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Purpose. The study is aimed at identifying echocardiographic and circulating biomarkers as well as hemodynamic indices of embolic stroke of undetermined etiology (ESUS) in patients aged <65. Methods. We prospectively investigated 520 patients with confirmed ischemic stroke and selected those 65 patients who were diagnosed with ESUS (age 54 (47-58) years, 42% male). An additional 36 without stroke but with a similar risk profile were included as a control group (age 53 (47-58) years, 61% male). All patients underwent echocardiography, noninvasive assessment of hemodynamic parameters using a SphygmoCor tonometer (AtCor Med., Australia), and measurements of selected biomarkers. Results. ESUS patients and controls were well matched for baseline characteristics including blood pressure and left ventricular ejection fraction (LVEF). Compared to controls, patients with ESUS had lower mean early diastolic (E′) and systolic (S′) mitral annular velocities and a higher ratio of the peak velocity of early diastolic transmitral flow to the peak velocity of early diastolic mitral annular motion (all p<0.01). The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in the control group (both p<0.01). The isovolumetric relaxation time (IVRT) was longer and the mean left atrial volume index (LAVI) was higher in ESUS patients compared to the control group. Parameters of arterial stiffness such as augmentation pressure, augmentation index, and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (p<0.05). Patients in the ESUS group had higher levels of asymmetric dimethylarginine, interleukin 6, and N-terminal probrain natriuretic peptide (NT-proBNP, all p<0.05) than those in the control group. In multivariate analysis, the following factors were significantly associated with the presence of ESUS: AIx75 (odds ratio (OR) 1.095, 95% confidence interval (CI) 1.004-1.194; p=0.04), IVRT (OR 1.045, 95% CI: 1.009-1.082; p=0.014), LAVI (OR 1.3, 95% CI: 1.099-1.537; p=0.002), and NT-proBNP (OR 1.003, 95% CI: 1.001-1.005; p=0.005). Conclusions. Increased arterial stiffness and indices of diastolic dysfunction as well as a higher NT-proBNP level are significantly associated with ESUS. These parameters require further scrutiny over time to understand their impact on the development of symptomatic heart failure. The ClinicalTrials.gov identifier is NCT03377465.

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Cardiogenic strokes comprised 11% of all strokes and 25% of ischemic strokes. An accurate identification of the cause of stroke is necessary in order to prepare an adequate preventive strategy. In this review the confirmed and potential causes of embolic strokes are presented, which can be detected in echocardiography in the context of present treatment guidelines and gaps in evidence. There remains a need for further studies assessing the meaning of potential cardiac sources of embolism and establishment of rules for optimal medical prevention (antiplatelet therapy [APT] vs. oral anticoagulation [OAC]) and interventional procedures to reduce the incidence of ischemic strokes. Currently available data does not provide definitive evidence on the comparative benefits of OAC vs. APT in patients with cryptogenic stroke or embolic stroke of undetermined source. There is a lack of antithrombotic treatment scheme in the time between stroke and the completed diagnosis of potential sources of thromboembolism.