Blackshear, Joseph L.

Abstract 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.

Abstract Background: Von Willebrand factor (VWF) is a multimeric glycoprotein synthesized in endothelium and megakaryocytes. Elevated total VWF antigen has been associated with arterial thrombosis, while in patients with left ventricular assist devices (LVAD), loss of high molecular weight multimers is associated with spontaneous bleeding. We hypothesized that the lower rotational speed of the Heartware LVAD would be associated with less severe disruption of VWF. Methods: A total of 22 patients were included. We compared samples from a) 17 patients with Heartmate II LVAD (HM II), 76% male, median age 67 (54-73) years, 24% non-white, 45 (33-59) months after implant, with b) 5 patients with Heartware (HW) LVAD, all male, age 64 (59-65) years, 20% non-white, 27 (14-29) months after implant. All patients received warfarin. All HW patients took aspirin, while 82% of HM II patients took aspirin. Samples were analyzed for VWF antigen, activity, platelet function analyzer-100 collagen adenosine diphosphate closure time (PFA) and VWF multimers by gel electrophoresis. Multimers were assessed qualitatively and quantitatively by dividing mers > 15 by mers 2-15 (multimer ratio) and with a normalized multimer ratio (multimer ratio of patient / normal plasma control from the same gel). Results: Although flow rates did not differ significantly between HM II and HW, 5.2 (4.6-6.5) versus 4.3 (4.2-5.4) liters per minute respectively, rotational speeds were very different, mean 9472 versus 2680 rpms, p<0.0001). There were no differences in hemoglobin, hematocrit, or platelet count at the time of sampling. Qualitative VWF multimers were abnormal in all patients, and PFA was non-clotting in 88% of HM II patients and 80% of HW patients. VWF activity to antigen ratio was not different: HM II 0.68 (0.63-0.74) versus HW 0.70 (0.63-0.71). However, VWF antigen was significantly higher in HM II patients, 199 (174-227) compared to HW, 139 (122-160), p=0.039 and the normalized VWF multimer ratio was significantly lower, suggesting greater loss of high molecular weight multimers in HM II, 0.43 (0.41-0.48) compared to HW, 0.53 (0.48-0.56), p=0.0025 (figure). Conclusion: The lower rotational speed associated with the Heartware LVAD appears to produce less elevation of VWF antigen, and slightly less loss of VWF high molecular weight multimers compared to the Heartmate II LVAD. Additional studies are needed to describe whether or not lower pump thrombosis rates and rates of spontaneous bleeding are associated with these differences. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Recent reports have utilized von Willebrand factor (VWF) multimerquantitation in the assessment of native cardiac lesions and prosthetic valve dysfunction. However there is no standardized method for quantitation. We compared 3 methods of assessment which utilized a normal plasma control. Methods: We analyzed 476 samples and their control plasma from 395 patients including normal subjects, patients with aortic stenosis, hypertrophic cardiomyopathy, mitral or aortic regurgitation, normal and abnormal left cardiac valve prostheses, and left ventricular assist device therapy (LVAD). VWF multimers were assessed as normal or abnormal, or as normalized (patient / normal plasma) VWF multimerratios of gel bands >15/2-15 (NMR 15) or gel bands > 10/2-10 (NMR 10). We tested whether one technique was more strongly associated with hemodynamic severity of the cardiac lesion, with a history of acquired bleeding, and compared the results to a separate test of VWF function, platelet function analyzer 15 00 (PFA). Results: Two hundred seventeen patient samples reflected normal or mildly abnormal hemodynamics, 111 moderate, and 113 severely abnormal hemodynamics. Abnormal multimers were present in only 19% of samples with normal or mildly abnormal hemodynamics compared to 79% abnormal in the presence of moderate to severe hemodynamic abnormality. The distinction between moderate and severe hemodynamic abnormality was less striking, 65% versus 88% (figure, left). Quantitative NMR values declined with increasing cardiac lesion severity (figure, middle). The two quantitative multimermethods showed similar relationships to lesion severity by ANOVA, r=0.40 (NMR 15) versus r=0.36 (NMR 10), and by Spearman correlation, r=0.68 for NMR 15, and r=0.66 for NMR 10, and PFA results were comparable (all p< 0.001). Bleeding rates were associated with NMR 15, 10 and PFA (Mann-Whitney p<0.001, figure, right). Conclusion: The dichotomous normal / abnormal VWF multimer method appears to distinguish ≥ moderate hemodynamic disruption, whereas there is a continuous relationship between hemodynamic severity and quantitative multimer methods, which may be clinically useful in circumstances in which clinical estimation of lesion severity is challenging, such as with dysfunctional prosthetic valves. Progressive loss of VWF multimersappears to be associated with bleeding, suggesting that quantitative measures may provide incremental value over the dichotomous normal / abnormal designation. Figure Figure. Disclosures Blackshear: Baxalta, Inc: Consultancy, Research Funding.

Abstract Abstract 1128 Background Dysfunctional or mismatched prosthetic heart valves can results in high shear stress related von Willebrand factor (VWF) impairment, and clinical bleeding. This mechanism is similar to that seen in aortic stenosis patients, where gastrointestinal bleeding related to VWF multimer loss is well described (Heyde syndrome). In this study, we compared the results of VWF testing of patients with normally functioning cardiac valve prostheses, dysfunctional prosthetic valves, severe native aortic stenosis, and normal controls. Methods A total of 75 patients, 31 female and 44 male with a median age of 79.5 years were recruited to this study. Thirty patients had severe aortic stenosis (mean gradient > 40 mm Hg); 39 patients had normally functioning prosthetic valves, 21 aortic (AVR) and 18 mitral valves (MVR); and 6 patients had with dysfunctional valves (4 aortic and 2 mitral). Whole blood and plasma samples were drawn from patients and tested for platelet function analyzer-100 collagen ADP closure time (PFA-CADP), VWF antigen (VWF:Ag), VWF activity by latex immunoassay (VWF:Ltx), VWF multimer analysis and VWF multimer densitometry ratio of large vs medium to low molecular weight multimers (>15 mers/2–15 mers). Results The 6 dysfunctional prosthetic valve patients included patient-prosthesis mismatch (2) and (one each), thrombosed mechanical aortic prosthesis, torn biological aortic prosthesis, severe tissue mitral prosthetic regurgitation, and post-mitral valve repair severe mitral regurgitation. Four of six patients had clinically significant bleeding. Most aortic stenosis and all 6 prosthetic dysfunction patients had abnormal VWF multimers which is rare in normally functioning prostheses and completely absent in normal donors. VWF:Ltx/Ag was lower in AS and MVR than normal. VWF:Ltx/Ag ratio, VWF:multimer ratio and PFA-CADP were all significantly abnormal in patients with dysfunctional prosthetic valve. VWF:multimer ratios in normally functioning prostheses tended to be intermediate between normals and than those of patients with severe AS or prosthetic valve dysfunction (Table). Conclusions VWF testing including quantitative von Willebrand multimer analysis and PFA-CADP reliably separate dysfunctional from normally functioning cardiac prostheses, and should be considered in the evaluation of patients with cardiac prostheses, especially those who have clinically significant bleeding. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Aortic stenosis-associated acquired von Willebrand syndrome (AS-AVWS) is caused by an accelerated degradation of the highest molecular weight von Willebrand factor (VWF) multimers (HMWM). We recently reported that the severity of the HMWM loss correlates with the severity of AS and patients’ bleeding tendency (Am J Cardiol, 2013;111:374-81). As for the missing HMWM, it is still uncertain if they are cleared from circulation or redistributed with medium-low MWMs, which can be assessed by VWF propeptide (Pro)/antigen (Ag) ratio. Besides the tedious VWF multimer analysis, it is uncertain if VWF activity by immunoturbidic method (Lx)/ Ag ratio or VWF collagen binding activity (CBA)/Ag ratio can be used as a screening test to predict AS-AVWS. It has been speculated in the literature that VWF:CBA is more sensitive than VWF:Lx for detecting a HMWM loss. Our goal was to exam the laboratory characteristics of various VWF tests in evaluating AS-AVWS and the potential mechanism of HMWM loss. Method: Sixty-six patients (between years 2010-2012, 43% male) with varying degrees of AS (16 mild, 20 moderate, and 30 severe) and separate 21 patients who had aortic valve replacement were assessed with VWF:Ag, VWF:Lx, VWF:CBA, platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP), VWF multimer analysis and multimer ratio by densitometry (Am J Cardiol, 2013;111:374-81) after their echocardiography. The clinical endpoints of this study are AS severity measured by mean gradient (MG) by echocardiography and clinically significant bleeding. Statistical analyses including Spearman rank correlation test, estimation of the area under the receiver operating characteristics (ROC) curve, and Wilcoxon rank sum tests were performed. Results: VWF:Lx and VWF:CBA had strong correlation (Spearman r=0.94, P<0.001), and the correlation of VWF:CBA/Ag and VWF:Ltx/Ag was 0.49, p<0.001). As previously published, in patients with AS, MG correlated with VWF:Lx/Ag (Spearman r = -0.41, p <0.001), PFA-CADP (r = 0.49, p <0.001), and VWF multimer ratio (r = -0.76, p <0.001). MG also correlated with VWF:CBA/Ag (r= -0.38, p=0.002), but not with VWF: Pro/Ag (r=-0.20, p=0.12). Among AS and AVR patients, the area under the ROC curve for detection of the loss of HMWM was 0.88 (95% CI: 0.80-0.95) by VWF multimer ratio, 0.76 (95% CI: 0.65-0.86) by PFA-CADP, 0.70 (95% CI: 0.58-0.82) by VWF:CBA/Ag ratio, 0.67 (95% CI: 0.56-0.70) by VWF:Lx/Ag ratio, and 0.53 (95% CI: 0.41-0.65) by VWF:Pro/Ag . In addition to previously published results, clinically significant bleeding, in 14% of AS patients, was not associated with VWF:CBA/Ag (p=0.25) or VWF:Pro/Ag ratio (p=0.83). VWF: CBA/Ag ratio was significantly lower in patients with severe AS (MG > 40 mmHg) compared to AVR patients (median: 0.84 vs. 1.06, p<0.001), while there was no evidence of a difference in VWF:Pro/Ag (p=0.45). Conclusion: HMWM losses are highly prevalent in patients with moderate to severe AS. Of the VWF tests, PFA-CADP and VWF multimer analysis and ratio had the highest predictive ability for AS-AVWS followed by VWF:CBA/Ag and VWF:Lx/Ag. The VWF:CBA is not overly superior than VWF:Lx for predicting a HMWM loss. The normal VWF:Pro/Ag suggests that AS-AVWS is different from other types of AVWS due to accelerated clearance of HMWM. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2230 Background: Heyde syndrome describes patients with severe aortic stenosis (AS) who have bleeding diathesis, especially gastrointestinal bleeding. Although acquired won Willebrand syndrome (AVWS) due to loss of the highest molecular weight multimers (HMWM) presents in most patients with severe AS, not all such patients develop Heyde syndrome. The goal of this study was to explore whether the severity of HMWM loss was significantly associated with Heyde syndrome. Methods: We first performed chart reviews on patients referred for double balloon enteroscopy (DBE) for GI bleeding or iron-deficiency anemia (GIB/FeDefic) in two time periods, from 2005–2008, and from 2009–2011. Next, patients who could have AVWS due to AS or other cardiovascular or hematologic disorders were identified. Laboratory tests including VWF antigen (VWF:Ag), VWF ristocetin cofactor activity or VWF latex immunoturgidic activity (VWF:Ltx) and/or VWF multimer analysis were performed as requested by physicians. From this population, patients with Heyde syndrome were identified. Their clinical and VWF laboratory testing results were compared to a separated group of patients with severe AS patients who had no clinically significant bleeding, but had matched gender and hemodynamic severity by echocardiogram (Matched AS Controls). These patients all had VWF:Ag, VWF:Ltx, and VWF multimers performed. In both Heyde syndrome patients and Matched AS controls, VWF multimer densitometry ratio of the HMWM (>15 mers) to low to intermediate multimers (2–15 mers) was assessed (VWF:multi ratio). Results: Overall, 437 patients underwent DBE for GIB/FeDef. Between 2005 and 2008, 1% of 318 patients had VWF testing. From 2009 to 2011, 23% of 119 patients were tested. Heyde syndrome was noted in 15 patients. Of the 437 patients, 134 patients (31%) likely had AVWS based on diagnoses of moderate-severe AS (30%), moderate to severe mitral regurgitation (25%), moderate to severe pulmonary hypertension (16%), prosthetic valve regurgitation or stenosis (13%), hypertrophic cardiomyopathy (10%), and hematologic disorders (4%). Among these 134 patients, 29 patients had VWF tests performed, and 22 had VWF multimer analysis. VWF antigen levels were similar in Heyde syndrome and Matched AS Controls (176±89% versus 155±77% respectively). Despite similar hemodynamic severity, more severe HMWM loss as indicated by lower VWF:Ltx/Ag and VWF:multi ratios was present in Heyde syndrome patients than matched AS controls (table, P<0.0007). Conclusion: If AVWS is suspected in patients with GIB/FeDef, laboratory testing for VWF indices is important to confirm the diagnosis of AVWS. Despite similar hemodynamic severity, Heyde syndrome patients have more severe VWF HMWM loss indicated by significantly decreased VWF:Ltx/VWF:Ag and VWF:multi ratios. Conversely, though highly sensitive for AVWS, PFA-CADP does not predict bleeding tendency in patients with severe AS. Disclosures: No relevant conflicts of interest to declare.

In observational studies, left ventricular mass (LVM) and structure are strong predictors of mortality and cardiovascular events. However, the effect of hypertension treatment on LVM reduction and its relation to subsequent outcomes is unclear, particularly at lower blood pressure (BP) targets. In an ancillary study of SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive BP control (target systolic BP target <120 mm Hg) versus standard BP control (<140 mm Hg), cardiac magnetic resonance imaging was performed at baseline and 18-month follow-up to measure: LVM, volumes, ejection fraction, and native T1 mapping for myocardial fibrosis. At baseline, 337 participants were examined (age: 64±9 years, 45% women); 300 completed the 18-month exam (153 intensive control and 147 standard control). In the intensive versus standard BP control group at 18 months, there was no difference in change in LVM (mean±SE =−2.7±0.5 g versus −2.3±0.7 g; P =0.368), ejection fraction, or native T1 ( P =0.79), but there was a larger decrease in LVM/end-diastolic volume ratio (−0.04±0.01 versus −0.01±0.01; P =0.002) a measure of concentric LV remodeling. There were fewer cardiovascular events in the intensive control group, but no significant association between the reduced events and change in LVM or any other cardiac magnetic resonance imaging measure. In SPRINT-HEART, contrary to our hypothesis, there were no significant between-group differences in LVM, function, or myocardial T1 at 18-month follow-up. These results suggests that mediators other than these LV measures contribute to the improved cardiovascular outcomes with intensive BP control.

Background: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years. Methods and Results: CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21–2.50; P <0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33–38.94; P <0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93–2.10; P =0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28–5.73; P <0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86–36.2; P =0.006) and late (adjusted HR=3.40; 95% CI, 2.09–5.53; P <0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09–3.84; P =0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09–65.5; P =0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97–3.64; P =0.062) contributing to the increased risk. Conclusions: In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00004732.

Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132–145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction ( P =0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles—a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP.