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Background: Worldwide, ≈1.3 million annual ischemic strokes (IS) occur in young adults (<50 years of age), of which up to 50% remain cryptogenic after a complete diagnostic work-up. In a pilot case-control study, we studied the value of arterial stiffness and related subendocardial viability in the search of underlying pathophysiology in these patients.Methods: We prospectively enrolled 51 patients aged 18-49 with recent imaging-positive cryptogenic IS and 51 age- and sex-matched stroke-free controls (NCT01934725). Measurements were done with an applanation tonometry (SphygmoCor). Augmentation Index (AIx) served as a measure of stiffness in small arteries. Aortic and brachial pulse wave velocities (aPWV; bPWV) reflected stiffness in large and intermediate-sized arteries, respectively. Subendocardial viability ratio (SEVR) was derived from radial artery waveform measures, reflecting myocardial oxygen supply and demand. Related-samples statistics were applied for univariate case-control analyses and linear regression to explore the relationship between parameters with significant association in case-control analysis.Results: AIx, aPWV, bPWV, heart rate, and systolic or diastolic blood pressures did not differ statistically between patients and controls. Mean SEVR was significantly lower in patients compared with controls (148±35 vs. 161±29, P=0.003). In patients, higher heart rate was inversely associated with SEVR (P<0.001). Age, sex, migraine with and without aura, smoking, and systolic and diastolic blood pressure showed no independent association with SEVR.Conclusions: To our knowledge, this is the first report to show an association between SEVR and stroke. Yet unrecognized subtle cardiovascular pathology may play a role in early-onset cryptogenic IS.