Clonal Hematopoiesis Mutations Are Present in Atherosclerotic Lesions in Peripheral Artery Disease
Abstract
:1. Introduction
2. Results
2.1. Patients and Tissue Sampling
2.2. CH Detection in PAD Patients
2.3. CH Detection in Whole Blood and Blood Sub-Populations
2.4. CH Detection in Atherosclerotic Lesions
2.5. CH Detection in Arterial Collaterals, Perivascular Fat and Subcutaneous Tissue
3. Discussion
Limitations
4. Methods and Materials
4.1. Patients
4.1.1. Study Cohort
4.1.2. Surgical Procedure and Follow-Up Visits
4.2. Sample Processing and Biobanking
4.3. Sequencing
4.4. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Libby, P.; Buring, J.E.; Badimon, L.; Hansson, G.K.; Deanfield, J.; Bittencourt, M.S.; Tokgözoğlu, L.; Lewis, E.F. Atherosclerosis. Nat. Rev. Dis. Prim. 2019, 5, 56. [Google Scholar] [CrossRef]
- Jaiswal, S.; Libby, P. Clonal haematopoiesis: Connecting ageing and inflammation in cardiovascular disease. Nat. Rev. Cardiol. 2020, 17, 137–144. [Google Scholar] [CrossRef]
- Jaiswal, S.; Natarajan, P.; Silver, A.J.; Gibson, C.J.; Bick, A.G.; Shvartz, E.; McConkey, M.; Gupta, N.; Gabriel, S.; Ardissino, D.; et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N. Engl. J. Med. 2017, 377, 111–121. [Google Scholar] [CrossRef]
- Jaiswal, S.; Fontanillas, P.; Flannick, J.; Manning, A.; Grauman, P.V.; Mar, B.G.; Lindsley, R.C.; Mermel, C.H.; Burtt, N.; Chavez, A.; et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014, 371, 2488–2498. [Google Scholar] [CrossRef] [Green Version]
- Stein, A.; Metzeler, K.; Kubasch, A.S.; Rommel, K.-P.; Desch, S.; Buettner, P.; Rosolowski, M.; Cross, M.; Platzbecker, U.; Thiele, H. Clonal hematopoiesis and cardiovascular disease: Deciphering interconnections. Basic Res. Cardiol. 2022, 117, 55. [Google Scholar] [CrossRef]
- Assmus, B.; Cremer, S.; Kirschbaum, K.; Culmann, D.; Kiefer, K.; Dorsheimer, L.; Rasper, T.; Abou-El-Ardat, K.; Herrmann, E.; Berkowitsch, A.; et al. Clonal haematopoiesis in chronic ischaemic heart failure: Prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. Eur. Heart J. 2021, 42, 257–265. [Google Scholar] [CrossRef]
- Mas-Peiro, S.; Hoffmann, J.; Fichtlscherer, S.; Dorsheimer, L.; Rieger, M.A.; Dimmeler, S.; Vasa-Nicotera, M.; Zeiher, A.M. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur. Heart J. 2020, 41, 933–939. [Google Scholar] [CrossRef] [Green Version]
- Aboyans, V.; Ricco, J.-B.; Bartelink, M.-L.E.L.; Björck, M.; Brodmann, M.; Cohnert, T.; Collet, J.-P.; Czerny, M.; de Carlo, M.; Debus, S.; et al. Editor’s Choice—2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur. J. Vasc. Endovasc. Surg. 2018, 55, 305–368. [Google Scholar] [CrossRef] [Green Version]
- Malgor, R.D.; Alahdab, F.; Alalahdab, F.; Elraiyah, T.A.; Rizvi, A.Z.; Lane, M.A.; Prokop, L.J.; Phung, O.J.; Farah, W.; Montori, V.M.; et al. A systematic review of treatment of intermittent claudication in the lower extremities. J. Vasc. Surg. 2015, 61, 54S–73S. [Google Scholar] [CrossRef] [Green Version]
- National Heart, Lung, Blood Institute; National Institute of Diabetes, Digestive, & Kidney Diseases (US). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. National Institutes of Health. Obes. Res. 1998, 6 (Suppl. S2), 51S–209S. [Google Scholar]
- Cosentino, F.; Grant, P.J.; Aboyans, V.; Bailey, C.J.; Ceriello, A.; Delgado, V.; Federici, M.; Filippatos, G.; Grobbee, D.E.; Hansen, T.B.; et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 2020, 41, 255–323. [Google Scholar] [CrossRef] [Green Version]
- Hollowell, J.G.; van Assendelft, O.W.; Gunter, E.W.; Lewis, B.G.; Najjar, M.; Pfeiffer, C. Hematological and iron-related analytes--reference data for persons aged 1 year and over: United States, 1988–1994. Vital Health Stat. 2005, 11, 1–156. [Google Scholar]
- Levin, A.; Stevens, P.E. Summary of Recommendation Statements. Kidney Int. Suppl. 2013, 3, 5–14. [Google Scholar] [CrossRef] [Green Version]
- Genovese, G.; Kähler, A.K.; Handsaker, R.E.; Lindberg, J.; Rose, S.A.; Bakhoum, S.F.; Chambert, K.; Mick, E.; Neale, B.M.; Fromer, M.; et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 2014, 371, 2477–2487. [Google Scholar] [CrossRef] [Green Version]
- Busque, L.; Patel, J.P.; Figueroa, M.E.; Vasanthakumar, A.; Provost, S.; Hamilou, Z.; Mollica, L.; Li, J.; Viale, A.; Heguy, A.; et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 2012, 44, 1179–1181. [Google Scholar] [CrossRef]
- Hecker, J.S.; Hartmann, L.; Rivière, J.; Buck, M.C.; van der Garde, M.; Rothenberg-Thurley, M.; Fischer, L.; Winter, S.; Ksienzyk, B.; Ziemann, F.; et al. CHIP and hips: Clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood 2021, 138, 1727–1732. [Google Scholar] [CrossRef]
- Böhme, M.; Desch, S.; Rosolowski, M.; Scholz, M.; Krohn, K.; Büttner, P.; Cross, M.; Kirchberg, J.; Rommel, K.-P.; Pöss, J.; et al. Impact of Clonal Hematopoiesis in Patients With Cardiogenic Shock Complicating Acute Myocardial Infarction. J. Am. Coll. Cardiol. 2022, 80, 1545–1556. [Google Scholar] [CrossRef]
- Fuster, J.J.; MacLauchlan, S.; Zuriaga, M.A.; Polackal, M.N.; Ostriker, A.C.; Chakraborty, R.; Wu, C.-L.; Sano, S.; Muralidharan, S.; Rius, C.; et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017, 355, 842–847. [Google Scholar] [CrossRef] [Green Version]
- Sano, S.; Oshima, K.; Wang, Y.; MacLauchlan, S.; Katanasaka, Y.; Sano, M.; Zuriaga, M.A.; Yoshiyama, M.; Goukassian, D.; Cooper, M.A.; et al. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J. Am. Coll. Cardiol. 2018, 71, 875–886. [Google Scholar] [CrossRef]
- Cook, E.K.; Luo, M.; Rauh, M.J. Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity. Exp. Hematol. 2020, 83, 85–94. [Google Scholar] [CrossRef] [Green Version]
- Abplanalp, W.T.; Cremer, S.; John, D.; Hoffmann, J.; Schuhmacher, B.; Merten, M.; Rieger, M.A.; Vasa-Nicotera, M.; Zeiher, A.M.; Dimmeler, S. Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. Circ. Res. 2021, 128, 216–228. [Google Scholar] [CrossRef] [PubMed]
- Arends, C.M.; Weiss, M.; Christen, F.; Eulenberg-Gustavus, C.; Rousselle, A.; Kettritz, R.; Eckardt, K.-U.; Chan, W.; Hoyer, K.; Frick, M.; et al. Clonal hematopoiesis in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Haematologica 2020, 105, e264–e267. [Google Scholar] [CrossRef] [Green Version]
- Troidl, K.; Schaper, W. Arteriogenesis versus angiogenesis in peripheral artery disease. Diabetes Metab. Res. Rev. 2012, 28 (Suppl. S1), 27–29. [Google Scholar] [CrossRef] [PubMed]
- Bitterli, L.; Afan, S.; Bühler, S.; DiSanto, S.; Zwahlen, M.; Schmidlin, K.; Yang, Z.; Baumgartner, I.; Diehm, N.; Kalka, C. Endothelial progenitor cells as a biological marker of peripheral artery disease. Vasc. Med. 2016, 21, 3–11. [Google Scholar] [CrossRef] [Green Version]
- Britton, K.A.; Fox, C.S. Perivascular adipose tissue and vascular disease. Clin. Lipidol. 2011, 6, 79–91. [Google Scholar] [CrossRef] [Green Version]
- Haase, J.; Weyer, U.; Immig, K.; Klöting, N.; Blüher, M.; Eilers, J.; Bechmann, I.; Gericke, M. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia 2014, 57, 562–571. [Google Scholar] [CrossRef]
- Fuster, J.J.; Zuriaga, M.A.; Zorita, V.; MacLauchlan, S.; Polackal, M.N.; Viana-Huete, V.; Ferrer-Pérez, A.; Matesanz, N.; Herrero-Cervera, A.; Sano, S.; et al. TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity. Cell Rep. 2020, 33, 108326. [Google Scholar] [CrossRef]
- Kadoglou, N.P.E.; Korakas, E.; Karkos, C.; Maratou, E.; Kanonidis, I.; Plotas, P.; Papanas, N.; Moutsatsou, P.; Ikonomidis, I.; Lambadiari, V. The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization. Cardiovasc. Diabetol. 2021, 20, 221. [Google Scholar] [CrossRef]
- Lloyd-Jones, D.M.; Leip, E.P.; Larson, M.G.; D’Agostino, R.B.; Beiser, A.; Wilson, P.W.F.; Wolf, P.A.; Levy, D. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006, 113, 791–798. [Google Scholar] [CrossRef]
- Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.; Anker, S.D.; et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017, 377, 1119–1131. [Google Scholar] [CrossRef]
- Dinarello, C.A.; Simon, A.; van der Meer, J.W.M. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 2012, 11, 633–652. [Google Scholar] [CrossRef] [Green Version]
- Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front. Immunol. 2019, 10, 2538. [Google Scholar] [CrossRef] [Green Version]
- Steensma, D.P. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv. 2018, 2, 3404–3410. [Google Scholar] [CrossRef]
- Papa, V.; Marracino, L.; Fortini, F.; Rizzo, P.; Campo, G.; Vaccarezza, M.; Vieceli Dalla Sega, F. Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review. J. Clin. Med. 2020, 9, 2480. [Google Scholar] [CrossRef]
- Rocha-Singh, K.J.; Zeller, T.; Jaff, M.R. Peripheral arterial calcification: Prevalence, mechanism, detection, and clinical implications. Catheter. Cardiovasc. Interv. 2014, 83, E212–E220. [Google Scholar] [CrossRef] [Green Version]
- Stokowy, T.; Eszlinger, M.; Świerniak, M.; Fujarewicz, K.; Jarząb, B.; Paschke, R.; Krohn, K. Analysis options for high-throughput sequencing in miRNA expression profiling. BMC Res. Notes 2014, 7, 144. [Google Scholar] [CrossRef] [Green Version]
- Li, H.; Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009, 25, 1754–1760. [Google Scholar] [CrossRef] [Green Version]
- Lai, Z.; Markovets, A.; Ahdesmaki, M.; Chapman, B.; Hofmann, O.; McEwen, R.; Johnson, J.; Dougherty, B.; Barrett, J.C.; Dry, J.R. VarDict: A novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016, 44, e108. [Google Scholar] [CrossRef] [Green Version]
- Wang, K.; Li, M.; Hakonarson, H. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010, 38, e164. [Google Scholar] [CrossRef]
Total 31 (100%) | CH 14 (45%) | No CH 17 (55%) | p-Value | |
---|---|---|---|---|
Male | 26 (84%) | 11 (79%) | 15 (88%) | 0.636 |
Age (years) | 68 (60–84) | 68 (57–88) | 68 (61–84) | 0.953 |
Hypertension | 28 (90%) | 14 (100%) | 14 (82%) | 0.232 |
BP systolic (mmHg) | 144 (123–193) | 141 (119–191) | 149 (122–198) | 0.891 |
BP diastolic (mmHg) | 74 (57–89) | 71 (54–92) | 75 (61–88) | 0.336 |
Diabetes mellitus | 14 (45%) | 6 (43%) | 8 (47%) | 1.000 |
Glucose (mmol/mL) | 5.9 (4.7–11.4) | 5.9 (4.9–19.1) | 5.9 (4.6–9.9) | 0.739 |
HbA1c (%) | 42.2 (34.7–74.8) | 42.7 (33.5–82.5) | 41.3 (34.9–65.9) | 0.720 |
HbA1c (mmol/mL) | 7.7 (5.2–9.3) | 7.9 (4.6–9.3) | 7.7 (5.1–9.5) | 0.830 |
Coronary artery disease | 10 (32%) | 5 (36%) | 5 (29%) | 1.000 |
Smoker | 21 (68%) | 11 (79%) | 10 (59%) | 0.280 |
COPD | 6 (19%) | 1 (7%) | 5 (29%) | 0.185 |
Obesity (BMI > 30 kg/m2) [10] | 6 (19%) | 2 (14%) | 4 (24%) | 0.664 |
Body mass index (kg/m2) | 24.6 (20.9–31.2) | 25.5 (19.2–30.8) | 24.6 (21.8–36.2) | 0.769 |
Hyperlipoproteinemia [11] | 25 (81%) | 13 (93%) | 12 (71%) | 0.185 |
Total Cholesterol (mmol/L) | 3.9 (3.0–5.6) | 3.8 (2.8–6.9) | 4 (2.9–5.3) | 0.560 |
LDL-Cholesterol (mmol/L) | 2.3 (1.5–4.0) | 1.9 (1.2–5.3) | 2.4 (1.6–3.3) | 0.212 |
HDL-Cholesterol (mmol/L) | 1.3 (0.8–2.1) | 1.2 (0.8–2.2) | 1.3 (0.9–2.0) | 0.527 |
Triglycerides (mmol/L) | 1.5 (0.8–2.7) | 1.7 (0.8–3.3) | 1.5 (0.9–2.5) | 0.432 |
Anemia [12] (Hb < 11.8 g/dL) | 11 (35%) | 5 (36%) | 6 (35%) | 1.000 |
Hb (g/dL) | 12.3 (8.4–14.8) | 12.6 (7.4–14.8) | 12.3 (8.2–15.3) | 0.860 |
RDW % | 13.9 (12.6–18.2) | 13.8 (12.2–16.8) | 14.4 (12.6–18.9) | 0.544 |
Renal Insufficiency (GFR < 60) [13] | 12 (39%) | 3 (21%) | 9 (53%) | 0.138 |
Creatinine (µmol/L) | 87 (60.6–142.2) | 83.5 (56–144) | 109 (69.2–146.4) | 0.138 |
GFR (mL/min/1.73 m²) | 66 (36–99.8) | 72 (33.5–102.5) | 59 (34–94.2) | 0.100 |
CRP (mg/L) | 7.3 (1.1–166.9) | 6.2 (0.6–177.4) | 7.4 (1.8–137.5) | 0.739 |
Medication | ||||
Antiplatelet therapy | 26 (84%) | 11 (79%) | 15 (88%) | 0.636 |
Oral anticoagulation | 3 (10%) | 2 (14%) | 1 (6%) | 0.576 |
Statins | 22 (71%) | 12 (86%) | 10 (59%) | 0.132 |
Clinical Presentation of PAD | ||||
Claudication | 13 (42%) | 5 (36%) | 8 (47%) | 0.717 |
CLTI | 18 (58%) | 9 (64%) | 9 (53%) | |
Morphology of Arterial lesion | ||||
Stenosis | 25 (81%) | 9 (64%) | 16 (94%) | 0.067 |
Occlusion | 6 (19%) | 5 (36%) | 1 (6%) | |
Severe calcification of lesion (PACSS) | 18 (58%) | 10 (71%) | 8 (47%) | 0.275 |
Re-do surgical procedure | 6 (19%) | 3 (21%) | 3 (18%) | 1.00 |
Blood | Tissue | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
IP | Gene | Base Position | PB | CD14+ | CD34+ | Residuals | Plaque | Collateral | ST | PVT |
n = 17 | n = 11 | n = 8 | n = 10 | n = 15 | n = 10 | n = 11 | n = 11 | |||
1 | TET2 | 105237044 | 0.0246 | 0.0967 | 0.1572 | 0.0558 | 0.0204 | 0.0058 | 0.0192 | 0.0188 |
105235051 | 0.0000 | 0.0074 | 0.0000 | 0.0309 | 0.0000 | 0.0000 | 0.0023 | 0.0000 | ||
2 | TET2 | 105259638 | 0.0395 | 0.1976 | 0.0476 | 0.1294 | 0.0000 | 0.0134 | 0.0214 | 0.0220 |
3 | DNMT3A | 25234307 | 0.0416 | 0.1452 | 0.0105 | 0.1009 | 0.0484 | 0.0092 | 0.0129 | 0.0153 |
4 | DNMT3A | 25240379 | 0.0653 | 0.0637 | l.c. | 0.0000 | 0.0130 | 0.0106 | 0.0305 | 0.0350 |
7 | DNMT3A | 25240699 | 0.0288 | n.a. | n.a. | n.a. | 0.0124 | 0.0032 * | 0.0027 * | 0.0037 * |
8 | DNMT3A | 25246671 | 0.0267 | 0.0255 | 0.0000 | 0.0322 | 0.0053 | 0.0090 | 0.0096 | 0.0082 |
TET2 | 105259678 | 0.0032 * | 0.0167 | 0.1261 | 0.0016 * | 0.0000 | 0.0000 | 0.0003 * | 0.0010 * | |
9 | ASXL1 | 32434825 | 0.0169 | l.c. | l.c. | l.c. | 0.0121 | 0.0044 * | 0.0000 | 0.0029 * |
TET2 | 105275568 | 0.0004 * | 0.0005 * | 0.0603 | l.c. | 0.0010 * | 0.0005 * | 0.0000 | 0.0002 * | |
10 | DNMT3A | 25244175 | 0.0266 | n.a. | n.a. | n.a. | 0.0065 * | 0.0045 * | 0.0027 * | 0.0124 |
TET2 | 105236178 | 0.0527 | n.a. | n.a. | n.a. | 0.0395 | 0.0218 | 0.0129 | 0.0407 | |
105275086 | 0.0352 | n.a. | n.a. | n.a. | 0.0503 | 0.0442 | 0.0119 | 0.0301 | ||
15 | TET2 | 105235270 | 0.0120 | 0.0221 | 0.0153 | 0.0051 | 0.0041 | 0.0029 | 0.0079 | 0.0019 |
19 | TET2 | 105243673 | 0.2022 | 0.2648 | 0.2576 | 0.1973 | 0.0582 | 0.0916 | 0.0577 | 0.0465 |
21 | TET2 | 105237312 | 0.0253 | 0.0159 | 0.0526 | 0.0168 | 0.0186 | 0.0014 * | 0.0087 * | 0.0020 * |
25 | DNMT3A | 25234323 | 0.0423 | n.a. | n.a. | n.a. | 0.0037 | 0.0043 | 0.0063 | 0.0048 |
26 | TET2 | 105235103 | 0.0192 | n.a. | n.a. | n.a. | 0.0175 | 0.0031 * | 0.0047 * | 0.0019 * |
28 | DNMT3A | 25240699 | 0.0342 | 0.0181 | l.c. | 0.0203 | 0.0438 | 0.0026 * | 0.0039 * | 0.0029 * |
25246755 | 0.0132 | 0.0085 * | 0.0080 * | 0.0116 | 0.0271 | 0.0001 * | 0.0010 * | 0.0047 * |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Büttner, P.; Böttner, J.; Krohn, K.; Baber, R.; Platzbecker, U.; Cross, M.; Desch, S.; Thiele, H.; Steiner, S.; Scheinert, D.; et al. Clonal Hematopoiesis Mutations Are Present in Atherosclerotic Lesions in Peripheral Artery Disease. Int. J. Mol. Sci. 2023, 24, 3962. https://doi.org/10.3390/ijms24043962
Büttner P, Böttner J, Krohn K, Baber R, Platzbecker U, Cross M, Desch S, Thiele H, Steiner S, Scheinert D, et al. Clonal Hematopoiesis Mutations Are Present in Atherosclerotic Lesions in Peripheral Artery Disease. International Journal of Molecular Sciences. 2023; 24(4):3962. https://doi.org/10.3390/ijms24043962
Chicago/Turabian StyleBüttner, Petra, Julia Böttner, Knut Krohn, Ronny Baber, Uwe Platzbecker, Michael Cross, Steffen Desch, Holger Thiele, Sabine Steiner, Dierk Scheinert, and et al. 2023. "Clonal Hematopoiesis Mutations Are Present in Atherosclerotic Lesions in Peripheral Artery Disease" International Journal of Molecular Sciences 24, no. 4: 3962. https://doi.org/10.3390/ijms24043962