By Dr Nicolas Martinez-Majander, Department of Neurology, Helsinki University Hospital, Finland

A large European study of young patients (n=3331) with first-ever ischemic stroke showed that crytogenic strokes are more common the younger the patient, with an average proportion of approximately 50%.1 Furthermore, there are several studies showing high rates of recurrence also in the young, e.g. in the FUTURE study the cumulative 20-year risk of recurrent stroke was 17.3% (95% CI 9.5-25.1) after transient ischemic attack and 19.4% (95% CI 14.6-24.3) after ischemic stroke. These rates of recurrence suggest an under-recognised active underlying pathology in young-onset cryptogenic strokes.2,3

Based on studies in vascular disease in other vascular bed one such mechanism might be an impaired endothelial function, also contributing to cerebrovascular disease and stroke.4 Most often, this dysfunction is due to atherosclerosis, which can e.g. produce thromboembolism or occlude an artery. Several factors, such as inflammation, diabetes and smoking can enhance development of atherosclerosis and modified lipids in the arterial wall inhibit endothelial nitric production.5 Damage to endothelium is usually subtle, multifactorial, but progressive. Several cardiovascular drugs, such as ACE inhibitors and angiotensin receptor blockers, as well as statins have several pleiotropic effects, including anti-inflammatory and antioxidant activities, thus improving endothelial function both in primary and secondary prevention of cardiovascular events, including stroke. In statins, this beneficial effect is also distinct and independent of their lipid-lowering effect.4

In prior studies, endothelial function has been measured with either flow-mediated vasodilatation test in the brachial artery or by using peripheral arterial tonometry. The latter measures the vasodilator function in fingertip microvasculature during reactive hyperemia. Both of these are quite non-invasive and validated.6

Also in the young-onset cryptogenic ischemic stroke, endothelial dysfunction might reflect a condition that alone or in interaction with other transient or chronic risk factors may lead to thrombus formation (so-called early vascular aging). Still, these associations have gone virtually uninvestigated in this patient group. There are however some hints from different studies. One study in young patients with spontaneous cervical artery dissection showed an impaired endothelium-dependent vasodilation that was not the result of stroke.7 Another study with middle-aged ischemic stroke patients also showed an impairment of flow-mediated vasodilation, but no significant differences between stroke subtypes according to TOAST classification.8   A few original studies focusing on young non-stroke individuals showed that e.g. binge drinking, male sex, body mass, smoking, diabetes, and ratio of total to high-density lipoprotein cholesterol have been association with endothelial dysfunction.9,10

Future investigations might improve our understanding of the clinical utility and predictive value of measuring endothelial dysfunction and its interaction with wider spectrum of risk factors. Knowledge of such causal pathways could further lead to more optimal secondary prevention, thus improving long-term outcome after young-onset cryptogenic ischemic strokes as well.




  1. Yesilot Barlas N, Putaala J, Waje-Andreassen U, et al. Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study. Eur J Neurol 2013;20:1431-1439.
  2. Rutten-Jacobs LC, Maaijwee NA, Arntz RM, et al. Long-term risk of recurrent vascular events after young stroke: The FUTURE study. Ann Neurol 2013;74:592-601.
  3. Putaala J, Haapaniemi E, Metso AJ, et al. Recurrent ischemic events in young adults after first-ever ischemic stroke. Ann Neurol 2010;68:661-671.
  4. Versari D, Daghini E, Virdis A, et al. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care. 2009;32 Suppl 2(Suppl 2):S314-S321.
  5. Madden JA. Role of the vascular endothelium and plaque in acute ischemic stroke. Neurology. 2012;79(13 Suppl 1):S58-S62.
  6. Hedetoft M, Olsen NV. Evaluation of endothelial function by peripheral arterial tonometry and relation with the nitric oxide pathway. Nitric Oxide. 2014;42:1-8.
  7. Lucas C, Lecroart JL, Gautier C, et al. Impairment of endothelial function in patients with spontaneous cervical artery dissection: evidence for a general arterial wall disease. Cerebrovasc Dis. 2004;17(2-3):170-174.
  8. Omisore AD, Ayoola OO, Ibitoye BO, et al. Sonographic Evaluation of Endothelial Function in Brachial Arteries of Adult Stroke Patients. J Ultrasound Med. 2017;36(2):345-351.
  9. Goslawski M, Piano MR, Bian JT, et al. Binge drinking impairs vascular function in young adults. J Am Coll Cardiol. 2013;62(3):201-207.
  10. Hamburg NM, Keyes MJ, Larson MG, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008;117(19):2467-2474.