HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

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 < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

Observational and Genetic Associations of Resting Heart Rate With Aortic Valve Calcium.

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.

Usefulness of precordial T-wave inversion to distinguish arrhythmogenic right ventricular cardiomyopathy from idiopathic ventricular tachycardia arising from the right ventricular outflow tract.

The 2 predominant causes of ventricular tachycardia (VT) arising from the right ventricle are arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic VT arising from the right ventricular outflow tract (RVOT). These arrhythmias can be adrenergically mediated and may be difficult to distinguish clinically. A minor criterion for the diagnosis of ARVC is T-wave inversion (TWI) in the right precordial leads during sinus rhythm. However, there have been reports of precordial TWI identified in patients with RVOT tachycardia. The purpose of this study was to determine whether patterns of precordial TWI could differentiate between the 2 groups. A multicenter registry of 229 patients with VT of right ventricular origin was evaluated. After appropriate exclusions (n = 29), 79 patients (58% men, mean age 40 +/- 14 years) had ARVC, and 121 patients (41% men, mean age 48 +/- 14 years) had RVOT tachycardia. During sinus rhythm, 37 patients (47%) with ARVC and 5 patients (4%) with RVOT tachycardia had TWI in leads V(1) to V(3). For the diagnosis of ARVC, TWI in leads V(1) to V(3) had sensitivity of 47% and specificity of 96%. In conclusion, in patients with VT of right ventricular origin, the presence of TWI in electrocardiographic leads V(1) to V(3) supports the diagnosis of ARVC.

Creating an ontology-based human phenotyping system: The Rockefeller University bleeding history experience.

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.

Predictive value of microvolt T-wave alternans in patients with left ventricular dysfunction.

OBJECTIVES: The 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. BACKGROUND: Microvolt TWA has been proposed as a useful tool in identifying patients unlikely to benefit from prophylaxis with implantable cardioverter-defibrillator (ICD) prophylaxis. METHODS: We evaluated 286 patients with an LV ejection fraction

Effect of bundle branch block on microvolt T-wave alternans and electrophysiologic testing in patients with ischemic cardiomyopathy.

BACKGROUND: T-wave alternans (TWA) and electrophysiology study (EPS) are used for risk stratification for sudden death. OBJECTIVE: The purpose of the study was to determine the effect of bundle branch block or intraventricular conduction delay on TWA and EPS. METHODS: 386 patients with coronary artery disease, nonsustained ventricular tachycardia, and left ventricular ejection fraction < or =40% underwent TWA and EPS, and were followed for 40 +/- 19 months. RESULTS: 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. CONCLUSION: 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.

Effect of oral beta-blocker therapy on microvolt T-wave alternans and electrophysiology testing in patients with ischemic cardiomyopathy.

BACKGROUND: Prior investigation has shown that intravenous beta-blockers decrease T-wave alternans (TWA) positivity in patients undergoing electrophysiology study (EPS). The present study examined whether oral beta-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 < or = 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. Beta-blocker status was determined based on oral beta-blocker use in the 24 hours preceding the test: beta-blocker (-) (n = 62), beta-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 beta-blocker use were calculated based on event-free 2-year survival. RESULTS: There was no difference in EPS (31 [50%] inducible off beta-blockers vs 166 [51%] on beta-blockers [P = .89]) or TWA (26 [42%] positive, 17 [27%] indeterminate off beta-blockers vs 136 [42%] positive, 81 [25%] indeterminate on beta-blockers [P = .89]). Beta-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 beta-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.

Bilateral total knee arthroplasty increases the propensity to trip on an obstacle.

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.