Predictors of Acquired Von Willebrand Syndrome in Patients with Aortic Stenosis,

Abstract 3318 Background: Acquired von Willebrand syndrome (AVWS) due to loss of high molecular weight multimers (HMWM), is a frequent cause of bleeding in aortic stenosis (AS), and is reversed by valve replacement. The goal of this study was to explore predictors of AVWS in patients with AS. Methods: A total of 91 patients (59 men, median age 79 years) with AS (n=64) or heart valve replacement (n=27) were included. We recorded peripheral blood count, vital signs, mean gradient (MG), peak velocity (peak vel), aortic valve time velocity integral (AV-TVI), aortic valve area (AVA) and valve area index (AVAi), time velocity integral ratio (TVI ratio), VWF antigen (VWF:Ag), VWF activity by latex immunoturbidity assay (VWF:Lx), VWF multimer analysis, closure times of platelet function analyzer ADP and epinephrine cartridges (PFA-CADP and –CEPI). HMWM losses were graded as normal, mild or severe when compared to HMWM analyses of pooled plasma samples from normal donors. Potential predictors of HMWM loss were explored using logistic regression analysis. Results: Of the 91 patients, 42 (46%) had loss of HMWM (23 mild and 19 severe). In single variable logistic regression analysis, AVWS was associated with a low AVA (<1.0 cm2; OR=5.08, P<0.001), and low AVAi (<0.60 cm2/m2; OR=5.54, P<0.001), low TVI ratio (<0.25; OR=10.80, P<0.001), prolonged PFA-CADP (≥121 sec; OR=6.76, P<0.001), and low VWF:Lx/Ag (≤0.8; OR=8.06, P=0.008). Moderate peak vel (3–4 m/sec) and high peak vel (>4 m/sec) were associated with loss of HMWM (OR[vs. <3 m/sec]=5.80 and 37.70 respectively, P<0.001) as were moderate MG (25–40 mmHg) and high MG (>40 mmHg), (OR [vs. <25mmHg]=4.50 and 32.50 respectively, P<0.001). In exploratory multivariable analysis, mean gradient remained one of the strongest predictor of loss of HMWM. The estimated sensitivity of MG (≥25mmHg) in diagnosing AVWS was 83% (35/42, 95% CI: 69%-93%) and estimated specificity was 71% (35/49, 95% CI: 57%-83%). Considering the very strong correlation with mean gradient, we also considered the diagnostic utility of peak vel. Peak vel≥ 3 m/sec had a sensitivity of 89% (38/42, 95% CI: 77%-97%) and a specificity of 59% (29/49, 95% CI: 44%-73%) in detecting loss of HMWM. Conclusion: Our data suggest that mean gradient (>25 mmHg) and peak vel (≥ 3 m/sec), both derived from the Doppler aortic valve velocity envelope, are accurate predictors for AS-AVWS, and should be incorporated into algorithmic approaches to laboratory screening for AVWS. Disclosures: No relevant conflicts of interest to declare.

Degree of Retrograde Flow and Its Effect on Local Hemodynamics and Plaque Distribution in an Aortic Regurgitation Murine Model of Atherosclerosis

Previously, Zhou et al. [1] presented a novel mouse model of aortic valve regurgitation (AR) to explore the effect of altered hemodynamics on atherogenesis. In these ldlr−/− mice with AR, extensive atherosclerotic plaque was found along the naturally lesion-free descending thoracic (DTAo) and abdominal aorta (AbAo), with distinct spatial distributions suggestive of a strong local hemodynamic influence (Fig. 1, top). Doppler ultrasound measurement showed that both DTAo and AbAo of the AR mice experienced an oscillatory flow pattern induced by the diastolic retrograde flow, as opposed to the consistent antegrade flow found in the non-AR mice. The study also suggested that the fraction of the DTAo surface covered by lesions tends to increase with the absolute diastolic retrograde Time-Velocity Integral (TVI) as measured from the Doppler ultrasound.

Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt-Oram syndrome

Tbx5 del/+ mice provide a model of human Holt-Oram syndrome. In this study, the cardiac functional phenotypes of this mouse model were investigated with 30-MHz ultrasound by comparing 12 Tbx5 del/+ mice with 12 wild-type littermates at 1, 2, 4, and 8 wk of age. Cardiac dimensions were measured with two-dimensional and M-mode imaging. The flow patterns in the left and right ventricular inflow channels were evaluated with Doppler flow sampling. Compared with wild-type littermates, Tbx5 del/+ mice showed significant changes in the mitral flow pattern, including decreased peak velocity of the left ventricular (LV) early filling wave (E wave), increased peak velocity of the late filling wave (A wave), and decreased or even reversed peak E-to-A ratio. The prolongation of LV isovolumic relaxation time was detected in Tbx5 del/+ neonates as early as 1 wk of age. In Tbx5 del/+ mice, LV wall thickness appeared normal but LV chamber dimension was significantly reduced. LV systolic function did not differ from that in wild-type littermates. In contrast, the Doppler flow spectrum in the enlarged tricuspid orifice of Tbx5 del/+ mice demonstrated increased peak velocities of both E and A waves and increased total time-velocity integral but unchanged peak E/A. In another 13 mice (7 Tbx5 del/+, 6 wild-type) at 2 wk of age, significant correlation was found between Tbx5 gene expression level in ventricular myocardium and LV filling parameters. In conclusion, the LV diastolic function of Tbx5 del/+ mice is significantly deteriorated, whereas the systolic function remains normal.