Intra- and inter-reader reproducibility in quantitative coronary plaque analysis on coronary computed tomography angiography.

PURPOSE: Coronary artery plaque burden, low attenuation non-calcified plaque (LAP), and pericoronary adipose tissue (PCAT) on coronary CT angiography (CCTA), have been linked to future cardiac events. The purpose of this study was to evaluate intra- and inter reader reproducibility in the quantification of coronary plaque burden and its characteristics using an artificial intelligence-enhanced semi-automated software. MATERIALS AND METHODS: A total of 10 women and 6 men, aged 52 (IQR 49-58) underwent CCTA using a Siemens Somatom Force, Somatom Definition AS and Somatom Definition Flash scanners. Two expert readers utilized dedicated semi-automatic software (vascuCAP, Elucid Bioimaging, Wenham, MA) to assess calcified plaque, low attenuation plaque and PCAT. Readers were blinded to all clinical information and repeated their analysis at 6 weeks in random order to minimize recall bias. Data analysis was performed on the right and left coronary arteries. Intra- and inter-reader reproducibility was compared using Pearson correlation coefficient, while absolute values between analyses and readers were compared with paired non-parametric tests. This is a sub-study of the Specialized Center of Research Excellence (SCORE) clinical trial (5U54AG062334). RESULTS: A total of 64 vessels from 16 patients were analyzed. Intra-reader Pearson correlation coefficients for calcified plaque volume, LAP volume and PCAT volumes were 0.96, 0.99 and 0.92 for reader 1 and 0.94, 0.94 and 0.95 for reader 2, respectively, (all p < 0.0001). Inter-reader Pearson correlation coefficients for calcified plaque volume, LAP and PCAT volumes were 0.92, 0.96 and 0.78, and 0.99, 0.99 and 0.93 on the second analyses, all had a p value <0.0001. There was no significant bias on the corresponding Bland-Altman analyses. CONCLUSION: Volume measurement of coronary plaque burden and PCAT volume can be performed with high intra- and inter-reader agreement.

Circulating Progenitor Cells and Coronary Collaterals in Chronic Total Occlusion.

BACKGROUND: The role of circulating progenitor cells (CPC) in collateral formation that occurs in the presence of chronic total occlusions (CTO) of a coronary artery is not well established. In stable patients with a CTO, we investigated whether CPC levels are associated with (a) collateral development and (b) ischemic burden, as measured by circulating high sensitivity troponin-I (hsTn-I) levels. METHODS: CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34 and both CD34 and CD133 epitopes. The association between CPC counts and both Rentrop collateral grade (0, 1, 2, or 3) and hsTn-I levels were evaluated using multivariate regression analysis, after adjusting for demographic and clinical characteristics. RESULTS: In 89 patients (age 65.5, 72% male, 27% Black), a higher CPC count was positively associated with a higher Rentrop collateral grade; [CD34+ adjusted odds ratio (OR) 1.49 95% confidence interval (CI) (0.95, 2.34) P = 0.082] and [CD34+/CD133+ OR 1.57 95% CI (1.05, 2.36) P = 0.028]. Every doubling of CPC counts was also associated with lower hsTn-I levels [CD34+ ß -0.35 95% CI (-0.49, -0.15) P = 0.002] and [CD34+/CD133+ ß -0.27 95% CI (-0.43, -0.08) P = 0.009] after adjustment. CONCLUSION: Individuals with higher CPC counts have greater collateral development and lower ischemic burden in the presence of a CTO.

Association of Psychosocial Risk Factors With Quality of Life and Readmissions 1 Year After LVAD Implantation.

BACKGROUND: Among patients with advanced heart failure (HF), treatment with a left ventricular assist device (LVAD) improves health-related quality of life (HRQOL). We investigated the association between psychosocial risk factors, HRQOL and outcomes after LVAD implantation. METHODS: A retrospective cohort (n = 9832) of adults aged ≥ 19 years who received durable LVADs between 2008 and 2017 was identified by using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Patients were considered to have psychosocial risk factors if ≥ 1 of the following were present: (1) substance abuse; (2) limited social support; (3) limited cognitive understanding; (4) repeated nonadherence; and (5) major psychiatric disease. Multivariable logistic and linear regression models were used to evaluate the association between psychosocial risk factors and change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 scores from baseline to 1 year, persistently poor HRQOL (KCCQ-12 score < 45 at baseline and 1 year), and 1-year rehospitalization. RESULTS: Among the final analytic cohort, 2024 (20.6%) patients had ≥ 1 psychosocial risk factors. Psychosocial risk factors were associated with a smaller improvement in KCCQ-12 scores from baseline to 1 year (mean ± SD, 29.1 ± 25.9 vs 32.6 ± 26.1; P = 0.015) for a difference of -3.51 (95% confidence interval [CI]: -5.88 to -1.13). Psychosocial risk factors were associated with persistently poor HRQOL (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.04-1.74), and 1-year all-cause readmission (adjusted hazard ratio [aHR] 1.11, 95% CI 1.05-1.18). Limited social support, major psychiatric disorder and repeated nonadherence were associated with persistently poor HRQOL, while major psychiatric disorder was associated with 1-year rehospitalization. CONCLUSION: The presence of psychosocial risk factors is associated with lower KCCQ-12 scores and higher risk for readmission at 1 year after LVAD implantation. These associations are statistically significant, but further research is needed to determine whether these differences are clinically meaningful.

Heart Rate Variability, Deceleration Capacity of Heart Rate, and Death: A Veteran Twins Study.

BACKGROUND: Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. METHODS AND RESULTS: This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24-hour Holter ECGs. During an average 12-year follow-up, all-cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1-SD increase in log-transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low-frequency HRV and DC were significantly associated with lower hazards of all-cause death. In within-pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1-SD increment in low-frequency HRV and DC, respectively. Higher low-frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. CONCLUSIONS: Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

Psychological Distress and the Risk of Adverse Cardiovascular Outcomes in Patients With Coronary Heart Disease.

BACKGROUND: Psychological distress is a recognized risk factor in patients with coronary heart disease (CHD), but its clinical significance is unclear. OBJECTIVES: The purpose of this study was to determine if an index of psychological distress is independently associated with adverse outcomes and significantly contributes to risk prediction. METHODS: Pooled analysis of 2 prospective cohort studies of patients with stable CHD (N = 891). A psychological distress score was constructed using measures of depression, anxiety, anger, perceived stress, and post-traumatic stress disorder, measured at baseline. The study endpoint included cardiovascular death or first or recurrent nonfatal myocardial infarction or hospitalization for heart failure at 5.9 years. RESULTS: In both cohorts, first and recurrent events occurred more often among those in the highest tertile of distress score than those in the lowest tertile. After combining the 2 cohorts, compared with the lowest tertile, the hazards ratio for having a distress score in the highest tertile was 2.27 (95% CI: 1.69-3.06), and for the middle tertile, it was 1.52 (95% CI: 1.10-2.08). Adjustment for demographics and clinical risk factors only slightly weakened the associations. When the distress score was added to a traditional clinical risk model, C-statistic, net reclassification index, and integrative discrimination index all significantly improved. CONCLUSIONS: Among patients with CHD, a composite measure of psychological distress was significantly associated with an increased risk of adverse events and significantly improved risk prediction.

Long-Term Outcomes in Patients With Chronic Total Occlusion.

Although a chronic total occlusion (CTO) in the setting of an acute coronary syndrome is associated with greater risk, the prognosis of patients with a CTO and stable coronary artery disease (CAD) remains unknown. This study aimed to investigate adverse event rates in patients with stable CAD with and without a CTO. In 3,597 patients with stable CAD (>50% coronary luminal stenosis) who underwent cardiac catheterization, all-cause mortality, cardiovascular mortality, and the composite major adverse cardiac event (MACE) rates for cardiovascular death, myocardial infarction, and heart failure hospitalization were evaluated. Cox proportional hazards and Fine and Gray subdistribution hazard models were used to compare event-free survival in patient subsets after adjustment for covariates. Event rates were higher in patients with CTOs than in those without CTOs after adjusting for demographic and clinical characteristics (cardiovascular death hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.05 to 1.57, p = 0.012). Patients with CTO revascularization had lower event rates than those of patients without CTO revascularization (cardiovascular death HR 0.43, CI 0.26 to 0.70, p = 0.001). Those with nonrevascularized CTOs were at particularly great risk when compared with those without CTO (cardiovascular death HR 1.52, CI 1.25 to 1.84, p <0.001). Moreover, those with revascularized CTOs had similar event rates to those of patients with CAD without CTOs. Patients with CTO have higher rates of adverse cardiovascular events than those of patients with significant CAD without CTO. This risk is greatest in patients with nonrevascularized CTO.

Clinical correlates of CT imaging-derived phenotypes among lean and overweight patients with hepatic steatosis.

The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI.

Metabolomic signatures of ideal cardiovascular health in black adults.

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease.

AIMS: To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels. METHODS AND RESULTS: In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment. CONCLUSION: Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

In patients with coronary artery disease (CAD), we demonstrate that nearly half of the higher risk of all-cause and cardiovascular mortality associated with lower educational attainment as a measure of socioeconomic status is mediated by systemic inflammation and immune dysregulation, which can be estimated by measuring the circulating soluble urokinase plasminogen activator receptor (suPAR) levels. Even after accounting for differences in cardiovascular risk factors, lower educational attainment is associated with higher mortality risk in patients with CAD and there is activation of inflammatory pathways and immune dysregulation in those with lower (≤high school) educational attainment than in those with higher (≥college) educational attainment, estimated as higher circulating suPAR levels.Almost half of the higher risk for adverse outcomes observed in those with lower educational attainment appears to be due to systemic inflammation and immune dysregulation and can be estimated from measuring suPAR levels.

High sensitivity troponin I as a biomarker for cardiac allograft vasculopathy: Evaluation of diagnostic potential and clinical utility.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) limits long-term survival in heart transplant (HTx) recipients. The use of biomarkers in CAV surveillance has been studied, but none are used in clinical practice. The predictive value of high-sensitivity troponin I (hsTnI) has not been extensively investigated in HTx recipients. METHODS: HTx patients undergoing surveillance coronary angiograms and enrolled in the Emory Cardiovascular Biobank had plasma hsTnI measured. CAV grade was assessed using ISHLT nomenclature. Multivariable cumulative link mixed modeling was performed to determine association between hsTnI level and CAV grade. Patients were followed for adverse outcomes over a median 10-year period. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. RESULTS: Three hundred and seventy-two angiograms were analyzed in 156 patients at a median 8.9 years after transplant. hsTnI levels were positively correlated with concurrent CAV grade after adjustment for age, age at transplant, sex, BMI, hypertension, diabetes, hyperlipidemia, estimated glomerular filtration rate, and history of acute cellular rejection (p = .016). In an adjusted Cox proportional hazard model, initial hsTnI level above the median (4.9 pg/mL) remained a predictor of re-transplantation or death (hazard ratio 1.82; 95% confidence interval 1.16-2.90; p = .01). CONCLUSION: An elevated hsTnI level reflects severity of CAV and is associated with poor long-term outcomes in patients with HTx.

Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF): A Trial Providing Out-of-Pocket Costs for Heart Failure Medications during Clinical Encounters.

BACKGROUND: Evidence-based medical therapy for heart failure with reduced ejection fraction (HFrEF) often entails substantial out-of-pocket costs that can vary appreciably between patients. This has raised concerns regarding financial toxicity, equity, and adherence to medical therapy. In spite of these concerns, cost discussions in the HFrEF population appear to be rare, partly because out-of-pocket costs are generally unavailable during clinical encounters. In this trial, out-of-pocket cost information is given to patients and clinicians during outpatient encounters with the aim to assess the impact of providing this information on medication discussions and decisions. HYPOTHESIS: Cost-informed decision-making will be facilitated by providing access to patient-specific out-of-pocket cost estimates at the time of clinical encounter. DESIGN: Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF) is a multicenter trial based at Emory Healthcare and University of Colorado Health. Adapting an existing patient activation tool from the EPIC-HF trial, patients and clinicians are presented a checklist with medications approved for treatment of HFrEF with or without patient-specific out-of-pocket costs (obtained from a financial navigation firm). Clinical encounters are audio-recorded, and patients are surveyed about their experience. The trial utilizes a stepped-wedge cluster randomized design, allowing for each site to enroll control and intervention group patients while minimizing contamination of the control arm. DISCUSSION: This trial will elucidate the potential impact of robust cost disclosure efforts and key information regarding patient and clinician perspectives related to cost and cost communication. It also will reveal important challenges associated with providing out-of-pocket costs for medications during clinical encounters. Acquiring medication costs for this trial requires an involved process and outsourcing of work. In addition, costs may change throughout the year, raising questions regarding what specific information is most valuable. These data will represent an important step towards understanding the role of integrating cost discussions into heart failure care. GOV IDENTIFIER: NCT04793880.

Immune Activation Mediates the Association of Advanced Hepatic Fibrosis With Adverse Outcomes in Patients With Coronary Artery Disease.

BACKGROUND: Literature suggests a bidirectional association between advanced hepatic fibrosis (AHF) and coronary artery disease (CAD). We evaluated the association of AHF with immune activation, systemic inflammation, and adverse outcomes in patients with CAD. METHODS AND RESULTS: A fibrosis-4 index cutoff value ≥2.67 was used to define AHF. Circulating levels of soluble urokinase plasminogen activator receptor and hsCRP (high-sensitivity C-reactive protein) were measured as markers for immune activation and systemic inflammation, respectively. The relationship of AHF with soluble urokinase plasminogen activator receptor, hsCRP, and adverse cardiovascular outcomes was evaluated. Among 3406 participants with CAD, 479 had AHF. Participants with AHF were older; were less likely to be Black individuals; and had a lower body mass index, worse renal function, and a prior history of heart failure. In multivariable linear regression models adjusted for clinical and demographic confounders, participants with AHF had 15.6% higher soluble urokinase plasminogen activator receptor and 24.0% higher hsCRP levels. They were more likely to experience the following adverse outcomes: all-cause death (adjusted hazard ratio [HR], 1.57 ([95% CI, 1.29-1.92]; P<0.001) and cardiovascular death: (subdistribution HR, 1.50 [95% CI, 1.14-1.95]; P=0.003). Mediation analysis showed that 47.0% (95% CI, 13.6%-81.2%]; P=0.006) of the indirect effect of AHF on cardiovascular death was mediated by circulating soluble urokinase plasminogen activator receptor levels. CONCLUSIONS: AHF is independently associated with immune activation, systemic inflammation, and adverse cardiovascular outcomes in patients with CAD. The association of AHF with adverse outcomes is partly mediated by immune activation, and targeting this pathway may help reduce the residual risk in patients with CAD.

Exaggerated Peripheral and Systemic Vasoconstriction During Trauma Recall in Posttraumatic Stress Disorder: A Co-Twin Control Study.

BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) face an increased risk of cardiovascular disease, but the mechanisms linking PTSD to cardiovascular disease remain incompletely understood. We used a co-twin control study design to test the hypothesis that individuals with PTSD exhibit augmented peripheral and systemic vasoconstriction during a personalized trauma recall task. METHODS: In 179 older male twins from the Vietnam Era Twin Registry, lifetime history of PTSD and current (last month) PTSD symptoms were assessed. Participants listened to neutral and personalized trauma scripts while peripheral vascular tone (Peripheral Arterial Tone ratio) and systemic vascular tone (e.g., total vascular conductance) were measured. Linear mixed-effect models were used to assess the within-pair relationship between PTSD and vascular tone indices. RESULTS: The mean age of participants was 68 years, and 19% had a history of PTSD. For the Peripheral Arterial Tone ratio analysis, 32 twins were discordant for a history of PTSD, and 46 were discordant for current PTSD symptoms. Compared with their brothers without PTSD, during trauma recall, participants with a history of PTSD had greater increases in peripheral (ß = -1.01, 95% CI [-1.72, -0.30]) and systemic (total vascular conductance: ß = -1.12, 95% CI [-1.97, -0.27]) vasoconstriction after adjusting for cardiovascular risk factors. Associations persisted after adjusting for antidepressant medication use and heart rate and blood pressure during the tasks. Analysis of current PTSD symptom severity showed consistent results. CONCLUSIONS: PTSD is associated with exaggerated peripheral and systemic vasoconstrictor responses to traumatic stress reminders, which may contribute to elevated risk of cardiovascular disease.

High Sensitivity Troponin Level and Benefits of Chronic Total Occlusion Revascularization.

Background The survival benefit of revascularization of chronic total occlusion (CTO) of the coronary arteries remains a subject of controversy. We measured high sensitivity troponin-I (hsTn-I) levels as an estimate of myocardial ischemia in patients with stable coronary artery disease, with the hypothesis that (1) patients with CTO have higher levels of hsTn-I than patients without CTO, (2) hsTn-I levels will predict adverse cardiovascular events in patients with CTO, and (3) patients with elevated hsTn-I levels will have a survival benefit from CTO revascularization. Methods and Results In 428 patients with stable coronary artery disease and CTO undergoing coronary angiography, adverse event rates were investigated. Cox proportional hazards models and Fine and Gray subdistribution hazard models were performed to determine the association between hsTn-I level and incident event rates in patients with CTO. HsTn-I levels were higher in patients with compared with those without CTO (median 6.7 versus 5.6 ng/L, P=0.002). An elevated hsTn-I level was associated with higher adverse event rates (adjusted all-cause mortality hazard ratio, 1.19 [95% CI, 1.08-1.32]; P=0.030) for every doubling of hsTn-I level. CTO revascularization was performed in 28.3% of patients. In patients with a high (>median) hsTn-I level, CTO revascularization was associated with substantially lower all-cause mortality (adjusted hazard ratio, 0.26 [95% CI, 0.08-0.88]; P=0.030) compared with those who did not undergo revascularization. In patients with a low (

Aggregate Clinical and Biomarker-Based Model Predicts Adverse Outcomes in Patients With Coronary Artery Disease.

Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD.

Is the association between cognitive disease progression and atrial fibrillation modified by sex?

INTRODUCTION: It is unclear if sex differences exist in cognitive disease progression in mild cognitive impairment (MCI) and dementia associated with atrial fibrillation (AF). METHODS: Using a variety of statistical methods, we examined sex differences between AF and neuropsychological tests and cognitive disease progression, using the National Alzheimer's Coordinating Center data (N = 43,630). RESULTS: AF is associated with higher odds of dementia (odds ratio [OR] 3.00, 95% confidence interval [CI] [1.22, 7.37] in women and MCI in women (OR 3.43, 95% CI [1.55, 7.55]) versus men. Women with AF and normal baseline cognition had a higher risk of disease progression (hazard ratio [HR] 1.26, 95% CI [1.06, 1.50]) from normal to MCI and from MCI to vascular dementia (HR3.27, 95% CI [1.89, 5.65]) than men with AF or men and women without AF. DISCUSSION: AF was associated with more rapid progression to MCI and dementia in women, but more research is needed to confirm these findings.

Mental Stress-Induced Change in Plasma Stromal Cell-Derived Factor-1 and Adverse Cardiovascular Outcomes: A Cohort Study.

Background: Acute psychological stress can provoke mental stress-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 (SDF1) is released in response to hypoxia, and higher levels of SDF1 are associated with adverse outcomes. We examined whether an increase in SDF1 level in response to mental stress predicts adverse outcomes in CAD patients. Methods: A total of 554 patients with stable CAD (mean age 63 years; 76% male; 26% Black) underwent standardized mental stress testing. Plasma SDF1 levels were measured at rest and 90 minutes after mental stress, and MSIMI was evaluated by 99mTc-sestamibi perfusion imaging. Participants were followed for 5 years for the primary endpoint of composite of death and myocardial infarction (MI) and the secondary endpoint of composite of death, MI, and heart failure hospitalization. Cox hazard models were used to assess the association between SDF1 change and incident adverse events. Results: Mean (standard deviation) SDF1 change with mental stress was +56.0 (230) pg/mL. During follow-up, a rise of 1 standard deviation in SDF1 with mental stress was associated with a 32% higher risk for the primary endpoint of death and MI (95% confidence interval, 6%-64%), independent of the resting SDF1 level, demographic and clinical risk factors, and presence of ischemia. A rise of 1 standard deviation in SDF1 was associated with a 33% (95% confidence interval, 11%-59%) increase in the risk for the secondary endpoint, independent of the resting SDF1 level, demographic, and clinical risk factors and presence of ischemia. Conclusions: An increase in SDF1 level in response to mental stress is associated with a higher risk of adverse events in stable CAD, independent of MSIMI.

Contexte: Un stress psychologique aigu peut provoquer une ischémie myocardique induite par le stress mental chez les patients atteints d'une coronaropathie. Le facteur dérivé des cellules stromales de type 1 (SDF1) est libéré en réponse à une hypoxie, et des taux accrus de SDF1 sont associés à des résultats défavorables. Nous avons examiné si une élévation des taux de SDF1 en réponse à un stress mental permettait de prévoir la survenue de résultats défavorables chez des patients atteints d'une coronaropathie. Méthodologie: Au total, 554 patients présentant une coronaropathie stable (âge moyen de 63 ans; 76 % d'hommes; 26 % de patients de race noire) ont subi une évaluation standardisée du stress mental. Les taux plasmatiques de SDF1 ont été mesurés au repos et 90 minutes après un stress mental, et l'ischémie myocardique induite par le stress mental a été évaluée par imagerie avec injection de Tc-99m sestamibi. Les participants ont fait l'objet d'un suivi pendant cinq ans afin de surveiller la survenue des événements constituant le paramètre d'évaluation principal composé (décès et infarctus du myocarde [IM]) et le paramètre d'évaluation secondaire composé (décès, IM et hospitalisation en raison d'une insuffisance cardiaque). Des modèles de Cox ont été utilisés pour évaluer le lien entre la modification des taux de SDF1 et les événements indésirables susceptibles de survenir. Résultats: La variation moyenne du taux de SDF1 (écart-type) associée au stress mental a été de +56,0 (230) pg/ml. Pendant le suivi, une augmentation de 1 écart-type du taux de SDF1 en raison du stress mental a été associée à un risque 32 % plus élevé de survenue de l'un des événements constituant le paramètre d'évaluation principal (décès et IM) [intervalle de confiance [IC] à 95 % : 6 % à 64 %], indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Une augmentation de 1 écart-type du taux de SDF1 a été associée à un risque 33 % plus élevé (IC à 95 % : 11 % à 59 %) de survenue de l'un des événements constituant le paramètre d'évaluation secondaire, indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Conclusions: Une augmentation du taux de SDF1 en réponse à un stress mental est associée à une augmentation du risque d'événements indésirables chez les patients atteints d'une coronaropathie stable, indépendamment de la présence d'une ischémie myocardique induite par le stress mental.

Mechanism of Antigen Presentation and Specificity of Antibody Cross-Reactivity Elicited by an Oligosaccharide-Conjugate Cancer Vaccine.

Polysaccharides have been successfully used as immunogens for the development of vaccines against bacterial infection; however, there are no oligosaccharide-based vaccines available to date and no previous studies of their processing and presentation. We reported here the intracellular enzymatic processing and antigen presentation of an oligosaccharide-conjugate cancer vaccine prepared from the glycan of Globo-H (GH), a globo-series glycosphingolipid (GSL). This oligosaccharide-conjugate vaccine was shown to elicit antibodies against the glycan moieties of all three globo-series GSLs that are exclusively expressed on many types of cancer and their stem cells. To understand the specificity and origin of cross-reactivity of the antibodies elicited by the vaccine, we found that the vaccine is first processed by fucosidase 1 in the early endosome of dendritic cells to generate a common glycan antigen of the GSLs along with GH for MHC class II presentation. This work represents the first study of oligosaccharide processing and presentation and is expected to facilitate the design and development of glycoconjugate vaccines based on oligosaccharide antigens.