:

   • Measure ABI in patients with risk factors or suspected PAD
   • If ABI ≤0.90: Confirm PAD diagnosis
   • If ABI 0.91-0.99: Perform exercise ABI testing
   • If ABI >1.40: Proceed to TBI measurement

2. For Confirmed PAD:

   • Assess severity with ankle pressure, toe pressure, and TcPO₂
   • Consider inflammatory markers (CRP, IL-6, IL-8) for prognostic assessment

3. For Patients with Foot Ulcers:

   • Measure toe pressure (target ≥30 mmHg)
   • Measure TcPO₂ (target ≥25 mmHg)
   • Consider urgent vascular imaging if toe pressure <30 mmHg or TcPO₂ <25 mmHg 1

4. For Non-healing Ulcers:

   • Consider urgent vascular imaging if ankle pressure <50 mmHg or ABI <0.5 1

Important Caveats

• ABI alone may be insufficient in patients with diabetes or end-stage renal disease due to arterial calcification
• Diabetic microangiopathy should not be considered the cause of poor wound healing in patients with foot ulcers 1
• Inflammatory biomarkers should be interpreted in conjunction with clinical assessment and hemodynamic parameters
• No single biomarker has perfect sensitivity and specificity; combining multiple biomarkers improves diagnostic accuracy
• Post-exercise ABI may reveal PAD in patients with normal resting ABI but typical symptoms 1

By systematically applying these biomarkers, clinicians can improve early diagnosis of PAD, assess prognosis more accurately, and guide appropriate therapeutic interventions to reduce morbidity and mortality.