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Ascending Aortic Dilatation in Athletes with Thoracic Outlet Syndrome and the Therapeutic Role of Telmisartan

  • Writer: Graham Exelby
    Graham Exelby
  • Sep 6
  • 6 min read

Dr Graham Exelby September 2025

Background: I have been involved in a long term longitudinal study of this problem, initially comparing ARBs of different types to calcium blockers and statins. Completing the Long COVID hypothesis provided the last pieces of the puzzle, where Telmisartan provides the main anchor, which may be augmented by Zinzino, a high level Omega 3 and fenofibrate. Peptides anecdotally appear to provide repair, but until we obtain formal research approvals, they remain essentially banned. I do see them being used, but often incorrectly, complicated by the number that are available, and unless combined with targetted metabolic assessment and ideally DNA, they are unable to achieve their potential. I share this up to date with you.


Abstract

Ascending aortic dilatation (AAD) is increasingly observed in overhead athletes, often in the absence of heritable aortopathies. This paper proposes an updated mechano-neuroinflammatory hypothesis incorporating thoracic outlet syndrome (TOS), sympathetic overactivation, regional perivascular hypoxia, and inflammatory remodelling via the RAGE–CCL2–STAT3 axis. We extend prior models by integrating the therapeutic potential of telmisartan, an angiotensin II type 1 receptor (AT1R) blocker with PPAR-γ agonist properties, shown to dampen this feed-forward inflammatory loop.


Telmisartan may attenuate sympathetic overdrive, stabilize vasa vasorum perfusion, inhibit vascular fibrosis, and modulate astroglial activation—key to preventing ECM degradation and elastin loss within the aortic wall. This revised model aligns with recent data from Long COVID research, implicating the same molecular and neurovascular pathways in vascular dysregulation. We advocate for biomarker-guided trials using telmisartan in athletic populations with TOS-associated dysautonomia and early aortic dilatation.


Introduction

Ascending aortic dilatation—typically defined as aortic diameter >40 mm in men or >36 mm in women (indexed to body surface area)—has been increasingly reported in overhead athletes (e.g., swimmers, rowers, cricket bowlers, baseball pitchers) lacking syndromic features of Marfan, Ehlers-Danlos, or bicuspid aortic valve disease.(1,2,3) Studies report prevalence as high as 20–31% in masters-level endurance athletes.(1,4)

Traditionally seen as a benign adaptive response, growing evidence suggests that some cases may reflect pathological vascular remodelling driven by repetitive mechanical strain, autonomic hyperactivity, and inflammatory signalling cascades.(6,7)

This paper extends the original hypothesis linking TOS with sympathetic neural irritation and aortic remodelling by further integrating mechanistic insights into the RAGE–CCL2–STAT3 inflammatory axis and exploring the therapeutic application of telmisartan.


Revised Mechanistic Framework


1.TOS and Sympathetic Ganglia Overactivation

  • TOS, particularly dynamic variants common in overhead athletes, induces mechanical irritation of the stellate ganglion (C7–T1) and cardiac plexus (T1–T4).(7,8)

  • This irritation leads to sustained sympathetic output, manifesting clinically as tachycardia, reduced heart rate variability, and potentially POTS-like symptoms.(10)

  • Chronic sympathetic vasoconstriction impairs vasa vasorum perfusion to the ascending aortic wall—resulting in regional hypoxia.


2. Hypoxia-Induced RAGE–CCL2–STAT3 Activation

  • Hypoxia upregulates HIF-1α, which promotes the expression of RAGE and its ligands (e.g., HMGB1, AGEs, S100 proteins).(11)

  • RAGE activation recruits monocytes/macrophages via CCL2, sustaining chronic inflammation and driving MMP-mediated elastin degradation.(12)(13)

  • The STAT3 pathway, activated via IL-6 and CCL2, further stabilizes this loop, enhancing aortic wall weakening and fibrosis.(14)


3. Feedforward Neurovascular Loop

This forms a self-reinforcing loop:


TOS → Stellate/Cardiac Plexus Irritation → Sympathetic Overdrive → Vasoconstriction → Vasa Vasorum Hypoxia → HIF-1α → RAGE → CCL2 → STAT3 → Inflammatory ECM Remodelling → AAD


This mirrors the persistent inflammatory and hypoxia-driven loops seen in Long COVID and POTS, further supporting a shared mechanistic substrate between athlete-associated AAD and post-viral syndromes.(15,16,17)


Therapeutic Potential of Telmisartan

Telmisartan’s Dual Action

Telmisartan offers a uniquely tailored intervention for this pathophysiology:

  • AT1R Blockade:

    • Reduces angiotensin II–mediated vasoconstriction, oxidative stress, and vascular wall stiffness.(18)

    • Enhances nitric oxide (NO) availability and endothelial function.(18)

  • PPAR-γ Agonism:

    • Suppresses NF-κB, IL-6, and CCL2 expression in glial and vascular cells.(19,20)

    • Attenuates STAT3-mediated ECM remodelling.(20)

    • Enhances mitochondrial function and redox balance in hypoxic vascular territories.(18,21)

Preclinical and Translational Evidence

  • In Alzheimer’s and TBI models, telmisartan improves cognition, reduces glial activation, and preserves microvascular integrity. (22, 23,24)

  • In vascular models, it reduces HMGB1/RAGE signalling, inhibits MMP-2/9 expression, and protects against elastin degradation. (18,23)


Implications for AAD in Athletes

Telmisartan may:

  • Modulate autonomic tone, lowering chronic sympathetic-mediated damage.(18)

  • Improve vasa vasorum perfusion, counteracting regional hypoxia.(18,21)

  • Suppress RAGE/STAT3/CCL2 pathways that promote elastin degradation and fibrosis.(20)

  • Act as a vascular anti-inflammatory agent targeting both endothelial and immune axes.(18,20)


Conclusion

Ascending aortic dilatation in athletes—particularly those with TOS and associated autonomic symptoms—may arise from a mechanically triggered, neuroinflammatory vascular remodelling process. This paradigm implicates the RAGE–CCL2–STAT3 axis, initiated by perivascular hypoxia and sustained sympathetic drive.


Telmisartan offers a promising disease-modifying intervention by simultaneously:

  • Reducing sympathetic tone

  • Reversing hypoxia-mediated transcription (HIF-1α)

  • Suppressing glial and vascular inflammation

  • Improving endothelial and ECM integrity


Future studies should stratify athletes with AAD using both functional autonomic markers and inflammatory biomarkers, and evaluate telmisartan’s ability to arrest or reverse aortic changes over time. The convergence of athlete aortopathy with mechanisms identified in Long COVID and POTS positions this as a fertile area for cross-disciplinary translational research.(25)


References

  1. Baggish,A., Churchill,T. Long-term Endurance Athletes Are at Marked Risk of Aortic Dilatation. 2020. https://advances.massgeneral.org/cardiovascular/journal.aspx?id=1608

  2. Understanding aortic enlargement in elite athletes. https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwaf082/8023332 (Published: Feb 19, 2025)

  3. Longitudinal Aortic Root Dilatation in Collegiate American‐Style Football Athletes. https://www.ahajournals.org/doi/10.1161/JAHA.122.030314 (Published: Jun 15, 2023)

  4. Kay S, Moore BM, Moore L, Seco M, Barnes C, Marshman D, Grieve SM, Celermajer DS. Rugby Player's Aorta: Alarming Prevalence of Ascending Aortic Dilatation and Effacement in Elite Rugby Players. Heart Lung Circ. 2020 Feb;29(2):196-201. doi: 10.1016/j.hlc.2019.06.714. Epub 2019 Jun 28. PMID: 31494040.

  5. Years of endurance competition may result in aortic dilatation. 2020. https://www.healio.com/news/cardiology/20200226/years-of-endurance-competition-may-result-in-aortic-dilatation

  6. Meagher,S., Braverman,A. CV Sports Chat: Dilated Aortas in Athletes. 2024.https://www.acc.org/Latest-in-Cardiology/Articles/2024/09/09/10/21/CV-Sports-Chat-Dilated-Aortas-in-Athletes

  7. Tso JV, Turner CG, Liu C, Prabakaran G, Jackson M, Galante A, Gilson CR, Clark C, Williams BR 3rd, Quyyumi AA, Baggish AL, Kim JH. Longitudinal Aortic Root Dilatation in Collegiate American-Style Football Athletes. J Am Heart Assoc. 2023 Jun 20;12(12):e030314. doi: 10.1161/JAHA.122.030314. Epub 2023 Jun 15. PMID: 37318010; PMCID: PMC10356022.

  8. Ohman JW, Thompson RW. Thoracic Outlet Syndrome in the Overhead Athlete: Diagnosis and Treatment Recommendations. Curr Rev Musculoskelet Med. 2020;13(4):457-471. doi:10.1007/s12178-020-09643-x

  9. Colbert L, Harrison C, Nuelle C. Rehabilitation in Overhead Athletes With Thoracic Outlet Syndrome. Arthrosc Sports Med Rehabil. 2022 Jan 28;4(1):e181-e188. doi: 10.1016/j.asmr.2021.11.007. PMID: 35141550; PMCID: PMC8811512.

  10. Gholamalizadeh, H., Ensan, B., Karav, S. et al. Regulatory effects of statins on CCL2/CCR2 axis in cardiovascular diseases: new insight into pleiotropic effects of statins. J Inflamm 21, 51 (2024). https://doi.org/10.1186/s12950-024-00420-y

  11. Kailash Prasad. AGE-RAGE stress play a role in aortic aneurysm: A comprehensive review and novel potential therapeutic target. Rev. Cardiovasc. Med. 2019, 20(4), 201–208. https://doi.org/10.31083/j.rcm.2019.04.57

  12. Li Y, Zheng X, Guo J, et al. Treatment With Small Molecule Inhibitors of Advanced Glycation End-Products Formation and Advanced Glycation End-Products-Mediated Collagen Cross-Linking Promotes Experimental Aortic Aneurysm Progression in Diabetic Mice. J Am Heart Assoc. 2023;12(10):e028081. doi:10.1161/JAHA.122.028081

  13. Camillo, Chiara & Abramov, Alexey & Allen, Philip & Castillero, Estíbaliz & Roberts, Emilia & Xue, Yingfei & Frasca, Antonio & Moreno, Vivian & Kurade, Mangesh & Robinson, Kiera & Spiegel, David & LaPar, Damien & Grau, Juan & Assoian, Richard & Bavaria, Joseph & Takayama, Hiroo & Ferrari, Giovanni. (2021). RAGE antagonist peptide mitigates AGE-mediated endothelial hyperpermeability and accumulation of glycoxidation products in human ascending aortas and in a murine model of aortic aneurysm. 10.1101/2021.10.22.465199

  14. Lannon,C. The Role of STAT3 in Aortic Dissection and the Potential for Targeted Medical Management Therapies. Proceedings of the Texas A&M Medical Student Grand Rounds. 2022. https://jmsgr.tamhsc.edu/the-role-of-stat3-in-aortic-dissection-and-the-potential-for-targeted-medical-management-therapies/

  15. Amekran Y, Damoun N, El Hangouche AJ. Postural orthostatic tachycardia syndrome and post-acute COVID-19. Glob Cardiol Sci Pract. 2022;2022(1-2):e202213. Published 2022 Jun 30. doi:10.21542/gcsp.2022.13

  16. Chadda KR, Blakey EE, Huang CL, Jeevaratnam K. Long COVID-19 and Postural Orthostatic Tachycardia Syndrome- Is Dysautonomia to Be Blamed? Front Cardiovasc Med. 2022 Mar 9;9:860198. doi: 10.3389/fcvm.2022.860198. PMID: 35355961; PMCID: PMC8959615.

  17. Exelby, G. Origin of Brainstem Hypoperfusion in POTS and Long COVID. 2025. https://www.mcmc-research.com/post/origin-of-brainstem-hypoperfusion-in-pots-and-long-covid-a-dual-gate-hypothesis-linking-mechanical

  18. Sonia Villapol, Juan M. Saavedra, Neuroprotective Effects of Angiotensin Receptor Blockers, American Journal of Hypertension, Volume 28, Issue 3, March 2015, Pages 289–299, https://doi.org/10.1093/ajh/hpu197

  19. Affram, K.O.; Janatpour, Z.C.; Shanbhag, N.; Villapol, S.; Symes, A.J. Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia. Neuroglia 2024, 5, 182-201. https://doi.org/10.3390/neuroglia5020014

  20. Ahire, Y.S., Bairagi, V.A., Somavanshi, D.B. et al. Expanding telmisartan’s therapeutic horizon: exploring its multifaceted mechanisms beyond cardiovascular disorders. Futur J Pharm Sci 10, 84 (2024). https://doi.org/10.1186/s43094-024-00655-9

  21. Huber G, Ogrodnik M, Wenzel J, et al. Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior. J Cereb Blood Flow Metab. 2021;41(9):2356-2369. doi:10.1177/0271678X211003497

  22. Kurata T, Lukic V, Kozuki M, Wada D, Miyazaki K, Morimoto N, Ohta Y, Deguchi K, Ikeda Y, Kamiya T, Abe K. Telmisartan reduces progressive accumulation of cellular amyloid beta and phosphorylated tau with inflammatory responses in aged spontaneously hypertensive stroke resistant rat. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):2580-2590. doi: 10.1016/j.jstrokecerebrovasdis.2014.05.023. Epub 2014 Sep 16. PMID: 25241340.

  23. Affram, K.O.; Janatpour, Z.C.; Shanbhag, N.; Villapol, S.; Symes, A.J. Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia. Neuroglia 2024, 5, 182-201. https://doi.org/10.3390/neuroglia5020014

  24. Hu W, Li Y, Zhao Y, et al. Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype. Front Aging Neurosci. 2020;12:154. Published 2020 Jun 9. doi:10.3389/fnagi.2020.00154

  25. Amekran Y, Damoun N, El Hangouche AJ. Postural orthostatic tachycardia syndrome and post-acute COVID-19. Glob Cardiol Sci Pract. 2022;2022(1-2):e202213. Published 2022 Jun 30. doi:10.21542/gcsp.2022.13

 

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