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OBJECTIVES: To assess the prognostic value of a new, comprehensive coronary computed tomography angiography (CTA) score compared with the stenosis severity component of the Coronary Artery Disease – Reporting and Data System (CAD-RAD S). BACKGROUND: Current risk assessment with coronary CTA is mainly focused on maximal stenosis severity. Integration of plaque extent, location and composition in a comprehensive model may improve risk stratification. METHODS: A total of 2,134 patients with suspected but without known CAD were included. The predictive value of the comprehensive CTA score (ranging from 0–42 and divided into three groups: 0–5, 6–20, and >20) was compared with the CAD-RADS combined into 3 groups (0 – 30%, 30 – 70% and ≥70% stenosis). Its predictive performance was internally and externally validated (using the 5-year follow-up dataset of the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM) registry, n = 1,971). RESULTS: Patients mean age was 55±13 years, mean follow-up 3.6 ± 2.8 years and 130 events (myocardial infarction or death) occurred. The new, comprehensive CTA score demonstrated strong and independent predictive value using Cox proportional hazard analysis. A model including clinical variables + comprehensive CTA score showed better discrimination of events compared with a model consisting of clinical variables + CAD-RADS (0.768 vs 0.742, P=0.001). Also, the comprehensive CTA score correctly reclassified a significant proportion of patients compared with conventional approach (net reclassification improvement 12.4%, P

Aims Patients hospitalized for heart failure (HF) are at high risk for 30-day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization. Methods and results Timing and cause of readmission in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0-7 days and 8-30 days post-discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post-randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180-day outcomes. Of the 6584 patients (92%) in the ASCEND-HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non-HF causes. The median time to rehospitalization was 11 days (interquartile range: 6-18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180-day all-cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93-2.94; P

Hypertension is an atherosclerosis factor and is associated with cardiovascular risk. We investigated the relationship between hypertension and the presence, extent, and severity of coronary atherosclerosis in coronary computed tomographic angiography and cardiac events risk. Of 17 181 patients enrolled in the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) who underwent ≥64-detector row coronary computed tomographic angiography, we identified 14 803 patients without known coronary artery disease. Of these, 1434 hypertensive patients were matched to 1434 patients without hypertension. Major adverse cardiac events risk of hypertension and non-hypertensive patients was evaluated with Cox proportional hazards models. The prognostic associations between hypertension and no-hypertension with increasing degree of coronary stenosis severity (nonobstructive or obstructive ≥50%) and extent of coronary artery disease (segment involvement score of 1-5, >5) was also assessed. Hypertension patients less commonly had no coronary atherosclerosis and more commonly had nonobstructive and 1-, 2-, and 3-vessel disease than the no-hypertension group. During a mean follow-up of 5.2±1.2 years, 180 patients experienced cardiac events, with 104 (2.0%) occurring in the hypertension group and 76 (1.5%) occurring in the no-hypertension group (hazard ratios, 1.4; 95% confidence intervals, 1.0-1.9). Compared with no-hypertension patients without coronary atherosclerosis, hypertension patients with no coronary atherosclerosis and obstructive coronary disease tended to have higher risk of cardiac events. Similar trends were observed with respect to extent of coronary artery disease. Compared with no-hypertension patients, hypertensive patients have increased presence, extent, and severity of coronary atherosclerosis and tend to have an increase in major adverse cardiac events.

Hypertension is an atherosclerosis factor and is associated with cardiovascular risk. We investigated the relationship between hypertension and the presence, extent, and severity of coronary atherosclerosis in coronary computed tomographic angiography and cardiac events risk. Of 17 181 patients enrolled in the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) who underwent ≥64-detector row coronary computed tomographic angiography, we identified 14 803 patients without known coronary artery disease. Of these, 1434 hypertensive patients were matched to 1434 patients without hypertension. Major adverse cardiac events risk of hypertension and non-hypertensive patients was evaluated with Cox proportional hazards models. The prognostic associations between hypertension and no-hypertension with increasing degree of coronary stenosis severity (nonobstructive or obstructive ≥50%) and extent of coronary artery disease (segment involvement score of 1-5,5) was also assessed. Hypertension patients less commonly had no coronary atherosclerosis and more commonly had nonobstructive and 1-, 2-, and 3-vessel disease than the no-hypertension group. During a mean follow-up of 5.2±1.2 years, 180 patients experienced cardiac events, with 104 (2.0%) occurring in the hypertension group and 76 (1.5%) occurring in the no-hypertension group (hazard ratios, 1.4; 95% confidence intervals, 1.0-1.9). Compared with no-hypertension patients without coronary atherosclerosis, hypertension patients with no coronary atherosclerosis and obstructive coronary disease tended to have higher risk of cardiac events. Similar trends were observed with respect to extent of coronary artery disease. Compared with no-hypertension patients, hypertensive patients have increased presence, extent, and severity of coronary atherosclerosis and tend to have an increase in major adverse cardiac events.

BACKGROUND It is unclear how patients hospitalized for acute heart failure (HF) who are long-term chronic HF survivors differ from those with more recent HF diagnoses. OBJECTIVES The goal of this study was to evaluate the influence of HF chronicity on acute HF patient profiles and outcomes. METHODS The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 hospitalized patients with acute HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. The present analysis compared patients according to duration of HF diagnosis before index hospitalization by using pre-specified cutoffs (0 to 1 month [i.e., "recently diagnosed"], >1 to 12 months, >12 to 60 months, and >60 months). RESULTS Overall, 5,741 (80.4%) patients had documentation of duration of HF diagnosis (recently diagnosed, n = 1,536; >1 to 12 months, n = 1,020; >12 to 60 months, n = 1,653; and >60 months, n = 1,532). Across HF duration groups, mean age ranged from 64 to 66 years, and mean ejection fraction ranged from 29% to 32%. Compared with patients with longer HF duration, recently diagnosed patients were more likely to be women with nonischemic HF etiology, higher baseline blood pressure, better baseline renal function, and fewer comorbidities. After adjustment, compared with recently diagnosed patients, patients with longer HF duration were associated with more persistent dyspnea at 24 h (>1 to 12 months, odds ratio [OR]: 1.20; 95% confidence interval [CI]: 0.97 to 1.48; >12 to 60 months, OR: 1.34; 95% CI: 1.11 to 1.62; and >60 months, OR: 1.31; 95% CI: 1.08 to 1.60) and increased 180-day mortality (>1 to 12 months, hazard ratio [HR]: 1.89; 95% CI: 1.35 to 2.65; >12 to 60 months, HR: 1.82; 95% CI: 1.33 to 2.48; and >60 months, HR: 2.02; 95% CI: 1.47 to 2.77). The influence of HF duration on mortality was potentially more pronounced among female patients (interaction p = 0.05), but did not differ according to age, race, prior ischemic heart disease, or ejection fraction (all interactions, p >= 0.23). CONCLUSIONS In this acute HF trial, patient profile differed according to duration of the HF diagnosis. A diagnosis of HF for

The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response.Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF).HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates.Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values0.05).In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Aims: A longitudinal and comprehensive analysis of health-related quality of life ( HRQOL ) was performed during hospitalization for heart failure ( HF ) or soon after discharge. Methods and results: A post-hoc analysis was performed of the ASCEND-HF trial. The EuroQOL five dimensions questionnaire ( EQ-5D ) was administered to study participants at baseline, 24 h, discharge/day 10, and day 30. EQ-5D includes functional dimensions mapped to corresponding utility scores ( i.e. 0 = death and 1 = perfect health ), and a visual analogue scale ( VAS ) ranging from 0 ( i.e. ‘worst imaginable health state’ ) to 100 ( i.e. ‘best imaginable health state’ ). The association between baseline and discharge EQ-5D measurements and subsequent clinical outcomes including death and rehospitalization were assessed using multivariable logistic regression and Cox proportional hazards regression. A total of 6943 patients ( 97% ) had complete EQ-5D data at baseline. Mapped utility and VAS scores ( mean ± SD ) increased over time, respectively, from 0.56 ± 0.23 and 45 ± 22 at baseline to 0.67 ± 0.26 and 58 ± 22 at 24 h and to 0.79 ± 0.20 and 68 ± 22 at discharge, and remained stable at day 30. Lower mapped utility scores at baseline [odds ratio ( OR ) per 0.1 decrease in utility score 1.03, 95% confidence interval ( CI ) 1.00–1.06] and discharge ( OR 1.10, 95% CI 1.05–1.15 ) and VAS scores at baseline ( OR per 10 point decrease 1.05, 95% CI 1.01–1.09 ) were significantly associated with increased risk of 30-day all-cause death or HF rehospitalization. Conclusions: Patients hospitalized for HF had severely impaired health status at baseline and, although this improved substantially during admission, health status remained abnormal at discharge.

Aims: We aimed to characterize abnormal liver function tests in patients with heart failure (HF), as they are commonly encountered yet poorly defined. Methods and results: We used data from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) to characterize associations with baseline liver function tests (LFTs). Each LFT was analysed as both a continuous and dichotomous variable [normal vs. abnormal; bilirubin > 1.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 35 mmol/L]. Logistic regression assessed the association of LFTs and 30-day all-cause mortality and HF rehospitalization, and Cox proportional hazards assessed the association with 180-day all-cause mortality among patients alive at a 30-day landmark. In ASCEND-HF, 4228 (59%) had complete admission LFT data. Of these, 42% had abnormal bilirubin, 22% had abnormal ALT, and 30% had abnormal AST. Patients with abnormal LFTs were younger, had lower body mass index, and lower left ventricular ejection fraction. In multivariable models, increased total bilirubin was associated with increased 30-day mortality or HF rehospitalization [hazard ratio (HR) 1.17 per 1 mg/dL increase, 95% confidence interval (CI) 1.04, 1.32; P = 0.012], but not with an increase in 180-day mortality (HR 1.10, 95% CI 0.97, 1.25; P = 0.13) per 1 mg/dl increase. Compared with normal bilirubin levels, abnormal bilirubin was associated with increased 30-day mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54; P = 0.048) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62; P = 0.007). We found no association with AST or ALT and outcomes. Conclusion: Greater than 40% of patients hospitalized with acute HF had abnormal LFTs. After multivariable adjustment, only elevated bilirubin was independently associated with worse clinical outcomes and may represent an important prognostic variable.

OBJECTIVES The purpose of this study was to describe the prevalence and severity of coronary artery disease (CAD) in relation to prognosis in symptomatic patients without coronary artery calcification (CAC) undergoing coronary computed tomography angiography (CCTA). BACKGROUND The frequency and clinical relevance of CAD in patients without CAC are unclear. METHODS We identified 10037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as 0 had a sensitivity specificity and negative and positive predictive values for stenosis =50 of 89 59 96 and 29 respectively. During a median of 2.1 years there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8907 patients with follow up for the composite endpoint 3.9 with a CAC score of 0 and =50 stenosis experienced an event (hazard ratio: 5.7; 95 confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8 of patients with a CAC score of 0 and no obstructive CAD. Receiver operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84). CONCLUSIONS In symptomatic patients with a CAC score of 0 obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.

OBJECTIVES We examined mortality in relation to coronary artery disease (CAD) as assessed by =64 detector row coronary computed tomography angiography (CCTA). BACKGROUND Although CCTA has demonstrated high diagnostic performance for detection and exclusion of obstructive CAD the prognostic findings of CAD by CCTA have not to date been examined for age and sex specific outcomes. METHODS We evaluated a consecutive cohort of 24775 patients undergoing =64 detector row CCTA between 2005 and 2009 without known CAD who met inclusion criteria. In these patients CAD by CCTA was defined as none (0 stenosis) mild (1 to 49 stenosis) moderate (50 to 69 stenosis) or severe (=70 stenosis). CAD severity was judged on a per patient per vessel and per segment basis. Time to mortality was estimated using multivariable Cox proportional hazards models. RESULTS At a 2.3 ± 1.1 year follow up 404 deaths had occurred. In risk adjusted analysis both per patient obstructive (hazard ratio [HR]: 2.60; 95 confidence interval [CI]: 1.94 to 3.49; p < 0.0001) and nonobstructive (HR: 1.60; 95 CI: 1.18 to 2.16; p = 0.002) CAD conferred increased risk of mortality compared with patients without evident CAD. Incident mortality was associated with a dose response relationship to the number of coronary vessels exhibiting obstructive CAD with increasing risk observed for nonobstructive (HR: 1.62; 95 CI: 1.20 to 2.19; p = 0.002) obstructive 1 vessel (HR: 2.00; 95 CI: 1.43 to 2.82; p < 0.0001) 2 vessel (HR: 2.92; 95 CI: 2.00 to 4.25; p < 0.0001) or 3 vessel or left main (HR: 3.70; 95 CI: 2.58 to 5.29; p < 0.0001) CAD. Importantly the absence of CAD by CCTA was associated with a low rate of incident death (annualized death rate: 0.28). When stratified by age

Cortical microelectrodes allow electrical contacts with neural cells and show promise as electrical interfaces to the brain, which allow for the treatment of several neurological deficits. However, the functionality of current electrodes decreases over time, in part due to neuron degeneration and foreign body encapsulation. One hypothesis is that the mismatch of the mechanical properties of the electrode and the brain tissue is a significant contributor to these events. We recently developed a new approach to chemically responsive, mechanically adaptive polymer nanocomposites, which are initially highly rigid, but soften considerably upon exposure to physiological conditions and aqueous environments in general. Initial in-vivo experiments suggest that the materials promise to be a useful platform for the design of next-generation intracortical devices.

ObjectiveWe sought to examine the risk of mortality associated with nonobstructive coronary artery disease (CAD) and to determine the impact of baseline statin and aspirin use on mortality.Approach and resultsCoronary computed tomographic angiography permits direct visualization of nonobstructive CAD. To date, the prognostic implications of nonobstructive CAD and the potential benefit of directing therapy based on nonobstructive CAD have not been carefully examined. A total of 27 125 consecutive patients who underwent computed tomographic angiography (12 enrolling centers and 6 countries) were prospectively entered into the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry. Patients, without history of previous CAD or obstructive CAD, for whom baseline statin and aspirin use was available were analyzed. Each coronary segment was classified as normal or nonobstructive CAD (1%-49% stenosis). Patients were followed up for a median of 27.2 months for all-cause mortality. The study comprised 10 418 patients (5712 normal and 4706 with nonobstructive CAD). In multivariable analyses, patients with nonobstructive CAD had a 6% (95% confidence interval, 1%-12%) higher risk of mortality for each additional segment with nonobstructive plaque (P=0.021). Baseline statin use was associated with a reduced risk of mortality (hazard ratio, 0.44; 95% confidence interval, 0.28-0.68; P=0.0003), a benefit that was present for individuals with nonobstructive CAD (hazard ratio, 0.32; 95% confidence interval, 0.19-0.55; P

BackgroundCoronary artery calcium (CAC) is a well-established predictor of clinical outcomes for population screening. Limited evidence is available as to its predictive value in symptomatic patients without obstructive coronary artery disease (CAD). The aim of the current study was to assess the prognostic value of CAC scores among symptomatic patients with nonobstructive CAD.MethodsFrom the COronary Computed Tomographic Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 7,200 symptomatic patients with nonobstructive CAD (0% but

ObjectiveWe examined the prevalence, extent, severity, and prognosis of coronary artery disease (CAD) in individuals with and without diabetes (DM) who are similar in CAD risk factors.Research design and methodsWe identified 23,643 consecutive individuals without known CAD undergoing coronary computed tomography angiography. A total of 3,370 DM individuals were propensity matched in a 1-to-2 fashion to 6,740 unique non-DM individuals. CAD was defined as none, nonobstructive (1-49% stenosis), or obstructive (≥ 50% stenosis). All-cause mortality was assessed by risk-adjusted Cox proportional hazards models.ResultsAt a 2.2-year follow-up, 108 (3.2%) and 115 (1.7%) deaths occurred among DM and non-DM individuals, respectively. Compared with non-DM individuals, DM individuals possessed higher rates of obstructive CAD (37 vs. 27%) and lower rates of having normal arteries (28 vs. 36%) (P < 0.0001). CAD extent was higher for DM versus non-DM individuals for obstructive one-vessel disease (19 vs. 14%), two-vessel disease (9 vs. 7%), and three-vessel disease (9 vs. 5%) (P < 0.0001 for comparison), with higher per-segment stenosis in the proximal and mid-segments of every coronary artery (P < 0.001 for all). Compared with non-DM individuals with no CAD, risk of mortality for DM individuals was higher for those with no CAD (hazard ratio 3.63 [95% CI 1.67-7.91]; P = 0.001), nonobstructive CAD (5.25 [2.56-10.8]; P < 0.001), one-vessel disease (6.39 [2.98-13.7]; P < 0.0001), two-vessel disease (12.33 [5.622-27.1]; P < 0.0001), and three-vessel disease (13.25 [6.15-28.6]; P < 0.0001).ConclusionsCompared with matched non-DM individuals, DM individuals possess higher prevalence, extent, and severity of CAD. At comparable levels of CAD, DM individuals experience higher risk of mortality compared with non-DM individuals.

Background— Large multicenter studies validating the prognostic value of coronary computed tomographic angiography (CCTA) and left ventricular ejection fraction (LVEF) are lacking. We sought to confirm the independent and incremental prognostic value of coronary artery disease (CAD) severity measured using 64-slice CCTA over LVEF and clinical variables. Methods and Results— A large international multicenter registry (CONFIRM Registry) was queried, and CCTA patients with LVEF data on CCTA were screened. Patients with a history of myocardial infarction, coronary revascularization, or cardiac transplantation were excluded. The National Cholesterol Education Program-Adult Treatment Panel III risk was calculated for each patient, and CCTA was evaluated for CAD severity (normal, nonobstructive, non–high-risk, or high-risk CAD) and LVEF Conclusions— Our results demonstrate that CCTA measures of CAD severity and LVEF have independent prognostic value. Incorporation of CAD severity provides incremental value for predicting all-cause death over routine clinical predictors and LVEF in patients with suspected obstructive CAD.

VCU Theses and Dissertations

ObjectivesWe examined mortality risk in relation to extent and composition of nonobstructive plaques by 64-detector row coronary computed tomographic angiography (CCTA).BackgroundThe prognostic significance of nonobstructive coronary artery plaques by CCTA is poorly understood.MethodsWe prospectively evaluated consecutive adults from 2 centers undergoing 64-detector row CCTA without prior documented coronary artery disease (CAD) and without obstructive (≥50%) CAD by CCTA. Luminal diameter stenosis severity was classified for each segment as none (0%) or mild (1% to 49%), and plaque composition was classified as noncalcified, calcified, or mixed.ResultsDuring 3.1 ± 0.5 years, 54 intermediate-term (≥90 days) deaths occurred among 2,583 patients (2.09%), with 4 early (

ObjectivesThis study sought to evaluate the impact of a multimodality-appropriate use criteria decision support tool (AUC-DST) on rates of appropriate testing and clinical decision making.BackgroundAUC have been developed to guide utilization of noninvasive imaging for individuals with suspected coronary artery disease (CAD). The effect of a point-of-order AUC-DST on rates of appropriateness and clinical decision making has not been examined.MethodsWe performed a prospective multicenter cohort study evaluating physicians who ordered CAD imaging tests for consecutive patients insured by 1 large private payer. During an 8-month study period, each study site was granted exemption from prior authorization requirements by radiology benefits managers. An AUC-DST was employed to determine appropriateness ratings for myocardial perfusion scintigraphy (MPS), stress echocardiography (STE), or coronary computed tomographic angiography (CCTA), as well as intended downstream testing and therapy.ResultsOne hundred physicians used the AUC-DST for 472 patients (age 55.6 ± 9.6 years, 61% male, 52% prior known CAD) over 8 months for MPS (72%), STE (24%), and CCTA (5%). The AUC-DST required an average of 137 ± 360 s to determine the appropriateness category that, by American College of Cardiology AUC, was considered appropriate in 241 (51%), uncertain in 96 (20%), inappropriate in 85 (18%), and not addressed in 50 (11%). For tests ordered in the first 2 months compared with the last 2 months, appropriate tests increased from 49% to 61% (p = 0.02), whereas inappropriate tests decreased from 22% to 6% (p < 0.001). During this period, intended changes in medical therapy increased from 11% to 32% (p = 0.001).ConclusionsA point-of-order AUC-DST enabled rapid determination of test appropriateness for CAD evaluation and was associated with increased and decreased testing for appropriate and inappropriate indications, respectively. These changes in test ordering were associated with greater intended changes in post-test medical therapy.

ObjectivesThe aim of this study was to determine the diagnostic performance of a new method for quantifying fractional flow reserve (FFR) with computational fluid dynamics (CFD) applied to coronary computed tomography angiography (CCTA) data in patients with suspected or known coronary artery disease (CAD).BackgroundMeasurement of FFR during invasive coronary angiography is the gold standard for identifying coronary artery lesions that cause ischemia and improves clinical decision-making for revascularization. Computation of FFR from CCTA data (FFRCT) provides a noninvasive method for identifying ischemia-causing stenosis; however, the diagnostic performance of this new method is unknown.MethodsComputation of FFR from CCTA data was performed on 159 vessels in 103 patients undergoing CCTA, invasive coronary angiography, and FFR. Independent core laboratories determined FFRCT and CAD stenosis severity by CCTA. Ischemia was defined by an FFRCT and FFR ≤0.80, and anatomically obstructive CAD was defined as a CCTA with stenosis ≥50%. Diagnostic performance of FFRCT and CCTA stenosis was assessed with invasive FFR as the reference standard.ResultsFifty-six percent of patients had ≥1 vessel with FFR ≤0.80. On a per-vessel basis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, for FFRCT and were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively, for CCTA stenosis. The area under the receiver-operator characteristics curve was 0.90 for FFRCT and 0.75 for CCTA (p = 0.001). The FFRCT and FFR were well correlated (r = 0.717, p < 0.001) with a slight underestimation by FFRCT (0.022 ± 0.116, p = 0.016).ConclusionsNoninvasive FFR derived from CCTA is a novel method with high diagnostic performance for the detection and exclusion of coronary lesions that cause ischemia. (The Diagnosis of ISChemia-Causing Stenoses Obtained Via NoninvasivE FRactional FLOW Reserve; NCT01189331)

Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.