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Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.

The lack of standardized methods for human phenotyping is a major obstacle in translational science. We have developed a bleeding history phenotyping system comprising an ontology, a questionnaire, a Web‐based phenotype recording instrument (PRI), and a database. The ontology facilitates transparency, collaboration, aggregation of data, and data analysis. The integrated system allows investigators worldwide to use the PRI, add their de‐identified data to the database, and query the aggregated data. Thus, this system can increase the power to detect genotype–phenotype–environment relationships and help new investigators begin their studies. We anticipate that this approach may be applicable to other disorders.

Background: Previous studies have suggested that the benefit of implantable cardioverter defibrillator (ICD) implantation in patients following coronary revascularization (CR) may be related to time elapsed since revascularization, with those receiving the device > 6 months after the procedure deriving the greatest benefit. Methods: We evaluated 163 patients (141 M/22 F, age 67 ± 11 y, LVEF 30 ± 8%) with a history of CR who underwent electrophysiology study (EPS) for risk stratification. ICD implantation was at the discretion of the treating physician. Oc- currence of arrhythmia in ICD patients was ascertained from regular device clinic follow-up. Vital status was assessed us- ing the National Death Index. Results: 101 patients (62%) had recent CR (� 6 months before EPS) vs 62 (38%) with remote CR (> 6 months). Median follow-up was 29 ± 17 months. There was no difference in arrhythmia-free survival (p = 0.89, 84 (83%) vs 52 (84%) at 12 months), time to appropriate ICD therapy (p = 0.35, 94 (93%) vs 55 (89%) at 12 months), or overall survival (p = 0.15, 91 (90%) vs 59 (95%) at 12 months) between recent and remote CR patients. Conclusions: Overall survival, arrhythmia-free survival, and time to first appropriate ICD therapy are similar between pa- tients with recent and remote CR undergoing an EPS-guided approach to risk stratification.

ObjectivesThe purpose of this study was to prospectively evaluate the utility of microvolt T-wave alternans (TWA) in predicting arrhythmia-free survival and total mortality in patients with left ventricular (LV) dysfunction.BackgroundMicrovolt TWA has been proposed as a useful tool in identifying patients unlikely to benefit from prophylaxis with implantable cardioverter-defibrillator (ICD) prophylaxis.MethodsWe evaluated 286 patients with an LV ejection fraction ≤35% who underwent TWA and electrophysiologic testing (EPS) owing to nonsustained ventricular tachycardia and/or syncope. Positive and indeterminate TWA results were grouped as non-negative. The primary end point was arrhythmia-free survival; the secondary end point was all-cause mortality.ResultsPatients were followed for a mean of 38 ± 11 months. There was no significant difference between the TWA-negative (n = 90; 31%) and non-negative (n = 196; 69%) groups with respect to ICD implant rates (54% vs. 64%, respectively; p = 0.95) or etiology of cardiomyopathy (ischemic: 73% vs. 76%; p = 0.71). The Kaplan-Meier curves demonstrated improved arrhythmia-free survival in TWA-negative patients (81% vs. 66% at 2 years; p < 0.001), including in both ischemic (79% vs. 64% at 2 years; p = 0.004) and nonischemic (88% vs. 71% at 2 years; p = 0.015) subgroups. Total mortality was lower in the TWA-negative group (10% vs. 18% at 2 years; p = 0.04). The negative predictive value of TWA for (2-year) total mortality was 90%, and 83% for EPS.ConclusionMicrovolt TWA predicts arrhythmia-free survival among patients with LV dysfunction. However, the event rate in the TWA-negative group suggests that TWA may not be capable of identifying a sufficiently low-risk subset in this population to obviate the need for ICD implantation.

T-wave alternans (TWA) and electrophysiology study (EPS) are used for risk stratification for sudden death.The purpose of the study was to determine the effect of bundle branch block or intraventricular conduction delay on TWA and EPS.386 patients with coronary artery disease, nonsustained ventricular tachycardia, and left ventricular ejection fractionor =40% underwent TWA and EPS, and were followed for 40 +/- 19 months.Patients with wide QRS were more likely than narrow QRS patients to have nonnegative TWA (77% vs 63%, P.01) or positive EPS (60% vs 48%, P = .03). Nonnegative TWA predicted the combined endpoint of ventricular tachyarrhythmia or death in narrow QRS (HR = 1.64, P = .04) but not wide QRS patients (HR = 1.04, P = .91). Similarly, positive EPS predicted the combined endpoint in narrow QRS (HR = 2.28, P.001) but not wide QRS patients (HR = 0.94, P = .84). In multivariate analysis, QRS width and TWA, as well as QRS width and EPS, were independent predictors of events. There was no TWA- or EPS-based difference in arrhythmia-free survival within any specific wide QRS morphology.TWA and EPS are more often abnormal in patients with a wide QRS than in those with a narrow QRS. In patients with narrow QRS, both TWA and EPS stratify patients according to their risk of ventricular tachyarrhythmia or death. However, among patients with a wide QRS, regardless of specific QRS morphology, the risk is high and comparable regardless of TWA or EPS results. Therefore, the only truly low-risk group consists of those patients with negative test results and a narrow QRS.

Background Prior investigation has shown that intravenous β -blockers decrease T-wave alternans (TWA) positivity in patients undergoing electrophysiology study (EPS). The present study examined whether oral β -blocker use within 24 hours of TWA influences yield and predictive value of TWA and EPS. Methods We prospectively evaluated 387 patients (312 [81%] men, mean age 67 ± 11 years) with coronary artery disease, left ventricular ejection fraction ≤40%, and nonsustained ventricular tachycardia who underwent EPS and were followed for a mean of 2.8 ± 1.4 years. T-Wave alternans was performed using an atrial pacing protocol and interpreted using standard criteria. β -Blocker status was determined based on oral β -blocker use in the 24 hours preceding the test: β -blocker (−) (n = 62), β -blocker (+) (n = 325). Follow-up for ventricular tachycardia, ventricular fibrillation, and death was obtained from chart review, device interrogation, and the Social Security Death Index. Estimated sensitivity and specificity of TWA and EPS stratified by β -blocker use were calculated based on event-free 2-year survival. Results There was no difference in EPS (31 [50%] inducible off β -blockers vs 166 [51%] on β -blockers [ P = .89]) or TWA (26 [42%] positive, 17 [27%] indeterminate off β -blockers vs 136 [42%] positive, 81 [25%] indeterminate on β -blockers [ P = .89]). β -Blocker use within 24 hours of testing did not affect the predictive value of TWA or EPS for overall or 2-year event-free survival. Conclusions Oral β -blocker therapy appears to have no effect on yield or predictive value of EPS or TWA in patients with coronary artery disease, diminished left ventricular function, and a history of nonsustained ventricular tachycardia.

Background: There is limited information regarding genetic contributions to atherosclerotic aortic calcification, an important predictor of cardiovascular disease. Methods: We conducted a genome-wide association study (GWAS) meta-analysis with subsequent replication analysis to define single nucleotide polymorphisms (SNPs) associated with abdominal (AAC) or thoracic aortic calcification (TAC). AAC and TAC were quantified using multi-detector computed tomography. SNPs were assayed by Illumina or Affymetrix arrays and imputation at the cohort level was performed using data from the 1000 Genomes project. Results: 9417 individuals of European descent from four cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium were included in the AAC discovery analysis and 8422 individuals from five cohorts in the TAC discovery analysis. SNPs achieving genome-wide significance were tested for replication in four additional cohorts with Hispanic-American (HA) and African-American (AA) participants. Two regions contained SNPs associated at a genome-wide level for AAC (p-8 , Table), the HDAC9 (chromosome 7, 6 SNPs) and RAP1GAP (chromosome 1, 2 SNPs) genetic loci. All six HDAC9 SNPs were associated with AAC in HA. Among these, rs2107595 was associated with AAC both in HA (p=2.8x10 -6 ) and in AA (p=0.01). SNPs in RAP1GAP were not associated with AAC in the replication analysis. No SNPs were associated with TAC at the genome-wide threshold. SNPs in the HDAC9 locus were associated with other forms of calcification (coronary artery calcification) as well as clinically apparent coronary heart disease (pHDAC9 locus are associated with the presence of AAC in participants of European descent. This association was replicated in other ethnic groups in the United States. These findings suggest a novel role for HDAC9 in the development of abdominal aortic calcification.

Tripping over an obstacle is the most frequent cause of falls. We examined the effects of total knee arthroplasty on obstacle avoidance success rates in older adults. Obstacle avoidance success rates, body mass index, visual acuity, contrast sensitivity, depth perception, and single-leg stance duration were evaluated in 29 subjects who had bilateral total knee arthroplasties (age range, 72.6 +/- 5.4 years) and 27 age-matched healthy control subjects (age range, 70.6 +/- 5.5 years). The patients who had total knee arthroplasties had a lower obstacle avoidance success rate, lower single-leg stance duration, and greater body mass index than control subjects. Age, contrast sensitivity, and depth perception were not different between patients who had total knee arthroplasties and control subjects. Obstacle avoidance success rates decreased linearly as single-leg stance duration decreased in the control group and across all groups, but not in the group that had total knee arthroplasties. Linear relationships between obstacle avoidance success rates and body mass index existed for all subjects but not for the group that had total knee arthroplasties or the control group individually. Total knee arthroplasty reduces obstacle avoidance success rate, suggesting that persons who have total knee arthroplasties have an increased propensity to trip on an obstacle and fall. Increased body mass index and decreased single-leg stance duration in patients who have total knee arthroplasties are associated with a decreased obstacle avoidance success rate.

To the editor: Desmopressin (dDAVP) is a synthetic analog of vasopressin that stimulates release of von Willebrand factor (VWF). This effect is attenuated in vitro by a type 2 vasopressin receptor (V2R) antagonist.[1][1] dDAVP is administered for prophylaxis and treatment of bleeding in von

Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0–3 for adult males, 0–5 for adult females and 0–2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.

The cardiologist is frequently called upon to assist in the management of patients with cardiovascular disease in the perioperative setting. Questions surrounding risk stratification, risk management, diagnostic testing, management of cardiovascular medications, and revascularization, among others, are germane to the optimal management of such patients. The cardiovascular consultant must be prepared to approach these questions in a systematic and evidence-based fashion.

Summary. Background: Comparing a patient’s bleeding symptoms with those of healthy individuals is an important component of the diagnosis of bleeding disorders, but little is known about whether bleeding symptoms in healthy individuals vary by sex, race, ethnicity, age, or aspirin use. Objectives, Patients/Methods: We developed a comprehensive, ontology-backed, Web-based questionnaire to collect bleeding histories from 500 healthy adults. The mean age was 43 years (range 19–86 years), 63% were female, 19% were Hispanic, 37% were African-American, 43% were Caucasian, 8% were Asian, and 4% were multiracial. Results: 18 of the 36 symptoms captured occurred with

Objective.To use the findings of an active surveillance program to delineate the unique epidemiology of vancomycin-resistant enterococci (VRE) in a mixed population of transplant and nontransplant patients hospitalized on a single patient care unit.Design.Surveillance survey and case-control analysis.Setting.A 19-bed adult bone marrow and stem cell transplant unit at a referral and primary-care center.Patients.The study included patients undergoing transplantation, patients who had previously received bone marrow or stem cell transplants, and patients with other malignancies and hematological disorders who were admitted to the study unit.Methods.Patients not previously identified as colonized with VRE had perirectal swab specimens collected at admission and once weekly while hospitalized on the unit. The prevalence of VRE colonization at admission and the incidence throughout the hospital stay, genotypes of VRE specimens as determined by pulsed field gel electrophoresis, and risk factors related to colonization were analyzed.Results.There was no significant difference in the prevalence or incidence of new colonization between nontransplant patients and prior or current transplant recipients, although overall prevalence at admission was significantly higher in the prior transplant group. Preliminary genotypic analysis of VRE isolates from transplant patients suggests that a proportion of cases of newly detected VRE carriage may represent prior colonization not detected at admission, with different risk factors suggestive of a potential epidemiological distinction.Conclusion.Examination of epidemiological and microbiological data collected by an active surveillance program provides useful information about the epidemiology of VRE that can be applied to inform rational infection control strategies.

Tripping on an object is the most frequent cause of falls. We examined the effects of painful osteoarthritis of the knee on obstacle avoidance success rates in older adults. Obstacle avoidance success rates, pain, body mass index, visual acuity, contrast sensitivity, depth perception, and single-leg stance duration were evaluated in 17 patients with painful osteoarthritis of the knees (age range, 59.6 +/- 8.1 years) and 14 age-matched healthy control subjects (age range, 61.1 +/- 10.0 years). The patients with osteoarthritis of the knees had a 37% lower obstacle avoidance success rate, a 54% lower single-leg stance duration, and a 24% greater body mass index than the control subjects. Age, visual acuity, contrast sensitivity, and depth perception were not different between the two groups. Obstacle avoidance success rates and single-leg stance durations decreased linearly as pain increased in the patients with osteoarthritis of the knees. Obstacle avoidance success rates also decreased linearly as single-leg stance duration decreased in the patients with osteoarthritis of the knees. Osteoarthritis of the knees reduced obstacle avoidance success rates, supporting epidemiologic studies that have found osteoarthritis to be a risk factor for falls. This study showed that pain associated with osteoarthritis of the knees increased the propensity to trip on an obstacle (the greater the pain the greater the propensity to trip and fall) and underscores the importance of treating pain associated with osteoarthritis.

Background Challenges in reporting subjective hemorrhagic symptoms consistently has led to the need for standardized, quantitative Bleeding Assessment Tools (BATs), some of which assign Bleeding Scores (BSs). The ISTH-BAT (International Society on Thrombosis and Hemostasis – Bleeding Assessment Tool (Rodeghiero et al JTH 2010; 8:2063)) aimed to consolidate and optimize advances made by its predecessors, which were based on the 2005 “Vicenza Bleeding Questionnaire”. It is important to note, however, that the scoring systems differ among the BATs, with each bleeding symptom scored from 0 to +3 for the original Vicenza, -1 to +4 for the MCMDM-1VWD and Condensed MCMDM-1VWD Bleeding Questionnaires and the PBQ (Pediatric Bleeding Questionnaire), and 0 to +4 for the ISTH-BAT. As a result, the normal ranges of BSs vary among questionnaires. To date, the normal range for the ISTH-BAT has not been established; the objective of this study was to determine the normal range of bleeding scores for the ISTH-BAT for both adults and pediatric patients. Patients and Methods BS data from different studies, originally generated using 4 different Vicenza-based BATs, were compiled using a bioinformatics system created to facilitate the collation and analysis using different scoring systems. Demographic and BS data, along with blood group, VWF:Ag/VWF:RCo/FVIII:C (when available) were collected from all enrolled subjects. Data were derived from multiple studies; all defined normal subjects as those without a known problem with bleeding or bruising. All BATs were expert-administered. The normal range for both adults and pediatrics was determined by: 1) removing outliers > 3 SD away from the mean and then, 2) selecting the mid-95th %ile. Results 1,422 normal subjects were included (adult: n=1,079, pediatric: n=343). Adult data were collected using MCMDM-1VWD (n=294), Condensed MCMDM-1VWD (n=660), and ISTH-BAT (n=125), while pediatric data were collected using PBQ (n=324) and ISTH-BAT (n=19). 48 adults were removed from the analysis because they had BSs > 6.3, (i.e., >3 SD away from the mean), leaving n=1,031 for determination of the normal range. For children, BSs > 3.5 were judged to be outliers and therefore 18 children were removed, leaving n=325 children for determination of the normal range. The remaining adults had a mean age of 43 yrs (range 18 – 88) with 695 females and 336 males. The remaining children had a mean age of 9 yrs (range 0.4 – 17 yrs), with 169 females and 156 males. The relationship between BSs and demographic and lab data are given in Table 1. For the ISTH-BAT, the normal range of BSs was 0 - 4 in adults (meaning that for individuals 18 yrs or older, a BS 5 or greater is positive or abnormal) and 0 - 2 in children (meaning that for individuals < 18 yrs, a BS 3 or greater is positive or abnormal). Conclusion The newly established normal BS ranges can now be used to objectively assess the bleeding symptoms of individuals by administration of the ISTH-BAT. They also highlight the strength of merging existing datasets to generate meaningful results. By making these data accessible to all investigators using the web-based ISTH-BAT system housed at Rockefeller University we hope to aid investigators initiating new studies and facilitate correlating bleeding symptoms with genotypic, molecular, and environmental data. Disclosures: Mauer: CSL Behring: Honoraria. James:CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Baxter: Honoraria; Bayer: Honoraria.