Does heart rate variability correlate with interleukin‑6 and other inflammatory markers such as C‑reactive protein and tumor necrosis factor‑α?

Heart Rate Variability Correlates Inversely with IL-6 and Other Inflammatory Markers

Yes, heart rate variability (HRV) demonstrates consistent inverse correlations with IL-6, C-reactive protein (CRP), and other inflammatory markers, with the relationship being strongest for IL-6 and most pronounced in low-frequency HRV measures rather than traditional vagal indices.

Strength and Pattern of Correlations

IL-6 Shows the Strongest Association

• IL-6 demonstrates the most robust inverse correlation with HRV measures (r = -0.2 to -0.4), remaining significant even after controlling for traditional cardiovascular risk factors including age, BMI, smoking, hypertension, diabetes, and depression 1, 2, 3
• In women with established coronary heart disease, IL-6 showed stronger correlation coefficients with HRV measures than any other evaluated factor, including traditional risk factors 3
• This relationship persists across multiple HRV parameters including SDNN, SDANN, total power, very low frequency (VLF), and low frequency (LF) power 1, 3

CRP Demonstrates Moderate Correlation

• CRP shows graded inverse relationships with most HRV parameters, with ultra-low frequency and very low frequency remaining significant predictors after multivariable adjustment (p < 0.01) 2
• The correlation between HRV and CRP is weaker than with IL-6 but remains clinically significant across multiple populations 1, 4, 5
• In critically ill children, the inverse correlation between HRV (measured as HRVi) and CRP persisted after adjusting for illness severity and age (p < 0.001) 5

TNF-α and IL-8 Correlations

• IL-8 shows inverse correlation with HRV that persists after adjustment for illness severity and age in critically ill populations (p < 0.001) 5
• The evidence base for TNF-α is more limited, though it is recognized as a key inflammatory marker in cardiovascular disease pathophysiology 6

Which HRV Measures Correlate Most Strongly

Low-Frequency Measures Predominate

• Contrary to traditional assumptions about vagal measures, low-frequency HRV (reflecting both parasympathetic and sympathetic activity) shows more consistent associations with inflammatory markers than high-frequency HRV 4
• Time-domain measures including MeanNN, SDNN, and SDANN demonstrate significant inverse associations with both CRP and IL-6 (p ≤ 0.02) 1
• High-frequency HRV (RMSSD), traditionally considered a pure vagal measure, shows weaker or non-significant associations with inflammatory markers 1, 3

Short vs. Long-Term Measurements

• The relationships between HRV and inflammatory markers are similar whether derived from ECG signals as short as 5-30 minutes or from 24-hour recordings 4
• This suggests that brief HRV assessments may be sufficient for evaluating inflammatory status

Clinical Populations Where This Relationship Applies

Stable Coronary Heart Disease

• In 862 outpatients with stable CHD, reduced cardiac autonomic control (lower HRV) was independently associated with increased systemic inflammation, with relationships largely independent of beta blocker use and cardiopulmonary history 1
• Women with CHD evaluated 1 year after acute events showed particularly strong IL-6/HRV correlations 3

Healthy and At-Risk Populations

• Middle-aged men free of symptomatic CAD demonstrate inverse relationships between HRV and both CRP and IL-6, even after controlling for traditional risk factors 2
• Patients with metabolic syndrome or impaired glucose tolerance show similar patterns 4

Critical Illness

• Critically ill children demonstrate inverse correlations between HRV and IL-6, IL-8, and CRP within 72 hours of PICU admission 5

Mechanistic Context

The Cholinergic Anti-Inflammatory Pathway

• The relationship likely reflects vagus nerve-mediated anti-inflammatory effects, as vagal activity modulates some components of HRV 4
• Autonomic dysregulation leading to inflammation may represent a pathway through which traditional cardiovascular risk factors promote disease development 2

Bidirectional Relationship

• The autonomic nervous system can both modulate and be modulated by inflammatory responses during illness 5
• Chronic low-grade systemic inflammation is a key component in atherogenesis, and decreased HRV is a strong predictor of cardiovascular events 1

Important Clinical Caveats

Confounding Factors

• Multiple contemporaneous factors influence both HRV and inflammatory markers, including environmental exposures (pollution), acute and chronic psychosocial stress, BMI, physical activity, smoking, depression, and medications 6, 2
• The temporal stability of inflammatory markers varies: strong to moderate stability over <6 months (r = 0.80-0.61), modest to moderate over 6 months-3 years (r = 0.60-0.51), and low stability >3 years (r = 0.39-0.30) 6

Measurement Considerations

• Single assessments of inflammatory markers may underestimate health risk; accounting for year-to-year variation in IL-6 increased CHD risk prediction by almost 50% over 12 years 6
• For clinical risk assessment, obtain two hs-CRP measurements optimally 2 weeks apart in metabolically stable patients, then average the results 7

Distinguishing Chronic from Acute Inflammation

• Use hs-CRP ≥2 mg/L but <10 mg/L to identify residual inflammatory risk in stable patients; values ≥10 mg/L indicate high-grade inflammation requiring investigation for acute infection or inflammatory conditions 7
• This distinction is critical when interpreting HRV-inflammation relationships in clinical practice