Blackshear, Joseph L.

Aortic stenosis is the most common acquired valvular heart disease. Currently, there are no medications approved to slow its progression. We set out to investigate the effect of ACE inhibitors/angiotensin receptor blockers and aldosterone antagonists on the rate of progression of mild aortic stenosis. We retrospectively reviewed the charts of 2,613 patients over 45 years old, who had a peak velocity between 1.8 and 3 meters/second on initial echo. Over 8 years of followup, 491 patients were prescribed angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and 130 patients were prescribed aldosterone receptor blockers. Patients prescribed ACE inhibitors/ARBs had a slower rate of progression of aortic stenosis compared to those not prescribed ACE inhibitors/ARBs (2.2 to 2.5 vs. 2.3 to 2.8 meters/second) (Figure 1). Also, patients prescribed aldosterone receptor blockers had a slower rate of progression of aortic stenosis compared to those who were not 2.2 to 2.4 vs. 2.3 to 2.8 meters/second) (Figure 2). Our findings suggest that angiotensin or aldosterone antagonism is associated with slower rate of progression of mild aortic stenosis.

Aortic stenosis (AS) requires repeat assessments to optimally time intervention. The utility of laboratory tests to complement clinical and hemodynamic assessments has not been established. We assessed clinical, echocardiographic, and laboratory data in 76 patients with AS or heart valve replacement (HVR), age 77 years, 37% women. Laboratory assessments included von Willebrand factor (VWF) antigen, activity, (Act/Ag, normal > 0.8), VWF multimer distribution (abnormal=loss of highest molecular weight multimers=Mult+), brain natriuretic peptide (BNP, abnormal > 155 pg/ml=BNP+), and platelet function analyzer 100 collagen-ADP closure time (PFA, normal < 121 seconds). Table: Coefficients of correlation, r, and F statistic. Chi-square, and probability. Correlation of BNP to mean gradient in patients with GFR>60 remained poor, r=0.29, while for PFA r = 0.65. Median (IQR) for PFA and BNP for mild, moderate, and severe AS and HVR are shown below. VWF multimers were abnormal in 3/14 mild AS, 6/14 moderate AS, 22/25 severe AS and 4/23 HVR patients. The severity of AS was most strongly associated with VWF multimer abnormality and prolonged PFA closure time, weakly with BNP, and not with VWF Act/Ag. Conclusion: Among various laboratory measures, PFA and VWF multimers are strongly associated with AS severity, and may merit assessment as complementary diagnostic and prognostic biomarkers in AS.

AbstractBackgroundHypertrophic cardiomyopathy (HCM) presents with a hypertrophied left ventricle (LV). It is often associated with LV outflow tract obstruction (LVOTO) and a risk for sudden death. This study aimed to describe outcomes of patients with HCM who underwent liver transplant (LT).MethodsA retrospective review was conducted for patients diagnosed with HCM undergoing LT. Patient characteristics, preoperative echocardiography results, HCM risk of sudden cardiac death prediction model score, and 5‐year mortality were examined. A univariable Cox proportional hazards model was used to evaluate the association between risk factors and 5‐year mortality. All tests were two‐sided with the alpha level set at .05.ResultsTwenty‐nine patients were included in the analysis. Six patients (21%) had a perioperative cardiopulmonary complication. The 5‐year survival rate was 61% (95% CI, 45–82). The analyzed risk factors showed that 5‐year post‐LT survival was significantly predicted by maximal LV outflow tract gradient at rest > 60 mmHg (hazard ratio, 1.04 [95% CI, 1.01‐1.06]).ConclusionsPreoperative LV outflow tract resting gradient > 60 mmHg was associated with 5‐year post‐LT mortality. The results suggest the severity of LVOTO identified by echocardiography is a prognostic tool for patients with HCM after LT.

Introduction: Elevations of troponin after subarachnoid hemorrhage (SAH) frequently occur and are associated with cardiopulmonary complications. The time to peak elevation remains poorly described in terms of the natural history after SAH. Our two objectives were to define the temporal profile of troponin T elevation after SAH and correlate levels of troponin T with baseline neurological status. We hypothesized that troponin T would peak early after initial presentation. Methods: We reviewed the medical records of all aneurysmal and non-traumatic SAH patients from March 2011-December 2012. Troponin T from patients with ≥ 2 values was recorded with respect to SAH symptom onset. Patients with ≥ 1 Troponin T value were stratified according to admission Glasgow Coma Scale (GCS). GCS was dichotomized to > 8 or ≤ 8. Fisher’s exact test was performed comparing elevated peak troponin T (≥0.01 ng/ml) versus normal against GCS status cutoffs > 8 or 8 or less. Results: We identified 124 patients who had both troponin T and GCS reported, and 30 patients had ≥2 troponin T measurements within the first 40 hours of hospitalization. The median time to peak troponin T in these patients was 11.2 hours with a standard deviation of 6.2 hours (Range: 4.9-35.0 hours). Elevated troponin T was seen in 52 of 124. GCS of ≤ 8 was present in 43 of 124. Patients with elevated levels of troponin T had a greater chance of lower GCS [Odds ratio = 4.8 (95% CI: 2.2 to 10.7)] (P= <0.0001). Conclusions: The median time to peak troponin T after SAH injury was 11 hours. There was a statistically significant association between troponin T elevation and worse neurologic status at presentation (GCS ≤ 8). Although our small sample size found large variation in time to peak troponin, it supports the hypothesis that troponin peaks early after the initial presentation. Future studies using troponin elevation as a biomarker should focus on sample acquisition at the time of admission and in the first 1-2 days.

Introduction: In hypertrophic cardiomyopathy (HCM), brain natriuretic peptide (BNP) has been weakly associated with septal thickness, diastolic function parameters, resting left ventricular outflow tract gradient ([[Unable to Display Character: &#8710;]]P), and more strongly associated with prognosis. Von Willebrand factor activity is known to be altered in HCM, and acquired bleeding may occur in up to ¼ of patients. Hypothesis: We hypothesized that indices of von Willebrand factor (VWF) activity would be more strongly related to [[Unable to Display Character: &#8710;]]P than BNP. Methods: We compared BNP and three independent measures of VWF function to echo/Doppler parameters in 84 HCM patients. Results: In obstructive (resting [[Unable to Display Character: &#8710;]]P ≥30 mm Hg), n-58 versus labile HCM (resting [[Unable to Display Character: &#8710;]]P <30 mm Hg, Valsalva [[Unable to Display Character: &#8710;]]P ≥30 mm Hg), n=28, VWF multimers were abnormal in 90% versus 52% (p=0.0005), VWF activity to antigen ratio was markedly lower, 0.76±0.09 vs 0.89±0.16, p<0.0001, and PFA markedly prolonged, 207±75 versus 129±61 seconds (p<0.0001), while BNP was moderately higher, 331±273 versus176±163 pg/ml, p=0.007. BNP correlated (Spearman rho, ρ), most strongly with echocardiographic E/e’ (ρ=0.51, p<0.001) and left atrial volume (ρ=0.34, p=0.003) but not peak gradient, [[Unable to Display Character: &#8710;]]P, (ρ=0.13, NS), while BNP normalized for age and gender was weakly associated with [[Unable to Display Character: &#8710;]]P, ρ=0.26,p=0.02 and powerfully associated with septal thickness (ρ=0.50, p<0.001), and left ventricular mass index (ρ=0.43, p<0.001). In contrast, quantitative VWF activity measures correlated strongly with [[Unable to Display Character: &#8710;]]P, VWF activity/antigen (ρ=-0.59, p<0.0001), and PFA (ρ=0.51, p<0.0001). In HCM patients with bleeding (n=31), VWF antigen level was higher than in those without bleeding suggesting that the combination of elevated total VWF antigen and absent high molecular weight multimers may be involved in the causation of bleeding. Conclusion: Our data suggest that BNP elevations are associated most strongly with E/e’, left atrial volume, septal thickness, and left ventricular mass, while VWF activity indices more strongly reflect [[Unable to Display Character: &#8710;]]P, and may thus have a complementary role in assessing therapeutic responses and prognosis. Loss of high molecular weight VWF multimers and elevated total VWF antigen concentration may be a novel marker of bleeding risk from acquired von Willebrand syndrome in HCM.

Introduction: Occurrence of stroke and myocardial infarction (MI) after carotid endarterectomy or stenting have each been associated with increased later mortality. Methods: In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) 69 strokes, 37 protocol MIs, and 19 biomarker + only events occurred within 30 days among 2272 patients followed up to 10 years. Mortality was determined and compared for patients with stroke, MI, or biomarker + only to those without. Cox proportional hazard models adjusting for age, sex, symptomatic status and treatment were calculated to assess the relationship between mortality and stroke and mortality and MI status. Kaplan-Meier survival curves were plotted. Results: Patients with peri-procedural stroke had a 67% greater likelihood of long-term mortality compared to those without stroke (HR=1.67, 95% CI 1.15,2.43; p<0.007)(Figure A). Patients with a protocol MI had a 249% greater likelihood of mortality, and biomarker+ only patients had a 104% greater likelihood of mortality, compared to those without MI (HR=3.49; 95%CI 2.20,5.53, p<0.0001; and HR=2.04; 95% CI 1.09,3.83, p=0.03)(Figure B). Discussion: Stroke, MI, and biomarker + only events following CEA or CAS are associated with increased long-term mortality. The higher risk for MI may be a marker for patients with serious underlying heart disease, rather than causal, providing an opportunity to decrease long-term mortality through aggressive diagnostic evaluation and preventive treatment.

It remains uncertain whether intensive control of blood pressure (BP) results in a lower risk of atrial fibrillation (AF) in patients with hypertension. Using data from SPRINT (Systolic Blood Pressure Intervention Trial), which enrolled participants with hypertension at increased risk of cardiovascular disease, we examined whether intensive BP lowering (target systolic BP [SBP] <120 mm Hg), compared with standard BP lowering (target SBP<140 mm Hg), results in a lower risk of AF. This analysis included 8022 participants (4003 randomized to the intensive arm and 4019 to standard BP arm) who were free of AF at the time of enrollment and with available baseline and follow-up electrocardiographic data. AF was ascertained from standard 12-lead electrocardiograms recorded at biannual study examinations and an exit visit. During up to 5.2 years of follow-up and a total of 28 322 person-years, 206 incident AF cases occurred; 88 in the intensive BP-lowering arm and 118 in the standard BP-lowering arm. Intensive BP lowering was associated with a 26% lower risk of developing new AF (hazard ratio, 0.74 [95% CI, 0.56–0.98]; P =0.037). This effect was consistent among prespecified subgroups of SPRINT participants stratified by age, sex, race, SBP tertiles, prior cardiovascular disease, and prior chronic kidney disease when interactions between treatment effect and these subgroups were assessed using Hommel adjusted P values. In conclusion, intensive treatment to a target of SBP <120 mm Hg in patients with hypertension at high risk of cardiovascular disease has the potential to reduce the risk of AF. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Abstract Abstract 3377 Background Bleeding from AVWS may occur in aortic stenosis (AS), hypertrophic cardiomyopathy (HCM), mitral regurgitation (MR), and prosthetic valve dysfunction (PVD) due to loss of von Willebrand factor (VWF) high molecular weight multimers caused by shear stress. Traditional laboratory testing for AVWS, including VWF antigen (VWF:Ag) and ristocetin cofactor activity lack sensitivity in this setting, and VWF multimer analysis, a costly and time-consuming test, must be used for confirmative diagnosis. The goal of this study is to develop a clinical and laboratory approach to predict the likelihood of AVWS, and consequently obviate the need for multimer analysis. Methods 160 patients with or without a bleeding history were prospectively enrolled with mild, moderate, or severe AS (n=65), HCM (n=32), MR (n=25), or with heart valve replacement (n=38). These patients were investigated at the time of clinically indicated echocardiography with VWF latex immunoturbidic activity (VWF:Ltx), VWF:Ag, (abnormal versus normal cutoff of VWF:Ltx/VWF:Ag is <0.80) platelet function analyzer 100 collagen ADP (PFA-CADP) and VWF multimer analysis. Single variable logistic regression analysis was performed to estimate clinical or laboratory variables that were strongly associated with the probability of abnormal multimers, including results of echocardiographic peak velocity and PFA-CADP. Associations with abnormal multimers were summarized with estimated relative risk (RR) and 95% CI. A scoring system was then created to evaluate the risk of abnormal multimers among cardiac patients. Results Overall, 50% of patients had abnormal multimers, indicating likely AVWS. The estimated probability of abnormal multimers showed a significant association between peak velocity, PFA-CADP and VWF:Lx/Ag (Table 1). Logistic regression analysis using forward selection identified only peak velocity (p<0.001) and PFA-CADP (p=0.033) as the factors showing the strongest evidence of association with abnormal multimers. VWF:Lx/Ag was no longer significant after adjusting for these two variables. Estimated relative risk of abnormal multimers for values of peak velocity and PFA-CADP were then derived (Table 2). From these relative risks a scoring algorithm was created in order to determine who should be screened for abnormal multimers. A value of 1 was subtracted from each relative risk and rounded to the nearest integer to obtain a score for peak velocity (<3 m/sec=0, 3.0–3.9 m/sec=3, 4.0–4.9 m/sec=5, >5.0 m/sec=7), and for PFA-CADP (≤120 sec=0, 121–180 sec=2, > 180 sec=3). The score from each of the two variables was added to obtain a total score ranging from 0 to 10. The risk score was categorized into four levels, which are 0, 2–3, 5–7, and 8–10, as shown in Table 3. Conclusion Both hemodynamic severity and PFA-CADP testing results could be incorporated into a scoring system to identify potential AVWS due to loss of HMWM in patients with various cardiovascular conditions. Further studies are needed to validate such a scoring system in a separate set of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Association of acquired von Willebrand syndrome (AVWS) with various cardiovascular (CV) disorders such as cardiac valve disease and hypertrophic cardiomyopathy (HCM) is well known and documented. The mechanism is thought to be related to shear stress induced loss of high molecular weight multimers (HMWM). The gold standard test to assess for loss of HMWM is von Willebrand protein electrophoresis and then visual assessment of loss of high molecular weight bands. This is both a costly and subjective test. Ratio of von Willebrand factor activity to antigen level is useful in patients with type IIA Von Willebrand Disease caused by loss of HMW multimer, but its sensitivity to detect CV-associated AVWS is unknown. Aim Our aim was to test whether routine VWF laboratory tests could be used to predict which patients with CV conditions are going to have high molecular weight multimer loss. We also aimed to assess whether these tests could be used to predict bleeding risk in patients with CV disorders. Methods We prospectively collected laboratory data of 234 patients with cardiovascular disorders known to be associated with AVWS: aortic stenosis (66), aortic insufficiency(22), aortic and mitral valve prostheses(38), mitral valve regurgitation (51) and hypertrophic cardiomyopathy(57). All patients had Von Willebrand factor antigen (VWF:Ag), Von Willebrand factor activity by latex method (VWF:Ltx), platelet function testing via PFA-100 CADP as well as von Willebrand factor multimers tested. All patients also completed a bleeding questionnaire. We used logistic regression model to calculate the relationship between the VWF:Ltx/VWF:Ag ratio and loss of high molecular weight multimers. Same analysis was performed for PFA-100. We also tested these associations for bleeding risk. Results Mean value for VWF:Ag was 142 IU/dL, VWF:Ltx 121%, PFA-100 151 seconds and 0.86 for the VWF:Ltx/Ag ratio. Over a half of patients (56%) had VWF multimer loss noted on protein electrophoresis testing and a quarter reported bleeding on bleeding questionnaire. The ratio of VWF:Ltx to VWF:Ag had strong correlation with HMW multimer loss (p<0.001) with AUC of 0.77. Correlation with PFA-100 was even stronger with AUC of 0.83. The ratio cut off value of 0.83 had sensitivity of 60% and specificity of 83% in predicting multimer loss. With the cut off of 0.77, specificity reached 95%. With PFA 100 value of 118 seconds, specificity was 76% and sensitivity was 80%. Increasing the cut off to 198 seconds improved the specificity to 95%. The association with bleeding was present for PFA-100 (p=0.01), but did not exist for the Ltx/Ag ratio. Conclusions PFA-100 CADP as well as VWF:Ag and VWF:Ltx can be used to detect acquired Von Willebrand disease in patients with cardiovascular disorders and may decrease the need for costly and time consuming testing of multimers. PFA-100 CADP also correlates with the bleeding risk in these patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3315 Background: Acquired von Willebrand syndrome (AVWS) is a frequent cause of bleeding in patients with severe aortic stenosis (AS). The goals of this study were to understand the incidence and patterns of bleeding in patients with various degree of AS and identify predictors for bleeding. Methods: Ninety-one patients (59 men, median age 79 years) with mild, moderate or severe aortic stenosis (AS) (n=64) or heart valve replacement (n=27) were studied. Clinically significant bleeding was determined based on the 2008 NHLBI VWD diagnostic guideline (Haemophilia. 2008, 14(2):171–232). We recorded blood counts, vital signs, mean gradient, peak aortic velocity, 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, and closure times of platelet function analysis ADP and epinephrine cartridges (PFA–CADP and –CEPI). VWF high molecular weight multimer (HMWM) losses were graded as normal/mild or severe when compared to pooled plasma samples from normal donors. Associations with bleeding tendency were explored using single variable and multivariable logistic regression models. Results: Of the 91 patients, 29 (32%) were taking warfarin, and 55 (60%) were taking aspirin. None received a thienopyridine. Clinically significant bleeding was seen in 27 (30%) patients with gastrointestinal (GI) bleeding being most common (n=13). Nine patients who bled required hospitalization. Bleeding tendency was more common in patients with a severe loss of HMWM (OR=3.18, 95% CI: 1.06–9.71, P=0.039) and in patients with AS-associated symptoms (OR=3.02, 95% CI: 1.14–8.24, P=0.027). No other echocardiographic, laboratory, or clinical features demonstrated a statistically significant association with bleeding tendency. Conclusion: The incidence of clinically significant bleeding in this population was about 30% with GI being the most common site. Bleeding tendency was associated with severe HMWM loss and AS-associated symptoms. This study underscores the importance of acquisition of a history of bleeding, cardiac symptoms, and VWF multimer analysis in clinical management of AS patients. Disclosures: No relevant conflicts of interest to declare.