The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Informed Consent and Recruitment
2.2. Medical Screening through Medical History and Physical Examination
2.3. Inclusion/Exclusion/Withdrawal Criteria
2.3.1. Inclusion Criteria:
- –
- Age > 18 years
- –
- Diagnosis of CLTI: presence of trophic lesions and/or rest pain plus ABI less than 0.4 and/or AP < 50 mmHg or plain or damped PPG curves or toe pressure (TP) < 30 mmHg [31].
- –
- Failure of a previous attempt of revascularization; patients considered at high risk of failure or at high risk of surgical complications during the procedure or in poor condition for surgery.
- –
- High risk of limb loss.
2.3.2. Exclusion Criteria
- –
- Pregnancy
- –
- Legally incapacitated.
- –
- Current cancer or during the last 5 years before the study.
- –
- Current pneumonia or sepsis or severe foot infection.
- –
- Untreated hypothyroidism and/or hypocortisolism.
2.3.3. Withdrawal Criteria
- –
- Patient’s own request.
- –
- Decision of the physician due to adverse reactions supposedly secondary to the drug.
- –
- Pneumonia/sepsis during the period of treatment.
- –
- Increase in levels of IGF-1 more than 2 standard deviations.
- –
- Increase in tumor markers.
2.4. Measurements
2.4.1. ABI and AP
2.4.2. Inflammatory and Vascular Circulating Biomarkers
2.4.3. Skeletal Muscle Samples
2.4.4. Real-Time PCR (RT-qPCR)
2.5. Statistical Analysis
3. Results
3.1. General Characteristics
3.2. Hemodynamic Parameters and Plasma Biomarkers
3.3. Basal mRNA Expression
3.4. Basal and Final mRNA Expression
3.5. Plasma Biomarkers and mRNA Expression
3.6. Mortality in the GHAS Trial
3.7. Statistical Study: Measures of Association of Variables
3.7.1. Univariate Analysis
3.7.2. Multivariate Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Sequence | Amplification Size | Annealing Tª |
---|---|---|---|
TBP | Fw: 5′-GCCCGAAACGCCGAATAT-3′ | 67 bp | 60 °C |
Rv: 5′-TTCGTGGCTCTCTTATCCTCATG-3′ | |||
Pb: 5′-TCCCAAGCGGTTTGCTGCGGTA-3′ | |||
VEGFA | Applied Biosystems: Hs00900055_m1 | 67 bp | 60 °C |
IGF1 | Applied Biosystems: Hs01547656_m1 | 68 bp | 60 °C |
NOS3 | Applied Biosystems: Hs01574665_m1 | 86 bp | 60 °C |
MSTN | Applied Biosystems: Hs00976237_m1 | 69 bp | 60 °C |
NOX4 | Applied Biosystems: Hs01379108_m1 | 64 bp | 60 °C |
MYOG | Applied Biosystems: Hs01072232_m1 | 76 bp | 60 °C |
KDR | Applied Biosystems: Hs00911700_m1 | 83 bp | 60 °C |
IL6 | Applied Biosystems: Hs00174131_m1 | 95 bp | 60 °C |
TNF | Applied Biosystems: Hs00174128_m1 | 80 bp | 60 °C |
TG | HDLc | LDLc | ABI | AP | Age | IGF-I | IGFBP3 | TNF-α | hsCRP | B2-M | CyC | HbA1C | NLR | Fibrin. | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | 164.1 | 45.5 | 97.9 | 0.23 | 38.6 | 71.5 | 134.9 | 3.06 | 10.66 | 1.6 | 0.4 | 1.45 | 6.5 | 3.5 | 560.21 |
Median | 132.5 | 41 | 100 | 0.2 | 31.5 | 72 | 125 | 2.9 | 10 | 0.95 | 0.3 | 1.2 | 6.3 | 2.6 | 505 |
SD | 88.1 | 15.1 | 32.1 | 0.23 | 37.02 | 12.4 | 53.2 | 1.1 | 4.9 | 2.2 | 0.3 | 0.9 | 1.02 | 2.8 | 128.51 |
Mín. | 46 | 29 | 36 | 0 | 0 | 49 | 38 | 0.5 | 4 | 0.1 | 0.14 | 0.55 | 5.1 | 0.4 | 403 |
Max. | 412 | 97 | 161 | 0.93 | 140 | 93 | 275 | 5.2 | 27 | 9.1 | 1.1 | 3.8 | 8.9 | 16.3 | 853 |
Plasma Marker | GH | Placebo | |||||
---|---|---|---|---|---|---|---|
Obs. | Mean | SD | Obs. | Mean | SD | p-Value | |
TNF-α (Basal) | 16 | 12.35 | 5.2 | 16 | 8.78 | 3.9 | 0.0184 * |
TNF-α (Final) | 15 | 10.93 | 5.12 | 14 | 8.04 | 3.6 | 0.0464 * |
hsCRP (Basal) | 18 | 2.07 | 2.86 | 16 | 0.79 | 0.70 | 0.0454 * |
hsCRP (Final) | 17 | 1.1 | 1.38 | 14 | 3.42 | 7.51 | 0.2188 |
B2M (Basal) | 7 | 0.47 | 0.27 | 16 | 0.22 | 0.08 | 0.1269 |
B2M (Final) | 8 | 0.56 | 0.51 | 14 | 0.21 | 0.12 | 0.3894 |
CyC (Basal) | 7 | 1.75 | 0.93 | 4 | 0.76 | 0.17 | 0.035 * |
CyC (Final) | 8 | 1.71 | 1.12 | 2 | 0.8 | 0.14 | 0.3054 |
Plasma Marker/ Gene | NOS3 (Basal) | NOS3 (Final) | VEGFA (Basal) | VEGFA (Final) | TNF (Basal) | |||||
---|---|---|---|---|---|---|---|---|---|---|
Both | Placebo | GH | GH | Both | GH | Placebo | Both | GH | ||
TNF-α (Basal) | r = −0.49 p = 0.015 | r = −0.78 p = 0.0064 | r = −0.432 p = 0.039 | r = −0.773 p = 0.005 | r = 0.588 p = 0.035 * | |||||
TNF-α (Final) | r = 0.866 p = 0.012 | |||||||||
TNF-α > 8.1 (Basal) | r = 0.802, p = 0.001 * | |||||||||
hsCRP (Basal) | r = 0.74 p = 0.009 | r = −0.632 p = 0.005 | r = −0.775 p = 0.041 | |||||||
hsCRP > 0.5 (Basal) | r = −0.693 p = 0.018 | r = −0.546 p = 0.019 | r = −0.866 p = 0.012 | |||||||
DM | hsCRP > 0.5 (Final) | r = −0.711 p = 0.021 * | r = −0.866, p = 0.012 | |||||||
NLR > 3 (Basal) | r = −0.645 p = 0.032 | |||||||||
NLR > 5 (Basal) | r = −0.69 p = 0.018 | |||||||||
HbA1C (Basal) | r = 0.728 p = 0.026 | |||||||||
HbA1C (Final) | r = −0.975 p = 0.005 | |||||||||
Non-DM | hsCRP (Basal) | r = −0.9 p = 0.037 | ||||||||
LDLc | r = −0.827 p = 0.002 |
Plasma Marker/ Gene | IGF-I (Basal) | IGF-I (Final) | MSTN (Basal) | MSTN (Final) | MYOG (Final) | KDR (Final) | NOX4 (Basal) | NOX4 (Final) | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Both | Placebo | GH | Both | GH | GH | Placebo | Placebo | Both | GH | ||
TNF-α (Basal) | r = 0.519 p = 0.011 | r = 0.821 p = 0.0341 | r = 0.8 p = 0.023 * | r = 0.305 p = 0.037 | |||||||
TNF-α > 8.1 (Basal) | r = 0.598 p = 0.003 | r = 0.586 p = 0.011 | |||||||||
hsCRP (Basal) | r = −0.648 p = 0.031 | ||||||||||
hsCRP (Final) | r = −0.691 p = 0.027 | r = 0.709 p = 0.003 * | |||||||||
DM | hsCRP > 0.5 (Final) | r = 0.773 p = 0.001 * | |||||||||
NLR > 3 (Basal) | r = −0.662 p = 0.019 | ||||||||||
NLR > 5 (Basal) | r = −0.857 p = 0.014 * | ||||||||||
HbA1C (Basal) | r = 0.597 p = 0.019 | ||||||||||
Non-DM | TNF-α (Basal) | r = 0.645 p = 0.032 | |||||||||
TNF-α > 8.1 (Basal) | r = 0.717 p = 0.009 | ||||||||||
hsCRP (Basal) | r = 0.9 p = 0.037 | r = −0.847 p = 0.016 |
0–2 Months | Mortality | p-Value | 2–12 Months | Mortality | p-Value | |
---|---|---|---|---|---|---|
Placebo | 0/16 | 0% | 2/16 | 12.5% | ||
GH | 1/18 | 5.5% | 0.42 | 5/17 | 29.4% | 0.23 |
Cumulative | 5.5% | 47.4% |
Predictors of Mortality in the GHAS Trial | |||
---|---|---|---|
p-Value | OR | CI (95%) | |
NLR ≥ 3 (Basal) | 0.019 | 6.9 | 0.71–353.7 |
TNF-α ≥ 8.1 (Basal) | 0.0487 | 2.5 | 0.23–136.6 |
COPD | 0.042 | 5.8 | 0.84–40.7 |
ASA4-ASA3 | 0.0119 | 15.7 | 0.87–284.9 |
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Caicedo, D.; Alvarez, C.V.; Perez-Romero, S.; Devesa, J. The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis. Biomedicines 2022, 10, 489. https://doi.org/10.3390/biomedicines10020489
Caicedo D, Alvarez CV, Perez-Romero S, Devesa J. The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis. Biomedicines. 2022; 10(2):489. https://doi.org/10.3390/biomedicines10020489
Chicago/Turabian StyleCaicedo, Diego, Clara V. Alvarez, Sihara Perez-Romero, and Jesús Devesa. 2022. "The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis" Biomedicines 10, no. 2: 489. https://doi.org/10.3390/biomedicines10020489