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BACKGROUND: Few studies characterize the epidemiology and outcomes of aortic stenosis (AS) in acute decompensated heart failure (ADHF). This study investigates the significance of AS in contemporary patients who have experienced an ADHF hospitalization. METHODS: The ARIC study (Atherosclerosis Risk in Communities) surveilled ADHF hospitalizations for residents ≥55 years of age in 4 US communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF). Demographic differences in AS burden and the association of varying AS severities with mortality were estimated using multivariable logistic regression. RESULTS: From 2005 through 2014, there were 3597 (weighted n=16 692) ADHF hospitalizations of which 48.6% had an LVEF CONCLUSIONS: Among patients who have experienced an ADHF hospitalization, AS is prevalent and portends poor mortality outcomes. Notably, mild/moderate AS is independently associated with 1-year mortality in this high-risk population.

Background: Neighborhood socioeconomic status (SES) is associated with worse health outcomes, yet its relationship with in-hospital heart failure (HF) outcomes and quality metrics are underexplored. We examined the association between socioeconomic neighborhood disadvantage and in-hospital HF outcomes for patients from diverse neighborhoods in the Get With The Guidelines-Heart Failure registry. Methods: SES-disadvantage scores were derived from geocoded US census data using a validated algorithm, which incorporated household income, home value, rent, education, and employment. We examined the association between SES-disadvantage quintiles with all-cause in-hospital mortality, adjusting for demographics and comorbidities. Results: Of 593 053 patients hospitalized for HF between 2017 and 2020, 321 314 (54%) had residential ZIP Codes recorded. Patients from the most compared with least disadvantaged neighborhoods were younger (mean age 67 versus 76 years), more often Black (42% versus 9%) or Hispanic (14% versus 5%), and had higher comorbidity burden. Demographic-adjusted length of stay increased by ≈1.5 hours with each increment in worsening SES-disadvantage quintiles. Adjusted-mortality odds ratios increased with worsening SES-disadvantage quintiles ( P trend =0.003), and was 28% higher (adjusted OR=1.28 [1.12–1.48]) for the most compared with least disadvantaged neighborhood groups. Conclusions: Patients hospitalized for HF from disadvantaged neighborhoods were younger and more often Black or Hispanic. SES disadvantage was independently associated with higher in-hospital mortality. Further research is needed to characterize care delivery patterns in disadvantaged neighborhoods and to address social determinants of health among patients hospitalized for HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02693509.

Objective: Nonatherosclerotic outward remodeling of the large intracranial arteries may facilitate propagation of excessive aortic pulsatile energy into the cerebral microcirculation and has been associated with adverse cognitive outcomes. We sought to determine the relationship between central artery stiffness, brain arterial diameters, and white matter hyperintensity (WMH) volume in the general population of older adults. Approach and Results: We examined data from 1275 stroke-free participants of the ARIC (Atherosclerosis Risk in Communities) study (59% female, 30% Black, mean age 77 years) who underwent carotid-femoral pulse wave velocity (cf-PWV) testing and brain magnetic resonance imaging. A cf-PWV >12 m/s was considered elevated. Relationships between WMH and arterial diameters at the M1A1 segment of the middle and anterior cerebral arteries (whichever larger) were analyzed in the absence of artery-specific plaque, adjusting for intracranial volume and potential confounders. The average cf-PWV was 11.7 m/s and WMH volume was 11.2 cm 3 . Each 0.5 mm increment in M1A1 diameter was associated with 24% greater WMH volume in participants with elevated cf-PWV (exponentiated β=1.24 [95% CI, 1.12–1.36]), compared with a 10% greater WMH volume in participants without elevated cf-PWV (exponentiated β=1.10 [95% CI, 1.01–1.19]), P value for interaction=0.04. Conclusions: In this examination of older adults from the general population, larger, plaque-free arterial diameters in the middle cerebral circulation were associated with greater WMH volume, particularly among participants with elevated central artery stiffness. Strategies to reduce central artery stiffness may mitigate the association between cerebrovascular outward remodeling and microvascular damage.

We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF).The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30-, 60-, and 90-day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In-hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90-day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53-5.02) than HFpEF (OR 0.94; 95% CI 0.36-2.41) (p-interaction = 0.05).Patients hospitalized with ADHF and coexisting obstructive CAD have higher short-term mortality, warranting the need for effective interventions and secondary prevention.

Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies. Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495). Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction

Objectives This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients. Background Few studies characterize the burden of MR in heart failure. Methods The ARIC (Atherosclerosis Risk In Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF): Results From 2005 to 2014, there were 17,931 weighted ADHF hospitalizations of which 49.2% had an LVEF Conclusions Patients with ADHF have a significant MR burden that varies with sex and race. In ADHF patients with an LVEF

Background: Patients with heart failure (HF) have multiple coexisting comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well established. Methods: HF-related hospitalizations were sampled by stratified design from 4 US areas in 2005 to 2014 by the community surveillance component of the ARIC study (Atherosclerosis Risk in Communities). Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction Results: A total of 5460 hospitalizations (24 937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF versus HFrEF, both for women (5.53 versus 4.94; P P P -trendP for interaction by HF type=0.02). The associated mortality risk per 1 higher comorbidity also increased significantly over time for patients with HFpEF and HFrEF, as well ( P for interaction with time=0.002 and 0.02, respectively) Conclusions: The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF versus HFrEF.

To study the correlation between intra-procedural left ventricular end-diastolic pressure (LVEDP) and the development of contrast-induced acute kidney injury (CI-AKI) in patients undergoing percutaneous coronary intervention (PCI).A single center retrospective observational study compared clinical and hemodynamic characteristics of patients who developed post-PCI CI-AKI with those did not. CI-AKI was defined as an absolute increase in serum creatinine ≥0.5 mg/dl or an increase ≥25% from baseline 48-72 h after the administration of contrast medium. Among 1301 consecutive patients who underwent PCI, 125 patients (9.6%) developed CI-AKI. The CI-AKI group had a higher average LVEDP (18.4 ± 8.7 vs 14.4 ± 6.6 mm Hg; p .0001) and higher prevalence of elevated LVEDP (≥20 mm Hg) than those without CI-AKI (47.2% vs 23.3%, p .0001). After adjustments, elevated LVEDP remained independently associated with CI-AKI (OR 2.21; 95% CI 1.40-3.50). LVEDP predicted the development of CI-AKI with a receiver operating characteristic area under curve (AUC) of 0.64. The association between elevated LVEDP and the risk of CI-AKI was stronger in patients with reduced ejection fraction (EF ≤ 40%) (OR = 4.08; 95% CI: 1.68-9.91) than those with preserved EF (OR = 1.69; 95% CI: 0.94-3.04) (p value for interaction = .0003). Patients who had LVEDP ≥ 20 mm Hg and LVEF ≤ 40% had a post-PCI incidence rate of developing CI-AKI of 36.5%.Elevated intra-procedural LVEDP (≥20 mm Hg) is independently associated with increased risk of CI-AKI for patients undergoing cardiac catheterization and PCI, especially in the setting of reduced LVEF (≤40%).

Background: Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain. Methods: From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks. Results: Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus P for interaction by HF type =0.02. Conclusions: In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF.

Stroke is commonly caused by thromboembolic events originating from atherosclerotic plaques in the carotid vasculature. To improve stroke risk prediction by delineating vulnerable plaque features, our group has developed ARFI Variance of Acceleration log(VoA) imaging. We herein evaluate the ability of trained, blinded readers to interpret in vivo ARFI log(VoA) images of human carotid plaques, with validation by matched histology. Patients undergoing carotid endarterectomy were imaged using a Siemens S3000 and a 9L4 transducer. From 21 plaques, one was excluded due to specimen damage during surgery. Parametric 2D images of ARFI log(VoA) were rendered and evaluated by 3 neuroradiologists, 1 abdominal radiologist, 1 sonographer, and 1 pathologist, all blinded to the histological gold standard. Receiver operating characteristic (ROC) curve analysis was performed, and area under the curve (AUC) was taken as a metric of performance for detecting lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Reader log(VoA) outcomes were compared to those achieved using ARFI peak displacement (PD) in a comparable prior study. Average AUC performance for plaque features were as follows: CAL, 0.77; COL, 0.76; LRNC, 0.79; IPH, 0.82. Grouping the stiff (COL and CAL) and soft (LRNC and IPH) features together increased average AUCs to 0.86 for stiff and 0.87 for soft. These log(VoA) AUC outcomes were higher than those achieved by blinded readers evaluating ARFI PD images. This study shows the relevance of ARFI log(VoA) imaging, as interpreted by trained, blinded readers, to delineating the structure and composition of carotid atherosclerotic plaque in humans, in vivo.

Rupture potential of atherosclerotic plaques in carotid arteries is conferred by both composition and structure of plaques. Previous studies have shown that from in vivo collected data, carotid plaque components such as collagen, calcium, necrotic core and intraplaque hemorrhage can be automatically detected by an ARFI imaging-derived machine learning classifier. Automatic classification considered normalized cross-correlation measurements of ARFI-induced displacement, signal-to-noise ratio and cross-correlation coefficients from an on-axis ARFI acquisition. We now extend our prior work by hypothesizing that using multiple ARFI data forms improves plaque feature detection and FC thickness measurement in human carotid plaques, relative to a single form of ARFI data. Carotid plaques were imaged in vivo prior to surgery in 20 patients undergoing carotid endarterectomy (CEA), and extracted plaque specimens were harvested after CEA for histological processing. ARFI data were acquired with cardiac gating to diastole with push (DP) and to systole without push (SNP) using fundamental low (FL), fundamental high (FH), and harmonic (H) tracking frequencies. Combinations of the resulting displacement profiles were used as inputs to the SVM classifier. The classifier was evaluated by 5-fold cross-validation, with the histological samples acting as gold standards. From the output SVM likelihood matrices, ROC curves were calculated for separating collagen from calcium and lipid-rich necrotic core from intraplaque hemorrhage. For all examined plaques, DP+FH+H achieved the highest average AUC of 0.926 (Sensitivity = 0.932, Specificity = 0.915) but required 2 acquisitions. The best data combination requiring only one acquisition (DP+FH) achieved an AUC of 0.917 (Sensitivity = 0.902, Specificity = 0.880). These results suggest that using multiple forms of frequency and gating of ARFI data as inputs to an automatic classifier improves discrimination of carotid plaque components, relevant for rupture vulnerability assessment.

An expanding number of therapies are now indicated for comorbidity management in heart failure with preserved ejection fraction (HFpEF). Whether comorbidity burdens differ for patients with HFpEF who are hospitalized for acute decompensated heart failure (ADHF) versus those with chronic stable heart failure (CSHF) who are hospitalized for other causes is uncertain. Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted adjudicated community surveillance of hospitalized heart failure. Hospitalized ADHF and CSHF were sampled identically, using prespecified discharge codes and demographic strata, but were differentiated by signs or symptoms of acute or worsening heart failure upon physician review of the medical record. HFpEF was defined by an ejection fraction ≥50%. All events were weighted by the inverse of the sampling probability for statistical analyses. From 2005 to 2014, 13,706 weighted (2,936 unweighted) hospitalizations (mean age 77 years, 64% women, 29% Black) were sampled among patients with HFpEF and adjudicated ADHF (86%) or CSHF (14%). Comorbidity prevalence was high both for ADHF and CSHF hospitalizations, irrespective of gender. Women hospitalized with ADHF versus CSHF had greater prevalence of hypertension (89% vs 84%) diabetes mellitus (48% vs 39%) and renal disease (85% vs 74%). Echocardiographic features such as left ventricular hypertrophy and valvular abnormalities were more common with ADHF than CSHF, for both genders. However, the 28-day and 1-year mortality risk were comparable for ADHF and CSHF. In conclusion, hospitalized patients with HFpEF have a high comorbidity burden and risk of death, irrespective of the cause of hospitalization.

Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long-term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987-2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95-1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16-4.12) than those without CKD (HR = 1.09; 95% CI: 0.74-1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01-1.42) overall, 1.44 (95% CI: 1.002-2.07) among those with CKD, and 1.15 (95% CI: 0.94-1.39) among those without CKD; P for interaction = .18. The long-term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of acoustic radiation force (ARF)-induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo . Validation of the imaging methods is provided by preclinical studies in pig kidneys, in which ARF-induced PD values were significantly higher ( $p , Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated ( $R^{2} = 0.95$ ) to the ratio of shear moduli measured by shear wave elasticity imaging. On the contrary, when a symmetric ARF was implemented, no significant difference in PD was observed ( $p > 0.01$ ). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no significant difference ( $p > 0.01$ ) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein-to-creatinine ratio in the same patient population ( $p> 0.01$ ). The results of this pilot in vivo clinical study suggest the feasibility of 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

While in vivo acoustic radiation force impulse (ARFI)-induced peak displacement (PD) has been demonstrated to have high sensitivity and specificity for differentiating soft from stiff plaque components in patients with carotid plaque, the parameter exhibits poorer performance for distinguishing between plaque features with similar stiffness. To improve discrimination of carotid plaque features relative to PD, we hypothesize that signal correlation and signal-to-noise ratio (SNR) can be combined, outright or via displacement variance. Plaque feature detection by displacement variance, evaluated as the decadic logarithm of the variance of acceleration and termed “log(VoA),” was compared to that achieved by exploiting SNR, cross correlation coefficient, and ARFI-induced PD outcome metrics. Parametric images were rendered for 25 patients undergoing carotid endarterectomy, with spatially matched histology confirming plaque composition and structure. On average, across all plaques, log(VoA) was the only outcome metric with values that statistically differed between regions of lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Further, log(VoA) achieved the highest contrast-to-noise ratio (CNR) for discriminating between LRNC and IPH, COL and CAL, and grouped soft (LRNC and IPH) and stiff (COL and CAL) plaque components. More specifically, relative to the previously demonstrated ARFI PD parameter, log(VoA) achieved 73% higher CNR between LRNC and IPH and 59% higher CNR between COL and CAL. These results suggest that log(VoA) enhances the differentiation of LRNC, IPH, COL, and CAL in human carotid plaques, in vivo , which is clinically relevant to improving stroke risk prediction and medical management.

Our group has previously found that in silico, mechanical anisotropy may be interrogated by exciting transversely isotropic materials with geometrically asymmetric acoustic radiation force excitations and then monitoring the associated induced displacements in the region of excitation. We now translate acoustic radiation force-based anisotropy assessment to human muscle in vivo and investigate its clinical relevance to monitoring muscle degeneration in Duchenne muscular dystrophy (DMD). Clinical anisotropy assessments were performed using Viscoelastic Response ultrasound, with a degree of anisotropy reflected by the ratios of Viscoelastic Response relative elasticity (RE) or relative viscosity (RV) measured with the asymmetric radiation force oriented parallel versus perpendicular to muscle fiber alignment. In vivo results from rectus femoris and gastrocnemius muscles of boys aged ∼7.9–10.4 y indicate that RE and RV anisotropy ratios in rectus femoris muscles of boys with DMD were significantly higher than those of healthy control boys (RE: DMD = 1.51 ± 0.87, control = 0.99 ± 0.69, p = 0.04, Wilcoxon rank sum test; RV: DMD = 1.04 ± 0.71, control = 0.74 ± 0.22, p = 0.02). In the gastrocnemius muscle, only the RV anisotropy ratio was significantly higher in dystrophic than control patients (DMD = 1.23 ± 0.35, control = 0.88 ± 0.31, p = 0.04). In the dystrophic rectus femoris muscle, the RE anisotropy ratio was inversely correlated (slope = –0.03/lbf, r = –0.43, p = 0.07, Pearson correlation) with quantitative muscle testing functional output measures but was not correlated with quantitative muscle testing in the dystrophic gastrocnemius. These results suggest that Viscoelastic Response RE and RV measures reflect differences in mechanical anisotropy associated with functional impairment with dystrophic degeneration that are relevant to monitoring DMD clinically.

Aims Shock index (SI), defined as the ratio of heart rate (HR) to systolic blood pressure (SBP), is easily obtained and predictive of mortality in patients with ST-segment elevation myocardial infarction. However, large-scale evaluations of SI in patients with non-ST-segment elevation myocardial infarction (NSTEMI) are lacking. Methods and results Hospitalizations for acute myocardial infarction were sampled from four US areas by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. Shock index was derived from the HR and SBP at first presentation and considered high when ≥0.7. From 2000 to 2014, 18 301 weighted hospitalizations for NSTEMI were sampled and had vitals successfully obtained. Of these, 5753 (31%) had high SI (≥0.7). Patients with high SI were more often female (46% vs. 39%) and had more prevalent chronic kidney disease (40% vs. 32%). TIMI (Thrombolysis in Myocardial Infarction) risk scores were similar between the groups (4.3 vs. 4.2), but GRACE (Global Registry of Acute Coronary Syndrome) score was higher with high SI (140 vs. 118). Angiography, revascularization, and guideline-directed medications were less often administered to patients with high SI, and the 28-day mortality was higher (13% vs. 5%). Prediction of 28-day mortality by SI as a continuous measurement [area under the curve (AUC): 0.68] was intermediate to that of the GRACE score (AUC: 0.87) and the TIMI score (AUC: 0.54). After adjustments, patients with high SI had twice the odds of 28-day mortality (odds ratio = 2.02; 95% confidence interval: 1.46–2.80). Conclusion The SI is easily obtainable, performs moderately well as a predictor of short-term mortality in patients hospitalized with NSTEMI, and may be useful for risk stratification in emergency settings.

Acoustic Radiation Force Impulse (ARFI) imaging employs sound impulses to induce and track tissue motion that conveys mechanical property. In application to carotid atherosclerotic plaque, ARFI noninvasively delineates features that convey risk for ischemic stroke: intraplaque hemorrhage, lipid-rich necrotic core, thin or ruptured fibrous cap, diffuse collagen, and calcium deposits. This talk will feature recent advances to in vivo ARFI atherosclerosis imaging technology, including the use of machine learning for automated feature classification, which are validated histologically in patients undergoing carotid endarterectomy. New developments, including incorporating vector blood flow estimation for combined shear strain assessment, will be highlighted.

Background Acute myocardial infarction (AMI) with in‐hospital onset (AMI‐IHO) has poor prognosis but is clinically underappreciated. Whether its occurrence has changed over time is uncertain. Methods and Results Since 1987, the ARIC (Atherosclerosis Risk in Communities) study has conducted adjudicated surveillance of AMI hospitalizations in 4 US communities. Our analysis was limited to patients aged 35 to 74 years with symptomatic AMI. Patients with symptoms initiating after hospital arrival were considered AMI‐IHO. A total of 26 678 weighted hospitalizations (14 276 unweighted hospitalizations) for symptomatic AMI were identified from 1995 to 2014, with 1137 (4%) classified as in‐hospital onset. The population incidence rate of AMI‐IHO increased in the 4 ARIC communities from 1995 through 2004 to 2005 through 2014 (12.7—16.9 events per 100 000 people; P for 20‐year trend P for 20‐year trend =0.03). The 10‐year proportions were stable for patients aged 35 to 64 years (3.0%–3.4%; P for 20‐year trend =0.3) but increased for patients aged ≥65 years (4.6%–7.8%; P for 20‐year trend =0.008; P for interaction by age group =0.04). AMI‐IHO had a more severe clinical course with lower use of AMI therapies or invasive strategies and higher in‐hospital (7% versus 3%), 28‐day (19% versus 5%), and 1‐year (29% versus 12%) mortality ( P< 0.0001 for all). Conclusions In this population‐based community surveillance, AMI‐IHO increased from 2005 to 2014, particularly among older patients. Quality initiatives to improve recognition and management of AMI‐IHO should be especially focused on hospitalized patients aged >65.

OBJECTIVES: This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients. BACKGROUND: Few studies characterize the burden of MR in heart failure. METHODS: The ARIC (Atherosclerosis Risk In Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF)

Introduction: Shock index (SI), defined as the ratio of heart rate (HR) to systolic blood pressure (SBP), is easily obtained and has been reported to predict all-cause mortality in acute myocardial infarction (AMI) hospitalizations, primarily among patients with STEMI. Large-scale investigations examining the prognostic value of SI in patients with NSTEMI are lacking. Methods: Hospitalizations for acute myocardial infarction were sampled from 4 US areas by the ARIC Study and classified by physician review. HR and SBP at first presentation were abstracted from the medical record. Pulseless patients, those with unobtainable SBP, and transfer patients were excluded. An SI value ≥0.7 was considered high. The TIMI risk score for NSTE-ACS was calculated using the established algorithm. Predictions of all-cause 28-day mortality were analyzed using receiver operating characteristics (ROC). Results: From 2000-2014, 18,301 weighted hospitalizations for NSTEMI patients were sampled and had vitals successfully obtained. Of these, 5753 (31%) had high SI (≥0.7). Patients with high SI were more often female (46% vs 39%) and older (65 vs 63 years), with more prevalent chronic kidney disease (40% vs. 32%), pneumonia (16% vs 8%), and complication by acute heart failure (42% vs 30%). However, the TIMI risk score was comparable for the 2 groups (4.3 vs. 4.2). Angiography (36% vs 58%), revascularization (19% vs 41%), and guideline-directed medications were less often administered to patients with high SI, and the 28-day mortality was nearly 3 times higher (13% vs 5%). Continuous values of SI were more predictive of 28-day mortality than the TIMI risk score, both overall (ROC-AUC: 0.68 vs 0.54; P P Conclusion: The SI outperformed the TIMI risk score for prediction of short-term mortality in patients hospitalized with NSTEMI, and may be useful for risk stratification in emergency settings.

Introduction: Bedside evaluation of congestion remains important in both heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF). Whether presence of physical exam findings have changed over time, or if prognosis of physical examination differs by HF type is uncertain. Methods: From 2005-2014, the Atherosclerosis Risk in Communities (ARIC) Study conducted hospital surveillance of acute decompensated heart failure (ADHF). Events were verified by physician review, and clinical data were abstracted from the medical record. We examined presence of 3 physical exam findings suggesting congestion: lower extremity edema, jugular venous distension, and pulmonary rales > 1/3 of the lung field. Analyses were weighted by sampling fractions. Results: Of 24,937 hospitalizations for ADHF (mean age 75 years, 53% women, 32% black), 47% were HFpEF. Presence of edema increased from 2005-2009 to 2010-2014, both for HFpEF (66% to 72%; P for annual trend = 0.002) and HFrEF (62% to 67%; P for annual trend = 0.009), while presence of rales and jugular distention remained stable. There were 2640 (11%) and 7766 (31%) deaths within 28 days and 1 year of hospitalization, respectively. Patients with HFpEF and all 3 physical exam signs had a greater risk of short- and long-term mortality ( Figure ). After adjustments for demographics and length of stay, there was a differential association between clinical signs and 28-day mortality by HF type ( P for interaction = 0.02). Presence of all 3 vs. Conclusion: The presence of edema on physical examination of patients with ADHF has increased in recent years, both for HFpEF and HFrEF. However, the prognostic utility of physical exam signs of congestion may differ by HF type.

Introduction: While patients with dysglycemia and known CV disease face high risks of transition to HF and benefit from risk reduction strategies (such as SGLT-2 inhibitors), identification of at-risk patients without CV disease for allocation of primary prevention interventions is less clear. Biomarkers may improve risk stratification and inform targeted application of preventive strategies. Methods: Participants free of CV disease from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were included. A biomarker score was developed incorporating hs-cTnT ≥ 6 ng/L, NT-proBNP ≥ 100 pg/mL, hs-CRP ≥ 3 mg/L, and LVH by electrocardiogram. Among participants with dysglycemia, 5-year risks of incident HF and the number of HF events potentially prevented per 1,000 participants treated with an SGLT-2 inhibitor for 5-years were estimated. Results: Among 6,799 participants with prediabetes (66.8%) and diabetes (33.3%), there were 891 incident HF events over median follow-up of 17 years. The biomarker score alone demonstrated good discrimination and calibration for predicting 5-year HF risk [C-statistic 0.76 (0.71 to 0.81), calibration p value = 0.62]. Among those with dysglycemia, 5-year risk of HF in the very low (score = 0) and low biomarker score groups (score = 1) were similar to that observed among individuals with euglycemia (0.74%). The 5-year risk of HF increased in a graded fashion across increasing biomarker score groups. For every 1,000 participants with diabetes treated with an SGLT-2 inhibitor for 5-years, the estimated number of HF events prevented was estimated to be 4, 5, 14, and 41, respectively for individuals with scores of 0, 1, 2, and 3-4. Conclusions: Among adults with prediabetes and diabetes, a biomarker score can inform HF risk stratification. Individuals with diabetes and high biomarker scores face the highest risk of HF and are expected to benefit the most from SGLT-2 inhibitors.

Background Peripheral artery disease (PAD) is both a common comorbidity and a contributing factor to heart failure. Whether PAD is associated with hospitalization for recurrent decompensation among patients with established heart failure is uncertain. Methods and Results Since 2005, the ARIC (Atherosclerosis Risk in Communities) study has conducted active surveillance of hospitalized acute decompensated heart failure (ADHF), with events verified by physician review. From 2005 to 2016, 1481 patients were hospitalized with ADHF and discharged alive (mean age, 78 years; 69% White). Of these, 207 (14%) had diagnosis of PAD. Those with PAD were more often men (55% versus 44%) and smokers (17% versus 8%), with a greater prevalence of coronary artery disease (72% versus 52%). Patients with PAD had an increased risk of at least 1 ADHF readmission, both within 30 days (11% versus 7%) and 1 year (39% versus 28%) of discharge from the index hospitalization. After adjustments, PAD was associated with twice the hazard of ADHF readmission within 30 days (HR, 2.02; 95% CI, 1.14–3.60) and a 60% higher hazard of ADHF readmission within 1 year (HR, 1.60; 95% CI, 1.25–2.05). The 1‐year hazard of ADHF readmission associated with PAD was stronger with heart failure with reduced ejection fraction (HR, 2.01; 95% CI, 1.29–3.13) than preserved ejection fraction (HR, 1.04; 95% CI, 0.69–1.56); P for interaction=0.05. Conclusions Patients with ADHF and concomitant PAD have a higher likelihood of ADHF readmission. Strategies to prevent ADHF readmissions in this high‐risk group are warranted.

Differentiating malignant from benign breast lesions remains a challenge that may be met by a new imaging biomarker: lesion-to-background mechanical anisotropy assessed by VisR ultrasound. VisR is an ultrasound imaging method that uses 2 consecutive acoustic radiation force excitations, separated in time and delivered to the same region of excitation, to directionally interrogate peak displacement (PD), relative elasticity (RE), and relative viscosity (RV). From these directional measurements, mechanical degree of anisotropy is measured. In a pilot clinical study involving 29 women with BIRADS-4 or −5 breast masses, VisR PD, RE, and RV were measured in lesions and in surrounding tissue at 0°, 30°, 60°, and 90° concentric orientations. From these measurements, lesion DoA (LDoA), surrounding tissue DoA (SDoA), and log(LDoA/SDoA) were assessed per parameter and compared between biopsy-confirmed malignant versus benign masses. Across all patients, PD-, RE-, and RV-based LDoA or SDoA alone did not achieve statistical difference between malignant and benign masses (Wilcoxon, $\mathrm{p} > 0.05$ ). However, PD-, RE-, and RV-based log(LDoA/SDoA) statistically differentiated malignant from benign masses (Wilcoxon, $\mathrm{p} ), with AUC values of 0.96 for PD-based, and 0.94 for RE- and RV-based outcomes. These results demonstrate the relevance of lesion-to-background mechanical anisotropy assessed by VisR ultrasound for differentiating malignant from benign breast masses in women, in vivo.

Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies.Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495).Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction 0.001) in the ACCORD, intensive lifestyle intervention (p-interaction = 0.002) in the Look AHEAD and early coronary revascularisation (p-interaction = 0.003) in the BARI 2D trial cohorts for the risk of the primary composite outcome. Favourable reduction in the risk of the primary composite outcome with these interventions was noted in low-risk participants of phenogroup 3 but not in other phenogroups. Compared with phenogroup 3, phenogroup 1 participants were more likely to have severe/symptomatic hypoglycaemic events and medication non-adherence on follow-up in the ACCORD and Look AHEAD trial cohorts.Clustering using FMMs was the optimal phenomapping strategy to identify replicable subgroups of patients with type 2 diabetes with distinct clinical characteristics, CVD risk and response to therapies.

Objectives This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions. Background Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown. Methods Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4). Results The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group. Conclusions Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies.

OBJECTIVE To evaluate the associations between long-term change and variability in glycemia with risk of heart failure (HF) among patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Among participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, variability in HbA1c was assessed from stabilization of HbA1c following enrollment (8 months) to 3 years of follow-up as follows: average successive variability (ASV) (average absolute difference between successive values), coefficient of variation (SD/mean), and SD. Participants with HF at baseline or within 3 years of enrollment were excluded. Adjusted Cox models were used to evaluate the association of percent change (from baseline to 3 years of follow-up) and variability in HbA1c over the first 3 years of enrollment and subsequent risk of HF. RESULTS The study included 8,576 patients. Over a median follow-up of 6.4 years from the end of variability measurements at year 3, 388 patients had an incident HF hospitalization. Substantial changes in HbA1c were significantly associated with higher risk of HF (hazard ratio [HR] for ≥10% decrease 1.32 [95% CI 1.08–1.75] and for ≥10% increase 1.55 [1.19–2.04]; reference CONCLUSIONS Substantial long-term changes and variability in HbA1c were independently associated with risk of HF among patients with T2DM.

Objective: Evaluate the associations between long-term change and variability in glycemia with risk of HF among patients with T2DM. Research Design and Methods: Among participants with T2DM enrolled in the ACCORD trial, variability in HbA1c was assessed from stabilization of HbA1c following enrollment (8 months) to 3 years of follow-up as follows: average successive variability (ASV=average absolute difference between successive values), coefficient of variation (CV=standard deviation/mean), and standard deviation. Participants with HF at baseline or within 3 years of enrollment were excluded. Adjusted Cox models were used to evaluate the association of % change (from baseline to 3 years of follow-up) and variability in HbA1c over the first 3 years of enrollment and subsequent risk of HF. Results: The study included 8,576 patients. Over a median follow-up of 6.4 years from the end of variability measurements at year 3, 388 patients had an incident HF hospitalization. Substantial changes in HbA1c were significantly associated with higher risk of HF [HR (95% CI) for ≥10% decrease = 1.32 (1.08-1.75), ≥10% increase = 1.55 (1.19-2.04), ref: Conclusions: Substantial long-term changes and variability in HbA1c were independently associated with risk of HF among patients with T2DM.

Introduction: Phenomapping can be used to identify subgroups of patients with similar risk factor profiles; however, there is no widely accepted clustering method. We compared 3 phenomapping strategies to identify groups of individuals with diabetes mellitus (DM) and high cardiovascular disease (CVD) risk. Methods: Participants with DM and no baseline CVD from the ACCORD trial (N = 6591) were included in this study. Among 45 mixed data variables, we used an informed variable selection method with optimization of the Wald index to select the top 20 covariates associated with survival. Gaussian mixture models (GMM), Latent Class Analysis (LCA), and finite mixture model-based clustering (FMM) were performed to identify mutually exclusive phenogroups. Bayesian information criterion (BIC) and Dunn index were calculated for each method and compared. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Results: FMM clustering with 3 phenogroups was the optimal clustering strategy as determined by the lowest BIC and highest Dunn index (Figs A-B). Phenogroup 1 had a higher burden of comorbidities and DM complications; phenogroup 2 were older with intermediate CV comorbidity burden, but lowest complications from DM; and phenogroup 3, the largest group, had a lower prevalence of CV-related comorbidities. In adjusted Cox models, over 4.9 years median follow-up, phenogroup 1 and 2 participants (vs. phenogroup 3) had a significantly higher risk of primary composite endpoint (Fig C). In Cox analysis, when group membership was added to 10 optimal predictors of primary composite endpoint, the C -index improved from 0.68 to 0.70 ( P = 0.02). Similar risk patterns were also observed in an external cohort (Look AHEAD trial, N = 4211) with the highest risk of adverse outcome seen in phenogroup 1 (Fig D). Conclusion: Semi-supervised clustering using FMM efficiently identifies phenogroups of patients with DM with distinct clinical characteristics and CVD risk.

Introduction: Patients with HF have multiple co-existing CV and non-CV comorbidities. The temporal trends in the burden of co-morbidities and associated risk of mortality among patients with acute decompensated HF (ADHF) is not well-established. Methods: HF related hospitalizations were captured in the ARIC surveillance cohort study across 4 US communities 2005 to 2014 using ICD-9 codes. HF hospitalizations were adjudicated using validated algorithm to identify ADHF with reduced ejection fraction (HFrEF, ejection fraction Results: Of the 22,805 hospitalizations sampled between 2005-2004, 8914 were classified as ADHF corresponding to 41,146 weighted hospitalizations for ADHF (53% HFrEF, 47% HFpEF). The burden of CV co-morbidities remained stable while that of and that of non-CV comorbidities increased significantly over time among patients with HFpEF and HFrEF. The overall burden of CV co-morbidities was not significantly associated with risk of mortality among patients with HFrEF and HFpEF. In contrast, greater burden of non-CV comorbidities was significantly associated with higher risk of in-hospital, 28-day, and 1-year mortality for both HFpEF and HFrEF. Among patients with HFrEF, the risk of mortality associated with higher burden of non-CV comorbidities did not change over time. In contrast, for HFpEF, there was a significant temporal decline in the non-CV burden associated risk of in-hospital mortality and an increase in the risk of 1-year mortality over time. Conclusion: The burden of non-CV co-morbidities among patients with ADHF has increased over time. Higher burden of non-CV comorbidities was associated with higher risk of mortality, with stable temporal associations in HFrEF and an increasing risk over time for 1-year mortality for HFpEF.

Introduction: Obesity is disproportionately prevalent in black populations and strongly associated with heart failure with preserved ejection fraction (HFpEF). An “obesity paradox” or lower mortality risk with obesity, has been reported in HFpEF populations. Whether racial differences exist in the temporal trends and outcomes of obesity is uncertain. Methods: Hospitalizations for acute decompensated heart failure (ADHF) were sampled from 2005-2014 by the ARIC Study Community Surveillance and classified by physician review. BMI was calculated using the admission height and weight. Associations between obesity and 1-year all-cause mortality were analyzed with multivariable Cox regression. Results: There were 10,147 weighted hospitalizations for ADHF with ejection fraction ≥50% (64% female, 74% white). Overall, black patients had a higher mean BMI than white patients (34 vs. 30 kg/m 2 ; P P P = 0.003 and P = 0.002) while remaining stable for black patients. Within BMI groups (18.5-24, 25-30, 30-35, 35-40, and ≥40 kg/m 2 ) a U-shaped mortality risk was observed, with the lowest risk among patients with a BMI of 30-35 kg/m 2 ( Figure ). When defining obesity by a BMI cutpoint ≥30 kg/m 2 , the “obesity paradox” was apparent in 2005-2009 for white obese vs. non-obese patients (HR = 0.58, 95% CI: 0.38 - 0.80), but attenuated by 2010-2014 (HR = 1.11; 95% CI: 0.80 - 1.48); P for interaction =0.006. Among black patients, there was no survival benefit for a BMI ≥30 kg/m 2 in 2005-2009 (HR = 1.15; 95% CI; 0.65 - 2.02) or 2010-2014 (HR = 1.06; 95% CI: 0.68 - 1.66). Conclusion: In this decade-long community surveillance of HFpEF patients hospitalized with ADHF, obesity and mean BMI were stable for black patients but steadily increased for white patients. A BMI ≥30 kg/m 2 was initially associated with better survival among white patients but the association dissipated as obesity and mean BMI increased over time.

BACKGROUND Pulmonary hypertension (PH) is frequently reported in patients with advanced chronic kidney disease and is associated with early allograft failure and death. However, the causes of PH are heterogeneous, and patient prognosis may vary by etiologic subtype. METHODS Data from the University of North Carolina Cardiorenal Registry were examined to determine associations between PH, with or without elevated left atrial pressure (eLAP), and mortality in candidates for kidney transplantation. PH and eLAP were determined by Doppler echocardiography and by tissue Doppler imaging, respectively. RESULTS From 2006 to 2013, 778 registry patients were screened preoperatively by echocardiography. Most patients were black (64%) and men (56%); the mean age was 56 years. PH was identified in 97 (12%) patients; of these, eLAP was prevalent in half. During a median follow-up of 4.4 years, 179 (23%) received a kidney transplant, and 195 (25%) died. After adjustments for demographics, comorbidities, dialysis vintage, and kidney transplantation, PH was associated with twice the 5-year mortality (hazard ratio [HR] = 2.11; 95% confidence interval [CI]: 1.48-3.03), with stronger associations in the absence of eLAP (HR = 2.87; 95% CI: 1.83-4.49) than with eLAP (HR = 1.11; 95% CI: 0.57-2.17), P for interaction = 0.01. CONCLUSIONS The mortality risk associated with PH among patients with advanced chronic kidney disease appears to differ by etiology. Patients with PH in the absence of eLAP are at high risk of death and in need of focused attention. Future research efforts should investigate potential strategies to improve outcomes for these patients.

Background The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. Methods Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12. Results Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing. Conclusions TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p 0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.