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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.

Objective Identification of echocardiographic, hemodynamic and biochemical predictors of unfavorable prognosis after embolic strokes of undetermined etiology (ESUS) in patients at age <65. Patients and Methods Out of 520 ischemic stroke patients we selected 64 diagnosed with ESUS and additional 36 without stroke but with similar risk profile. All patients underwent echocardiography, non-invasive assessment of hemodynamic parameters using SphygmoCor tonometer and measurements of selected biomarkers. Follow-up time was 12 months. Results Nine percent of patients died, and recurrent ischemic stroke occurred in 9% of patients only in the ESUS group. Atrial fibrillation (AF) occurred in 10% of patients and the ESUS group had a significantly poorer outcome of AF in the first 2 months after hospitalization. The outcome of re-hospitalization was 28% in the ESUS group and 17% in the control group. In the multivariate analysis mean early diastolic (E’) mitral annular velocity (OR 0.75, 95% CI: 0.6–0.94; p=0.01) was significantly associated with cardiovascular hospitalizations. The only independent predictor of recurrent stroke was the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic mitral annular motion (E/E’) (OR 0.75, 95% CI: 0.6–0.94; p=0.01). E/E’ was independently associated with composite endpoint (death, hospitalization and recurrent stroke) (OR 1.90, 95% CI 1.1–3.2, p=0.01). Conclusion The indices of diastolic dysfunction are significantly associated with unfavorable prognosis after ESUS. There is a robust role for outpatient cardiac monitoring especially during the first 2 months after ESUS to detect potential AF.

Purpose The study aimed to identify echocardiographic, hemodynamic and biochemical predictors of unfavourable prognosis after ischemic strokes of undetermined etiology (ESUS) in patients (pts) at age <65. Methods Out of 520 ischemic stroke pts we selected 64 pts diagnosed with ESUS [mean age 54 (SD: 47–58) years, 42% males] and additional 36 without stroke but with similar risk profile, which were treated as a reference group [age 53 (SD: 47–58) years, 61% males]. All pts underwent echocardiography, non-invasive assessment of hemodynamic parameters using SphygmoCor tonometer (Atcor Med., Australia), HDL subfraction distribution using Lipoprint (Quantimetrix) as well as measurements of selected biomarkers. Follow-up was 12 months. Results At 12-month follow-up 9% of patients had died, and recurrent ischemic stroke also occurred in 9% of patients - only in the ESUS group (Figure). Patients who died had significantly lower levels of LDL and HDL cholesterol (included HDL-8 and -9 subfractions) and higher level of triglicerides (p=0.01, p=0.01, and p=0.02; respectively), lower level of adiponectin (p=0.01), lower value of mean early diastolic (E') mitral annular velocity (p=0.04) and lower diastolic blood pressure (p=0.04). The atrial fibrillation (AF) occurred in 10% of pts during the 12 months (log-rang, p=0.254) (Figure). The log-rank test showed that ESUS group had a significantly poorer outcome of AF in the first 2 months after hospitalization compared to reference group (11% vs 5%, p=0.041). Based on a Kaplan-Meier analysis, the outcome of re-hospitalizationin the 1st year was 28% (18/64) in the ESUS group and 17% (6/36); log-rank, p=0.058. In the multivariate analysis mean early diastolic (E') mitral annular velocity (odds ratio [OR] 0.75, 95% confidence interval [CI]: 0.6–0.94; p=0.01) was significantly associated with CV hospitalizations assessed at 12-month follow-up. The only independent predictor of AF occurrence in the 12-month follow-up was lower value of Tissue Doppler-derived right ventricular systolic excursion velocity S' (OR 0.65, 95% Cl 0.45–0.93; p=0.01). The only independent predictor of recurrent stroke was the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic mitral annular motion as determined by pulsed wave Doppler (E/E') (OR 0.75, 95% CI: 0.6–0.94; p=0.01). E/E' ratio was also independently associated with composite endpoint consisting of death, hospitalization and recurrent stroke (OR 1.90, 95% CI 1.1–3.2, p=0.01). Kaplan-Meier Analysis - survival and AF Conclusions The indices of diastolic dysfunction are significantly associated with unfavourable prognosis after ESUS. There is a robust role for outpatient cardiac monitoring especially during first 2 months after ESUS to detect potential AF. Acknowledgement/Funding The study was financed by research grants no. 502-03/5-139-02/502-54-229-18 of the Medical University of Lodz

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