EC Neurology

Research Article Volume 15 Issue 6 - 2023

Increased TGF-β as a Biomarker of Connective Tissue Dysplasia in Cervical Artery Dissection

Kalashnikova LA*, Danilova MS, Shabalina AA, Gubanova MV, Shamtieva KV, Dreval MV and Dobrynina LA

3rd Neurological Department, Research Center of Neurology, Moscow, Russia

*Corresponding Author: Kalashnikova LA, 3rd Neurological Department, Research Center of Neurology, Moscow, Russia.
Received: April 26, 2023; Published: May 22, 2023

Introduction: The cause of cervical artery dissection (CeAD), one of the main causes of ischemic stroke (IS) at a young age, is the arterial wall weakness. Its morphological changes have been poorly studied, because the lethal outcome in these cases is rare. It is assumed that the weakness of the arterial wall is associated with connective tissue disorder. To assess this assumption the study of transforming growth factor beta (TGF-β), a cytokine that regulates the homeostasis of tissues, including connective tissue, can be helpful as its level increases in the hereditary connective tissue diseases.

Aim of the Study: The aim was to study TGF-β in patients with CeAD.

Materials and Methods: TGF-β in serum blood was studied by enzyme immunoassay in 74 of 336 patients with CeAD observed at the Research Center of Neurology (Moscow) from 2000 to 2021. The average patient’s age at the time of the study was 41.6 ± 9.8 years; the proportion of women - 51%. TGF-β was studied in the first month of the disease (9 patients), for 2-3 months (12 patients) and during the late period (mean - 4.3 ± 5.03 years) (53 patients). The control group consisted of 20 healthy volunteers, comparable in gender and age. Dissection occurred in ICA (42 patients), VA (29 patients), ICA+VA (3 patients) and involved 1 artery (58 patients) or 2 - 3 arteries (16 patients). Clinical manifestations included IS (49 patients), isolated cervical-cephalic pain (23), lower cranial nerve palsy (2). Pathological CeAD tortuosity was detected by angiography in 13 patients, and a dissecting aneurysm in 15 patients.

Results: TGF-β1 and TGF-β2 were elevated in patients with CeAD compared with the control: TGF-β1 - 4990 [3950; 7900] pg/ml vs. 3645 [3230; 4250] pg/ml, p = 0.001; TGF-β2 - 6120 [4680; 7900] pg/ml vs. 3155 [2605; 4605] pg/ml, p = 0.001. The highest TGF-β1 and TGF-β2 levels were noted at 2-3 months of the disease. There was no correlation between the TGF-β level and various clinical and angiographic parameters.

Conclusion: Increased TGF-β level confirms that patients with CeAD have connective tissue disorder that underlies the arterial wall weakness. A higher TGF-β level at 2-3 months of CeAD seems to be connected with an active reparative process in arterial wall after dissection. TGF-β can be used as a biomarker of connective tissue dysplasia in patients with CeAD.

Keywords: TGF-β; Connective Tissue Dysplasia; Dissection; Ischemic Stroke; Young Age

  1. Kalashnikova LA and Dobrynina LA. “Dissection of brain arteries: ischemic stroke and other clinical manifestations”. M.: Izd-vo “Vako” (2013): 208.
  2. Dobrynina LA., et al. “Causes of ischemic stroke in young adults. S.S”. Korsakov Journal of Neurology and Psychiatry3 (2011): 4-8.
  3. Kalashnikova LA and Dobrynina LA. “Ischemic stroke in young adults. S.S”. Korsakov Journal of Neurology and Psychiatry8 (2017): 3-12.
  4. Lee VH., et al. “Incidence and outcome of cervical artery dissection: a population-based study”. Neurology10 (2006): 1809-1812.
  5. Putaala J., et al. “Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry”. Stroke4 (2009): 1195-1203.
  6. Debette S and Leys D. “Cervical-artery dissections: predisposing factors, diagnosis, and outcome”. Lancet Neurology7 (2009): 668-678.
  7. Debette S. “Pathophysiology and risk factors of cervical artery dissection: what have we learnt from large hospital-based cohorts?” Current Opinion in Neurology1 (2014): 20-28.
  8. De Bray JM., et al. “Fibromuscular dysplasia may herald symptomatic recurrence of cervical artery dissection”. Cerebrovascular Diseases5-6 (2007): 448-452.
  9. Arnold M., et al. “Postpartum cervicocephalic artery dissection”. Stroke8 (2008): 2377-2379.
  10. Kalashnikova LA., et al. “Lоwer cranial nerve palsiаs in the internаl carotid artery dissection”. Annals of Clinical and Experimental Neurology 1 (2008): 22-27.
  11. Kalashnikova LA., et al. “Ischemic stroke in young age due to dissection of intracranial carotid artery and its branches (clinical and morphological study)”. Annals of Clinical and Experimental Neurology1 (2009): 18-24.
  12. Kalashnikova LA., et al. “Dissection of the internal carotid artery as a cause of severe ischemic stroke with a fatal outcome (clinical and pathomorphological study)”. Zhurnal nevrologii i psihiatrii im. S.S. Korsakova.12 (2015): 34-38.
  13. Kalashnikova LA., et al. “Intimal rupture of the displastic middle cerebral artery wall complicated by thrombosis and fatal ischemic stroke”. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova3-2 (2018): 9-14.
  14. Brandt T., et al. “Pathogenesis of cervical artery dissections: Association with connective tissue abnormalities”. Neurology 57 (2001): 24-30.
  15. Giossi A., et al. “Connective tissue anomalies in patients with spontaneous cervical artery dissection”. Neurology22 (2014): 2032-2037.
  16. Gubanova MV., et al. “Markers of connective tissue dysplasia in dissection of the main arteries of the head and provoking factors of dissection”. Annaly klinicheskoj i jeksperimental'noj nevrologii4 (2017): 19-28.
  17. Debette S., et al. “CADISP-plus consortium. Familial occurrence and heritable connective tissue disorders in cervical artery dissection”. Neurology22 (2014): 2023-2031.
  18. Kalashnikova LA., et al. “Mitochondrial arteriopathy as a cause of spontaneous dissection of cerebral arteries”. Zh Nevrol Psikhiatr Im S S Korsakova4-2 (2010): 3-11.
  19. Kalashnikova LA., et al. “Ultrastructural changes of skin arteries in patients with spontaneous cerebral artery dissection”. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova7 (2011): 54-60.
  20. Sakharova AV., et al. “Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessels in a patient with cerebral artery dissection associated with MELAS syndrome”. Arkhiv Patologii2 (2010): 51-56.
  21. Tay SH., et al. “Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes”. Archives of Neurology2 (2006): 281-283.
  22. McEntee CP., et al. “Regulation of barrier immunity and homeostasis by integrin-mediated transforming growth factor β activation”. Immunology2 (2020): 139-148.
  23. Tzavlaki K and Moustakas A. “TGF-β Signaling”. Biomolecules3 (2020): 487.
  24. Nabel EG., et al. “Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia”. Proceedings of the National Academy of Sciences of the United States of America22 (1993): 10759-10763.
  25. Morikawa M., et al. “TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology”. Cold Spring Harbor Perspectives in Biology5 (2016): a021873.
  26. Lichtman MK., et al. “Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis”. Wound Repair and Regeneration2 (2016): 215-222.
  27. Benke K., et al. “Loeys-Dietz syndrome”. Advances in Experimental Medicine and Biology 802 (2014): 95-105.
  28. Wagner AH., et al. “Marfan syndrome: A therapeutic challenge for long-term care”. Biochemical Pharmacology 164 (2019): 53-63.
  29. Mallat Z., et al. “The Pathogenic Transforming Growth Factor-β Overdrive Hypothesis in Aortic Aneurysms and Dissections: A Mirage?” Circulation Research11 (2017): 1718-1720.
  30. Zeigler SM., et al. “Pathophysiology and Pathogenesis of Marfan Syndrome”. Advances in Experimental Medicine and Biology 1348 (2021): 185-206.
  31. Ganesh SK., et al. “Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features”. The FASEB Journal8 (2014): 3313-3324.
  32. Pezzini A., et al. “Mutations in TGFBR2 gene cause spontaneous cervical artery dissection”. Journal of Neurology, Neurosurgery, and Psychiatry12 (2011): 1372-1374.
  33. Robertson JJ and Koyfman A. “Cervical Artery Dissections: A Review”. Journal of Emergency Medicine5 (2016): 508-518.
  34. Kalashnikova LA., et al. “Internal carotid and vertebral artery dissection: morphology, pathophysiology and provoking factors”. Bulletin of RSMU 5 (2019): 78-85.
  35. Kloss M., et al. “Recurrence of cervical artery dissection: An underestimated risk”. Neurology16 (2018): e1372-e1378.
  36. Kalashnikova LA., et al. “Internal carotid and vertebral artery dissection: an approach to patient management”. Annals of Clinical and Experimental Neurology1 (2021): 5-12.
  37. Pakyari M., et al. “Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing”. Advances in Wound Care5 (2013): 215-224.
  38. Gubanova MV., et al. “Fibromuscular dysplasia and its neurological manifestations”. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova11 (2020): 116-123.
  39. Bonacina S., et al. “Spontaneous cervical artery dissection and fibromuscular dysplasia: Epidemiologic and biologic evidence of a mutual relationship”. Trends in Cardiovascular Medicine2 (2022): 103-109.

Kalashnikova LA., et al. “Increased TGF-β as a Biomarker of Connective Tissue Dysplasia in Cervical Artery Dissection”. EC Neurology  15.6 (2023): 45-51.