Comparing Inflammatory Biomarkers in Cardiovascular Disease: Insights from the LURIC Study
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics According to Inflammatory Biomarker Combinations
2.1.1. hsCRP and SAA Stratification
Variables | Both Low (N = 1279) | CRP High (N = 372) | SAA High (N = 371) | Both High (N = 1278) | p-Value |
---|---|---|---|---|---|
Age (years) | 61.3 ± 10.8 | 63.2 ± 10.3 | 63.3 ± 10.4 | 63.7 ± 10.4 | <0.001 |
Female sex (%) | 25.4 | 28.0 | 42.9 | 32.6 | <0.001 |
Body mass index (kg/m2) | 26.9 ± 3.61 | 27.9 ± 4.05 | 27.4 ± 3.81 | 28 ± 4.52 | <0.001 |
Smoking (current or ex, %) | 60.8 | 70.2 | 56.3 | 68.9 | <0.001 |
LDL-cholesterol (mg/dL) | 118 ± 33.4 | 116 ± 33.4 | 121 ± 37.6 | 114 ± 34.4 | 0.008 |
HDL-cholesterol (mg/dL) | 40.5 ± 10.6 | 36 ± 9.52 | 43.2 ± 10.8 | 36.4 ± 10.6 | <0.001 |
Triglycerides (mg/dL) | 141 (105–195) | 161 (122–222) | 140 (106–192) | 150 (110–203) | 0.006 |
Systolic blood pressure (mmHg) | 141 ± 23.1 | 144 ± 23.7 | 143 ± 23.5 | 139 ± 24.0 | 0.023 |
Diastolic blood pressure (mmHg) | 81.9 ± 11.1 | 81.7 ± 11.9 | 81.9 ± 11.6 | 79.5 ± 11.5 | <0.001 |
Pulse pressure (mmHg) | 59.6 ± 17.7 | 62.5 ± 18.9 | 60.7 ± 17.5 | 59.9 ± 18.6 | 0.795 |
hsCRP (mg/L) | 1.18 (0.68–1.9) | 5.23 (4.22–6.8) | 1.82 (1.21–2.61) | 10.1 (6.5–22.2) | 0 |
SAA (mg/L) | 2.7 (2–3.5) | 3.5 (2.7–4.4) | 7.1 (5.9–8.85) | 16.8 (8.6–43.7) | 0 |
IL-6 (ng/L) | 2.01 (1.39–3.32) | 3.66 (2.37–5.81) | 2.52 (1.58–4.02) | 5.62 (3.26–9.99) | <0.001 |
HbA1c (%) | 6.11 ± 1.06 | 6.45 ± 1.5 | 6.33 ± 1.19 | 6.47 ± 1.33 | <0.001 |
Diabetes mellitus (%) | 32.0 | 43.3 | 37.5 | 47.5 | <0.001 |
eGFR (mL/min/1.73 m2) | 86.6 ± 17.7 | 81.2 ± 19.6 | 81.8 ± 19 | 76.9 ± 21.8 | <0.001 |
NT-proBNP (pg/mL) | 186 (80–490) | 326 (122–854) | 267 (109–682) | 490 (171–1470) | <0.001 |
Albumin (g/dL) | 4.47 ± 0.56 | 4.35 ± 0.55 | 4.43 ± 0.53 | 4.29 ± 0.54 | <0.001 |
Hypertension (%) | 69.7 | 76.3 | 74.4 | 74.3 | 0.015 |
Heart failure (%) | 15.3 | 30.3 | 21.2 | 30.0 | <0.001 |
Coronary artery disease (%) | 71.8 | 81.2 | 76.0 | 83.6 | <0.001 |
Peripheral artery disease (%) | 8.76 | 13.4 | 4.85 | 10.8 | 0.0002 |
Friesinger score | 4 (1–8) | 6 (3–9) | 5 (2–8) | 6 (3–9) | <0.001 |
Gensini score | 24 (1.5–54.5) | 34.8 (11.5–68.1) | 28.5 (4.5–63) | 36.5 (12–72) | <0.001 |
2.1.2. IL-6 and SAA Stratification
Variable | Both Low (N = 1095) | IL6 High (N = 556) | SAA High (N = 551) | Both High (N = 1098) | p-Value |
---|---|---|---|---|---|
Age (years) | 60.6 ± 10.8 | 63.9 ± 10.2 | 62 ± 10.2 | 64.4 ± 10.4 | <0.001 |
Female sex (%) | 25.5 | 27 | 42.8 | 30.9 | <0.001 |
Body mass index (kg/m2) | 27 ± 3.77 | 27.3 ± 3.66 | 27.8 ± 4.11 | 27.8 ± 4.5 | <0.001 |
Smoking (current or ex, %) | 61.9 | 64.9 | 60.1 | 69 | <0.001 |
LDL-cholesterol (mg/dL) | 118 ± 33.6 | 116 ± 32.9 | 119 ± 38.6 | 114 ± 33.3 | 0.005 |
HDL-cholesterol (mg/dL) | 40.5 ± 10.7 | 37.5 ± 9.94 | 40.7 ± 11.3 | 36.6 ± 10.6 | 0.001 |
Triglycerides (mg/dL) | 144 (105–198) | 150 (113–205) | 147 (108–205) | 149 (111–199) | 0.088 |
Systolic blood pressure (mmHg) | 142 ± 22.7 | 143 ± 24.4 | 141 ± 23.1 | 140 ± 24.3 | 0.040 |
Diastolic blood pressure (mmHg) | 82 ± 11 | 81.7 ± 11.8 | 81 ± 11.1 | 79.6 ± 11.8 | <0.001 |
Pulse pressure (mmHg) | 59.6 ± 17.3 | 61.5 ± 19.4 | 60 ± 17.8 | 60.2 ± 18.7 | 0.669 |
hsCRP (mg/L) | 1.28 (0.68–2.4) | 2.45 (1.21–4.74) | 4 (1.73–7.87) | 10.3 (5.72–22.8) | <0.001 |
SAA (mg/L) | 2.7 (2–3.6) | 3.2 (2.4–4) | 8.2 (6.3–14) | 16.8 (8.2–45.2) | 0 |
IL-6 (ng/L) | 1.73 (1.22–2.29) | 5.07 (3.88–7.06) | 1.96 (1.42–2.54) | 6.98 (4.63–11.6) | 0 |
HbA1c (%) | 6.1 ± 1.08 | 6.36 ± 1.33 | 6.3 ± 1.07 | 6.51 ± 1.4 | <0.001 |
Diabetes mellitus (%) | 29.9 | 43.7 | 39.2 | 48.3 | <0.001 |
eGFR (mL/min/1.73 m2) | 87.8 ± 17.5 | 80.7 ± 18.7 | 82.5 ± 19.5 | 75.8 ± 21.8 | <0.001 |
NT-proBNP (pg/mL) | 164 (76–426) | 333 (129–907) | 248 (101–638) | 552 (201–1690) | <0.001 |
Albumin (g/dL) | 4.47 ± 0.557 | 4.4 ± 0.567 | 4.42 ± 0.498 | 4.27 ± 0.548 | <0.001 |
Hypertension (%) | 69.9 | 73.7 | 76.6 | 73.1 | 0.029 |
Heart failure (%) | 15.6 | 24.6 | 19.7 | 32.2 | <0.001 |
Coronary artery disease (%) | 71.7 | 78.2 | 74.4 | 85.7 | <0.001 |
Peripheral artery disease (%) | 8.4 | 12.6 | 5.08 | 11.7 | <0.001 |
Friesinger score | 4 (1–7) | 6 (2.75–9) | 5 (1–8) | 6 (3–9) | <0.001 |
Gensini score | 23.5 (1.5–53.5) | 32.8 (7–66.1) | 26.5 (3–60) | 39.2 (17.6–75) | <0.001 |
2.1.3. hsCRP and IL-6 Stratification
Variable | Both Low (N = 1175) | IL6 High (N = 475) | CRP High (N = 471) | both High (N = 1179) | p-Value |
---|---|---|---|---|---|
Age (years) | 60.9 ± 10.8 | 64 ± 10.4 | 61.7 ± 10.3 | 64.3 ± 10.4 | <0.001 |
Female sex (%) | 29.3 | 29.5 | 36.3 | 29.6 | 0.029 |
Body mass index (kg/m2) | 26.9 ± 3.69 | 27.2 ± 3.56 | 28.3 ± 4.25 | 27.8 ± 4.48 | <0.001 |
Smoking (current or ex, %) | 59.4 | 60.8 | 66.0 | 70.4 | <0.001 |
LDL-cholesterol (mg/dL) | 120 ± 35 | 117 ± 32.8 | 116 ± 36.2 | 114 ± 33.4 | <0.001 |
HDL-cholesterol (mg/dL) | 41.5 ± 10.8 | 40.1 ± 10.5 | 38.2 ± 10.9 | 35.6 ± 10.1 | <0.001 |
Triglycerides (mg/dL) | 140 (103–195) | 140 (110–193) | 156 (113–218) | 151 (114–202) | <0.001 |
Systolic blood pressure (mmHg) | 141 ± 22.6 | 143 ± 24.6 | 142 ± 23.3 | 140 ± 24.2 | 0.187 |
Diastolic blood pressure (mmHg) | 81.9 ± 10.9 | 82.1 ± 11.7 | 81.1 ± 11.3 | 79.6 ± 11.8 | <0.001 |
Pulse pressure (mmHg) | 59.2 ± 17 | 61.3 ± 19.1 | 60.9 ± 18.4 | 60.3 ± 18.8 | 0.166 |
hsCRP (mg/L) | 1.19 (0.685–1.92) | 1.63 (1.05–2.49) | 6.1 (4.43–9.02) | 9.94 (6.06–21.8) | 0 |
SAA (mg/L) | 3 (2.1–4.5) | 3.4 (2.4–5.35) | 6.8 (4.2–13.9) | 13.9 (6.4–41.9) | <0.001 |
IL-6 (ng/L) | 1.68 (1.19–2.24) | 4.76 (3.76–6.82) | 2.12 (1.58–2.65) | 6.82 (4.63–11.2) | 0 |
HbA1c (%) | 6.1 ± 1.05 | 6.33 ± 1.18 | 6.34 ± 1.16 | 6.51 ± 1.44 | <0.001 |
Diabetes mellitus (%) | 29.4 | 42.7 | 42.0 | 48.3 | <0.001 |
eGFR (mL/min/1.73 m2) | 87.7 ± 17.3 | 80.2 ± 18.7 | 81.8 ± 20.1 | 76.3 ± 21.6 | <0.001 |
NT-proBNP (pg/mL) | 169 (78–415) | 320 (120–917) | 272 (103–673) | 541 (197–1660) | <0.001 |
Albumin (g/dL) | 4.47 ± 0.55 | 4.43 ± 0.564 | 4.4 ± 0.505 | 4.27 ± 0.549 | <0.001 |
Hypertension (%) | 69.7 | 73.3 | 78.1 | 73.4 | 0.005 |
Heart failure (%) | 14.0 | 23.0 | 24.6 | 32.3 | <0.001 |
Coronary artery disease (%) | 70.7 | 77.7 | 77.3 | 85.4 | <0.001 |
Peripheral artery disease (%) | 7.06 | 9.89 | 7.86 | 12.8 | <0.001 |
Friesinger score | 4 (1–7) | 6 (2–9) | 5 (2–8) | 6 (3–9) | <0.001 |
Gensini score | 22.5 (1–53) | 32.5 (7–64) | 31 (5–61) | 38.5 (17–75) | <0.001 |
2.2. Association with Mortality
2.2.1. Combined Impact of Elevated hsCRP and SAA Concentrations on All-Cause and Cardiovascular Mortality
2.2.2. Combined Impact of Elevated Il-6 and SAA Concentrations on All-Cause and Cardiovascular Mortality
2.2.3. Combined Impact of Elevated hsCRP and Il-6 Concentrations on All-Cause and Cardiovascular Mortality
2.3. Predictive Performance of Individual and Combined Inflammatory Biomarkers
3. Discussion
3.1. Inflammatory Biomarker Profiles and Baseline Characteristics
3.2. Prognostic Value of Combined Biomarker Elevation
3.3. Diagnostic Accuracy and Clinical Utility
3.4. Strengths and Limitations
3.5. Practical and Analytical Considerations
4. Materials and Methods
4.1. Study Design and Participants
4.2. Clinical Assessment, Definitions, and Endpoints
4.3. Laboratory Procedures
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACS | Acute Coronary Syndrome |
AHA | American Heart Association |
AUC | Area Under the Curve |
BMI | Body Mass Index |
CAD | Coronary Artery Disease |
CKD-EPI | Chronic Kidney Disease Epidemiology Collaboration |
CRP | C-reactive Protein |
CV | Cardiovascular |
eGFR | Estimated Glomerular Filtration Rate |
ELISA | Enzyme-Linked Immunosorbent Assay |
ESC/ESH | European Society of Cardiology/European Society of Hypertension |
HDL | High-Density Lipoprotein |
hsCRP | High-Sensitivity C-Reactive Protein |
IL-6 | Interleukin-6 |
LDL | Low-Density Lipoprotein |
LURIC | Ludwigshafen Risk and Cardiovascular Health |
MI | Myocardial Infarction |
NT-proBNP | N-terminal pro-B-type Natriuretic Peptide |
PAD | Peripheral Artery Disease |
ROC | Receiver Operating Characteristic |
SAA | Serum Amyloid A |
SD | Standard Deviation |
SPSS | Statistical Package for the Social Sciences |
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All-Cause Mortality | Cardiovascular Mortality | |||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Crude | ||||
both low | 1 | - | 1 | - |
hsCRP high | 1.52 (1.23–1.88) | <0.001 | 1.18 (0.87–1.58) | 0.286 |
SAA high | 1.13 (0.89–1.42) | 0.319 | 1.02 (0.75–1.39) | 0.910 |
both high | 1.92 (1.66–2.22) | <0.001 | 2.09 (1.74–2.51) | <0.001 |
Model 1 | ||||
both low | 1 | - | 1 | - |
hsCRP high | 1.38 (1.12–1.71) | 0.003 | 1.07 (0.80–1.44) | 0.646 |
SAA high | 1.09 (0.86–1.38) | 0.457 | 0.99 (0.72–1.35) | 0.938 |
both high | 1.75 (1.51–2.02) | <0.001 | 1.90 (1.58–2.29) | <0.001 |
Model 2 | ||||
both low | 1 | - | 1 | - |
hsCRP high | 1.10 (0.87–1.39) | 0.447 | 0.81 (0.58–1.13) | 0.214 |
SAA high | 0.92 (0.71–1.18) | 0.503 | 0.83 (0.59–1.16) | 0.280 |
both high | 1.25 (1.06–1.48) | 0.009 | 1.36 (1.10–1.67) | 0.004 |
Model 3 | ||||
both low | 1 | - | 1 | - |
hsCRP high | 1.02 (0.81–1.29) | 0.862 | 0.76 (0.55–1.07) | 0.112 |
SAA high | 0.88 (0.68–1.14) | 0.318 | 0.80 (0.57–1.12) | 0.195 |
both high | 1.09 (0.91–1.31) | 0.351 | 1.20 (0.96–1.51) | 0.110 |
All-Cause Mortality | Cardiovascular Mortality | |||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Crude | ||||
both low | 1 | - | 1 | - |
Il-6 high | 1.85 (1.52–2.24) | <0.001 | 1.80 (1.40–2.33) | <0.001 |
SAA high | 1.09 (0.87–1.36) | 0.437 | 1.21 (0.92–1.61) | 0.176 |
both high | 2.49 (2.12–2.92) | <0.001 | 2.80 (2.28–3.44) | <0.001 |
Model 1 | ||||
both low | 1 | - | 1 | - |
IL-6 high | 1.53 (1.26–1.86) | <0.001 | 1.50 (1.16–1.94) | 0.002 |
SAA high | 1.09 (0.87–1.36) | 0.460 | 1.21 (0.91–1.61) | 0.184 |
both high | 2.08 (1.77–2.44) | <0.001 | 2.34 (1.90–2.88) | <0.001 |
Model 2 | ||||
both low | 1 | - | 1 | - |
IL-6 high | 1.36 (1.10–1.68) | 0.005 | 1.34 (1.01–1.78) | 0.042 |
SAA high | 0.94 (0.74–1.20) | 0.622 | 1.13 (0.83–1.53) | 0.438 |
both high | 1.50 (1.25–1.81) | <0.001 | 1.70 (1.33–2.17) | <0.001 |
Model 3 | ||||
both low | 1 | - | 1 | - |
IL-6 high | 1.33 (1.07–1.65) | 0.010 | 1.31 (0.98–1.74) | 0.066 |
SAA high | 0.88 (0.68–1.14) | 0.330 | 1.05 (0.76–1.45) | 0.757 |
both high | 1.35 (1.07–1.70) | 0.010 | 1.52 (1.14–2.05) | 0.005 |
All-Cause Mortality | Cardiovascular Mortality | |||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Crude | ||||
both low | 1 | - | 1 | - |
IL6 high | 1.96 (1.60–2.40) | <0.001 | 2.17 (1.67–2.81) | <0.001 |
hsCRP high | 1.37 (1.10–1.72) | 0.005 | 1.57 (1.18–2.08) | 0.002 |
both high | 2.62 (2.24–3.07) | <0.001 | 2.85 (2.32–3.50) | <0.001 |
Model 1 | ||||
both low | 1 | - | 1 | - |
IL6 high | 1.64 (1.33–2.01) | <0.001 | 1.81 (1.39–2.35) | <0.001 |
hsCRP high | 1.36 (1.09–1.70) | 0.007 | 1.55 (1.17–2.06) | 0.002 |
both high | 2.18 (1.85–2.55) | <0.001 | 2.37 (1.92–2.91) | <0.001 |
Model 2 | ||||
both low | 1 | - | 1 | - |
IL6 high | 1.44 (1.15–1.80) | 0.001 | 1.48 (1.11–1.97) | 0.007 |
hsCRP high | 1.11 (0.87–1.42) | 0.403 | 1.21 (0.89–1.65) | 0.217 |
both high | 1.60 (1.33–1.93) | <0.001 | 1.69 (1.32–2.15) | <0.001 |
Model 3 | ||||
both low | 1 | - | 1 | - |
IL6 high | 1.44 (1.15–1.80) | 0.001 | 1.47 (1.10–1.96) | 0.008 |
hsCRP high | 1.12 (0.87–1.44) | 0.388 | 1.14 (0.83–1.57) | 0.420 |
both high | 1.62 (1.31–2.00) | <0.001 | 1.53 (1.16–2.01) | 0.002 |
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Moissl, A.P.; Delgado, G.E.; Scharnagl, H.; Siekmeier, R.; Krämer, B.K.; Duerschmied, D.; März, W.; Kleber, M.E. Comparing Inflammatory Biomarkers in Cardiovascular Disease: Insights from the LURIC Study. Int. J. Mol. Sci. 2025, 26, 7335. https://doi.org/10.3390/ijms26157335
Moissl AP, Delgado GE, Scharnagl H, Siekmeier R, Krämer BK, Duerschmied D, März W, Kleber ME. Comparing Inflammatory Biomarkers in Cardiovascular Disease: Insights from the LURIC Study. International Journal of Molecular Sciences. 2025; 26(15):7335. https://doi.org/10.3390/ijms26157335
Chicago/Turabian StyleMoissl, Angela P., Graciela E. Delgado, Hubert Scharnagl, Rüdiger Siekmeier, Bernhard K. Krämer, Daniel Duerschmied, Winfried März, and Marcus E. Kleber. 2025. "Comparing Inflammatory Biomarkers in Cardiovascular Disease: Insights from the LURIC Study" International Journal of Molecular Sciences 26, no. 15: 7335. https://doi.org/10.3390/ijms26157335
APA StyleMoissl, A. P., Delgado, G. E., Scharnagl, H., Siekmeier, R., Krämer, B. K., Duerschmied, D., März, W., & Kleber, M. E. (2025). Comparing Inflammatory Biomarkers in Cardiovascular Disease: Insights from the LURIC Study. International Journal of Molecular Sciences, 26(15), 7335. https://doi.org/10.3390/ijms26157335