Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction
Abstract
:1. Introduction
2. Methods
2.1. Clinical Assessments
2.2. RNA Isolation, Reverse Transcription, and qRT-PCR
2.3. Biomarker Measurements
2.4. Cell Stimulation Assays
2.5. Skeletal Muscle Tissue Biopsy
2.6. Statistical Analysis
3. Results
3.1. Baseline Characteristics
3.1.1. Body Composition
3.1.2. Oxygen Consumption
3.2. Immune Markers
3.2.1. Cytokine Gene Expression
3.2.2. LPS Stimulation
3.2.3. Association of STAT and SOCS Genes with Cytokine Gene Expression
3.2.4. Association of Gene Expressions with Body Composition
3.2.5. Association of STAT- and SOCS Expression with Cytokine Release upon LPS Stimulation
3.3. Markers of Oxidative Stress and Vasoconstriction
3.3.1. Mid-Regional Pro-Adrenomedullin
3.3.2. C-Terminal Pro-Endothelin 1
3.4. Skeletal Muscle Biopsies
3.4.1. Proteasome 20S Subunit Beta 2 (PSMB2)
3.4.2. Calpain-1 Catalytic Subunit (CAPN1)
3.4.3. Solute Carrier Family 2 Member 4 (SLC2A4)
3.5. Cytokine, STAT and SOCS Expressions and Severity of CHF
4. Discussion
4.1. Inflammation Is Increased in Cardiac Cachexia
4.2. Cytokine-Induced Cellular Stress and Damage in the Cachectic Muscle
4.3. SLC2A4 Expression of the Skeletal Muscle
4.4. Lipolysis
5. Conclusions
6. Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CAPN1 | calpain-1 catalytic subunit |
CHF | chronic heart failure |
cCHF | chronic heart failure patients with cachexia |
Glucose Transporter 4 | Glut4 |
hs | high sensitivity |
ncCHF | chronic heart failure patients without cachexia |
Peak VO2 | maximum oxygen consumption |
LVEF | left ventricular ejection fraction |
TNF | tumor necrosis factor |
TGF | transforming growth factor |
IL | interleukin |
TNF | tumor necrosis factor |
JAK | janus (tandem) kinase |
PBC | peripheral blood cells |
STAT | signal transducer and activator of transcription |
SOCS | suppressors of cytokine signaling |
PSMB2 | proteasome 20S subunit beta 2 |
SLC2A4 | solute carrier family 2 member 4 |
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Control Subjects (n = 17) | ncCHF Patients (n = 19) | cCHF Patients (n = 18) | cCHF vs. ncCHF Patients p-Value | ANOVA-p | |
---|---|---|---|---|---|
Number (female) | 11(6) | 14 (5) | 15 (3) | 0.5 | |
NYHA class | 2.3 ± 0.5 | 2.9 ± 0.3 | 0.0003 | ||
Ejection Fraction (%) | 70± 7 | 31 ± 7 * | 27 ± 7 * | 0.1 | <0.0001 |
Ischaemic aetiology | 13/19 | 13/18 | 0.9 | ||
Age (years) | 63.4 ± 5.7 | 67.6 ± 8.8 | 66.9 ± 10.2 | 0.8 | |
Weight (kg) | 80.8 ± 14.5 | 93.9 ± 22.7 * | 71.8 ± 9.2 | 0.0003 | 0.001 |
Height (cm) | 173.4 ± 9.7 | 175.6 ± 9.6 | 171.6 ± 6.0 | 0.3 | |
BMI (kg/m2) | 27.5 ± 4.6 | 30.2 ± 5.0 | 24.3 ± 2.5 * | 0.0002 | 0.0008 |
Fat mass/height [kg/m] | 14.9 ± 6.6 | 17.2 ± 4.9 * | 10.8 ± 4.5 | 0.002 | 0.0077 |
Fat free mass/height [kg/m] | 30.0 ± 5.1 | 34.4 ± 6.6 * | 29.5 ± 3.0 | 0.008 | 0.01 |
Bone mass/height [kg/m] | 1.6 ± 0.2 | 1.6 ± 0.2 | 1.6 ± 0.2 | 0.97 | |
Peak VO2 (mL/min/kg body weight) | 24.9 ± 7.1 | 14.7 ± 4.6 * | 13.5 ± 3.2 * | 0.5 | <0.0001 |
Mid regional pro atrial natriuretic peptide (pmol/L) | 73 ± 32 | 165 ± 102 * | 341 ± 165 * | p < 0.0001 | <0.0001 |
Mid regional pro Adrenomedullin (nmol/L) | 0.5 ± 0.1 | 0.9 ± 0.5 * | 1.1 ± 0.7 * | 0.08 | <0.0001 |
White Blood Cells (×109/L) | 6.6 ± 1.2 | 7.3 ± 1.6 | 7.0 ± 1.9 | 0.4 | |
High sensitive C-reactive Protein (µg/mL) | 2.4 ± 3.6 | 2.9 ± 2.7 | 6.5 ± 5.8 * | p < 0.05 | <0.006 |
Beta blocker | 84% | 94% | 0.3 | ||
Angiotensin converting enzyme (ACE) inhibitor | 74% | 56% | 0.4 | ||
AT1 receptor blocker (ARB) | 32% | 39% | 0.6 | ||
Mineralocorticoid receptor antagonist | 53% | 83% | 0.08 | ||
Loop diuretic | 63% | 89% | 0.2 | ||
Statin | 74% | 83% | 0.7 |
Gene Expression [RU +] | Control Subjects (n = 17) | All CHF Patients (n = 36) | ncCHF Patients (n = 19) | cCHF Patients (n = 18) | p-Value cCHF vs. ncCHF | ANOVA-p |
---|---|---|---|---|---|---|
STAT1 | 0.97 ± 0.76 | 1.30 ± 1.13 | 0.96 ± 0.90 | 1.67 ± 1.26 * | <0.03 | <0.05 |
STAT3 | 3.70 ± 2.49 | 4.40 ± 3.14 | 3.63 ± 3.03 | 5.20 ± 3.12 | <0.05 | 0.07 |
SOCS1 | 0.47 ± 0.30 | 0.88 ± 0.68 | 0.50 ± 0.32 | 1.22 ± 0.73 * | <0.0003 | <0.0002 |
SOCS3 | 1.0 ± 0.92 | 1.80 ± 2.80 | 0.90 ±1.46 | 2.51 ± 3.51 * | <0.01 | <0.03 |
TNF | 0.12 ± 0.10 | 0.20 ± 0.24 | 0.12 ± 0.14 | 0.28 ± 0.30 * | <0.004 | <0.009 |
IL10 | 0.002 ± 0.004 | 0.003 ± 0.005 | 0.002 ± 0.002 | 0.005 ± 0.006 * | <0.008 | <0.02 |
TGFB1 | 88.9 ± 63.8 | 85.6 ± 60.6 | 85.4 ± 74.3 | 83.4 ± 47.7 | 0.2 | 0.4 |
Control Subjects (n = 12) | All CHF Patients (19) | ncCHF Patients (n = 14) | cCHF Patients (n = 5) | All CHF Patients vs. Controls p-Value | |
---|---|---|---|---|---|
Stimulated tumor necrosis factor per blood cells [pg × 10−6] | 2.26 ± 1.18 | 4.41 ± 2.34 | 4.31 ± 2.30 | 4.64 ± 2.69 | 0.007 |
Stimulated interleukin 10 per blood cells [pg × 10−6] | 0.17 ± 0.12 | 0.38 ± 0.28 | 0.35 ± 0.24 | 0.43 ± 0.38 | 0.02 |
White blood Cells (×109/L) | 6.7 ± 1.1 | 7.6 ± 1.6 | 7.5 ± 1.6 | 8.0 ± 1.6 | 0.07 |
Red blood cells (×109/L) | 4.5 ± 0.4 | 4.4 ± 0.5 | 4.4 ± 0.5 | 4.2 ± 0.5 | 0.6 |
Blood thrombocytes (×109/L) | 228 ± 39 | 222 ± 85 | 232 ± 97 | 199 ± 48 | 0.6 |
Number (female) | 6 (6) | 15 (4) | 10 (4) | 5 (0) | 0.13 |
Age (years) | 66 ± 4 | 68 ± 9 | 67 ± 9 | 72 ± 10 | 0.3 |
NYHA class | 2.3 ± 0.5 | 2.1 ± 0.4 | 2.8 ± 0.4 | ||
Ejection Fraction (%) | 71 ± 7 | 31 ± 7 | 32 ± 6 | 28 ± 8 | |
Ischaemic aetiology | 14/19 | 10/14 | 4/5 | ||
BMI (kg/m2) | 28 ± 5 | 28 ± 5 | 29 ± 5 | 24 ± 2 | 0.8 |
Fat mass/height [kg/m] | 16.4 ± 6.3 | 14.7 ± 5.7 | 16.5 ± 5.0 | 9.8 ± 2.6 | 0.4 |
Fat-free mass/height [kg/m] | 29.2 ± 5.4 | 32.6 ± 6.0 | 33.6 ± 6.7 | 29.8 ± 1.9 | 0.13 |
Peak VO2 (mL/min/kg body weight) | 22.6 ± 4.2 | 15.0 ± 4.5 | 15.9 ± 4.3 | 12.1 ± 4.2 | <0.0001 |
Mid regional pro atrial natriuretic peptide (pmol/L) | 75 ± 35 | 176 ± 113 | 130 ± 68 | 304 ± 121 | 0.006 |
Mid regional pro Adrenomedullin (nmol/L) | 0.5 ± 0.8 | 0.8 ± 0.3 | 0.7 ± 0.3 | 1.0 ± 0.3 | 0.005 |
High sensitive C-reactive Protein (µg/mL) | 3.3 ± 4.0 | 3.7 ± 5.4 | 2.1 ± 2.0 | 8.2 ± 9.3 | 0.8 |
Beta blocker | 89% | 86% | 100% | ||
Angiotensin converting enzyme (ACE) inhibitor | 74% | 71% | 80% | ||
AT1 receptor blocker (ARB) | 32% | 36% | 20% | ||
Mineralocorticoid receptor antagonist | 68% | 64% | 80% | ||
Loop diuretic | 58% | 50% | 80% | ||
Statin | 74% | 71% | 80% |
Gene Expression | |||||
---|---|---|---|---|---|
STAT1 | STAT3 | SOCS1 | SOCS3 | ||
Controls | blood hsCRP levels | p = 0.4, r = 0.1 | p = 0.6, r = 0.1 | p = 0.5, r = 0.2 | p = 0.6, r = 0.2 |
blood IL-6 levels | p = 0.5, r = 0.2 | p = 0.6, r = 0.2 | p = 1.0, r = 0.01 | p = 0.4, r = 0.3 | |
TNF expression | p = 0.0005, r = 0.8 | p < 0.0001, r = 0.9 | p < 0.0001, r = 0.9 | p < 0.0001, r = 0.9 | |
IL-10 expression | p = 0.1, r = 0.4 | p = 0.051, r = 0.5 | p = 0.02, r = 0.6 | p < 0.0001, r = 0.9 | |
TGFβ1 expression | p < 0.0001, r = 0.8 | p < 0.0001, r = 1.0 | p < 0.0001, r = 0.8 | p < 0.0001, r = 0.9 | |
ncCHF | blood hsCRP levels | p = 0.8, r = 0.1 | p = 0.8, r = 0.1 | p = 0.14, r = 0.4 | p = 0.5, r = 0.2 |
blood IL-6 levels | p = 1.0, r = 0.01 | p = 0.7, r = 0.1 | p = 0.2, r = 0.4 | p = 0.6, r = 0.2 | |
TNF expression | p < 0.0001, r = 0.9 | p = 0.0002, r = 0.8 | p < 0.0001, r = 0.8 | p < 0.0001, r = 0.9 | |
IL-10 expression | p = 0.054, r = 0.5 | p = 0.1, r = 0.4 | p = 0.2, r = 0.3 | p < 0.0001, r = 0.9 | |
TGFβ1 expression | p = 0.001, r = 0.7 | p = 0.0002, r = 0.7 | p = 0.007, r = 0.6 | p = 0.0002, r = 0.7 | |
cCHF | blood hsCRP levels | p = 0.5, r = 0.2 | p = 0.3, r = 0.3 | p = 0.4, r = 0.3 | p = 0.8, r = 0.1 |
blood IL-6 levels | p = 0.2, r = 0.5 | p = 0.4, r = 0.3 | p = 0.3, r = 0.4 | p = 0.1, r = 0.6 | |
TNF expression | p = 0.4, r = 0.2 | p = 0.01, r = 0.6 | p = 0.4, r = 0.2 | p = 0.6, r = 0.1 | |
IL-10 expression | p = 0.5, r = 0.2 | p = 0.5, r = 0.2 | p = 0.5, r = 0.2 | p = 0.6, r = 0.1 | |
TGFβ1 expression | p = 0.06, r = 0.5 | p < 0.0001, r = 0.9 | p = 0.4, r = 0.2 | p = 0.9, r = 0.03 |
Control Subjects (n = 12) | ncCHF Patients (n = 10) | cCHF Patients (n = 5) | cCHF vs. ncCHF Patients p-Value | |
---|---|---|---|---|
Proteasome 20S subunit beta 2 | 1.0 ± 0.6 | 0.7 ± 0.2 | 0.9 ± 0.2 | 0.086 |
Calpain-1 catalytic subunit | 0.6 ± 0.4 | 0.7 ± 0.3 | 1.1 ± 0.5 | 0.086 |
Solute carrier family 2 member 4 | 1.1 ± 0.6 | 0.8 ± 0.4 | 1.3 ± 0.4 | <0.03 |
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Sandek, A.; Gertler, C.; Valentova, M.; Jauert, N.; Wallbach, M.; Doehner, W.; von Haehling, S.; Anker, S.D.; Fielitz, J.; Volk, H.-D. Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction. J. Clin. Med. 2024, 13, 733. https://doi.org/10.3390/jcm13030733
Sandek A, Gertler C, Valentova M, Jauert N, Wallbach M, Doehner W, von Haehling S, Anker SD, Fielitz J, Volk H-D. Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction. Journal of Clinical Medicine. 2024; 13(3):733. https://doi.org/10.3390/jcm13030733
Chicago/Turabian StyleSandek, Anja, Christoph Gertler, Miroslava Valentova, Nadja Jauert, Manuel Wallbach, Wolfram Doehner, Stephan von Haehling, Stefan D. Anker, Jens Fielitz, and Hans-Dieter Volk. 2024. "Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction" Journal of Clinical Medicine 13, no. 3: 733. https://doi.org/10.3390/jcm13030733