Association of Urinary Metals With Cardiovascular Disease Incidence and All-Cause Mortality in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net. RESULTS: During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the HR (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted HRs (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality. CONCLUSIONS: This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health.

Identifying an acceptable number of ambulatory blood pressure measurements for accuracy of average blood pressure and nocturnal dipping status.

We aimed to identify the minimum number of ambulatory blood pressure (ABP) measures to accurately determine daytime and nighttime systolic blood pressure (BP) averages and nocturnal dipping status (i.e., relative daytime:nighttime change). A total of 43 midlife participants wore an ABP monitor for 24 h with measurements every 20/30 min during the daytime/nighttime, as identified by a sleep diary. We calculated daytime/nighttime systolic BP average and dipping status from all available measurements per participant (i.e., normative data). We then calculated daytime and nighttime BP per participant based on a random selection of 8-20 and 4-10 measurements and replicated random selections 1,000 times. We calculated accuracy by checking the proportion from 1,000 different randomly selected samples for a particular number of measurements that systolic BP was ±5 mmHg of normative data, and dipping status remained unchanged for each participant compared with the normative value. The best fit for the regression model estimated the minimal number of measurements for an accuracy of 95% in BP averages. For a 95% accuracy in estimating daytime and nighttime systolic BP, 11 daytime and 8 nighttime measurements were required. The highest accuracy for dipping status was 91.6 ± 13.4% using 20 daytime and 10 nighttime measures, while the lowest was (83.4 ± 15.1%) using 8 daytime and 4 nighttime measures. In midlife adults, 11 daytime and 8 nighttime measurements are likely enough to calculate average systolic BPs accurately. However, no minimum number is suggested to accurately calculate dipping status.NEW & NOTEWORTHY We found that a minimum of 11 blood pressure (BP) measures are necessary to calculate an accurate average daytime BP, and 8 nighttime measures are necessary to calculate an accurate nighttime average if 95% accuracy is acceptable. Regarding BP dipping status, the current recommendations (20 daytime/7 nighttime) inaccurately classified the dipping status 10.5% of the time, suggesting that guidelines may need to be updated to classify patients as nocturnal dippers or nondippers correctly.

Evaluating outcomes and toxicities for a newly implemented MRI-based brachytherapy program for cervical cancer.

OBJECTIVE: We report an updated analysis of the outcomes and toxicities of MRI-based brachytherapy for locally advanced cervical cancer from a U.S. academic center. METHODS: A retrospective review was performed on patients treated with MRI-based brachytherapy for cervical cancer. EBRT was standardly 45 Gy in 25 fractions with weekly cisplatin. MRI was performed with the brachytherapy applicator in situ. Dose specification was most commonly 7 Gy for 4 fractions with optimization aim of D90 HR-CTV EQD2 of 85-95 Gyα/ß=10 Gy in 2 implants each delivering 2 fractions. RESULTS: Ninety-eight patients were included with median follow up of 24.5 months (IQR 11.9-39.8). Stage IIIA-IVB accounted for 31.6% of cases. Dosimetry results include median GTV D98 of 101.0 Gy (IQR 93.3-118.8) and HR-CTV D90 of 89 Gy (IQR 86.1-90.6). Median D2cc bladder, rectum, sigmoid, and bowel doses were 82.1 Gy (IQR 75.9-88.0), 65.9 Gy (IQR 59.6-71.2), 65.1 Gy (IQR 57.7-69.6), and 55 Gy (IQR 48.9-60.9). Chronic grade 3+ toxicities were seen in the bladder (8.2%), rectosigmoid (4.1%), and vagina (1.0%). Three-year LC, PFS, and OS were estimated to be 84%, 61.7%, and 76.1%, respectively. CONCLUSION: MRI-based brachytherapy demonstrates excellent local control and acceptable rates of high-grade morbidity. These results are possible in our population with relatively large volume primary tumors and extensive local disease.

Belonging, endurance, and resistance: Black placemaking theory in primary care.

Black-Americans continue to experience pervasive health disparities. Factors contributing to increased disease risk include a general mistrust of biomedical institutions among Black Americans. The purpose of this focus group study was to identify, among Black patients who regularly seek care from a primary provider, salient themes regarding barriers to 1) receiving quality primary care; and 2) adhering to medical recommendations. We examined transcripts of eight focus groups held remotely with 29 Black patients (aged 30-60 years) who had established primary care providers. Using grounded theory and an inductive thematic analysis of the transcripts, we identified three themes (belonging, endurance, and resistance) consistent with Black placemaking theory. Our findings suggest that reducing health disparities for Black Americans will require clinical initiatives that emphasize: 1) attention to social influences on health behavior and to features of medical institutions that mark them as White spaces (belonging); 2) recognition of, as well as sensitivity to, community awareness of the systemic and interpersonal barriers to health and safety that many Black adults endure; and 3) reframing avoidant (resistant) behaviors as protective strategies among Black patients. Examining primary care in this way-through the lens of Black placemaking theory-reveals how culturally meaningful approaches to harnessing the specialized knowledge and resilience that clearly exists among many Black communities can improve health care delivery.

Circadian alignment, cardiometabolic disease, and sex specific differences in adults with overweight/obesity.

OBJECTIVE: Circadian disruption promotes weight gain and poor health. The extent to which sex plays a role in the relationship between the circadian timing of behaviors and health outcomes in individuals with overweight/obesity is unclear. We investigated the sex-specific associations between circadian alignment and cardiometabolic health markers in females and males with overweight/obesity. METHODS: Thirty volunteers with overweight/obesity (15 female; BMI≥25.1kg/m2) underwent an evening in-laboratory assessment for dim-light melatonin onset (DLMO), body composition via dual energy x-ray absorptiometry, and a fasted blood sample. Circadian alignment was determined as the time difference between DLMO and average sleep onset over 7-days (phase angle), with participants categorized into narrow/wide phase angle groups based on median phase angle split. Due to known differences in metabolic markers between sexes, participants were subdivided based on sex into narrow and wide phase angle groups. RESULTS: Males in the narrow phase angle group had higher android/gynoid body fat distribution, triglycerides, and Metabolic Syndrome risk scores, while females had higher overall body fat percentage, glucose, and resting heart rates (all p<0.04). Furthermore, a narrower phase angle in males was negatively associated with android/gynoid body fat (r=-0.53, p=0.04) and negatively associated with body fat (r=-0.62, p=0.01) and heart rate (r=-0.73, p<0.01) in females. CONCLUSION: Circadian disruption may not only promote a trajectory of weight gain but could also contribute to negative health consequences in a sex-dependent manner in those already with overweight/obesity. These data may have implications for clinical utility in sex-specific sleep and circadian interventions for adults with overweight/obesity.

Effectiveness of Hypertension Management Strategies in SPRINT-Eligible US Adults: A Simulation Study.

BACKGROUND: Despite reducing cardiovascular disease (CVD) events and death in SPRINT (Systolic Blood Pressure Intervention Trial), intensive systolic blood pressure goals have not been adopted in the United States. This study aimed to simulate the potential long-term impact of 4 hypertension management strategies in SPRINT-eligible US adults. METHODS AND RESULTS: The validated Blood Pressure Control-Cardiovascular Disease Policy Model, a discrete event simulation of hypertension care processes (ie, visit frequency, blood pressure [BP] measurement accuracy, medication intensification, and medication adherence) and CVD outcomes, was populated with 25 000 SPRINT-eligible US adults. Four hypertension management strategies were simulated: (1) usual care targeting BP <140/90 mm Hg (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure usual care), (2) intensive care per the SPRINT protocol targeting BP <120/90 mm Hg (SPRINT intensive), (3) usual care targeting guideline-recommended BP <130/80 mm Hg (American College of Cardiology/American Heart Association usual care), and (4) team-based care added to usual care and targeting BP <130/80 mm Hg. Relative to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure usual care, among the 18.1 million SPRINT-eligible US adults, an estimated 138 100 total CVD events could be prevented per year with SPRINT intensive, 33 900 with American College of Cardiology/American Heart Association usual care, and 89 100 with team-based care. Compared with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure usual care, SPRINT intensive care was projected to increase treatment-related serious adverse events by 77 600 per year, American College of Cardiology/American Heart Association usual care by 33 300, and team-based care by 27 200. CONCLUSIONS: As BP control has declined in recent years, health systems must prioritize hypertension management and invest in effective strategies. Adding team-based care to usual care may be a pragmatic way to manage risk in this high-CVD-risk population.

Deep phenotyping of dementia in a multi-ethnic cardiovascular cohort: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Our understanding of the specific aspects of vascular contributions to dementia remains unclear. OBJECTIVES: We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort. METHODS: A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events. RESULTS: Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex. CONCLUSION: In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.

Association of Water Arsenic With Incident Diabetes in U.S. Adults: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study.

OBJECTIVE: We examined the association of arsenic in federally regulated community water systems (CWS) and unregulated private wells with type 2 diabetes (T2D) incidence in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially and ethnically diverse urban U.S. communities. RESEARCH DESIGN AND METHODS: We evaluated 1,791 participants from SHFS and 5,777 participants from MESA who had water arsenic estimates available and were free of T2D at baseline (2001-2003 and 2000-2002, respectively). Participants were followed for incident T2D until 2010 (SHFS cohort) or 2019 (MESA cohort). We used Cox proportional hazards mixed-effects models to account for clustering by family and residential zip code, with adjustment for sex, baseline age, BMI, smoking status, and education. RESULTS: T2D incidence was 24.4 cases per 1,000 person-years (mean follow-up, 5.6 years) in SHFS and 11.2 per 1,000 person-years (mean follow-up, 14.0 years) in MESA. In a meta-analysis across the SHFS and MESA cohorts, the hazard ratio (95% CI) per doubling in CWS arsenic was 1.10 (1.02, 1.18). The corresponding hazard ratio was 1.09 (0.95, 1.26) in the SHFS group and 1.10 (1.01, 1.20) in the MESA group. The corresponding hazard ratio (95% CI) for arsenic in private wells and incident T2D in SHFS was 1.05 (0.95, 1.16). We observed statistical interaction and larger magnitude hazard ratios for participants with BMI <25 kg/m2 and female participants. CONCLUSIONS: Low to moderate water arsenic levels (<10 µg/L) were associated with T2D incidence in the SHFS and MESA cohorts.

Variability in prostate cancer detection among radiologists and urologists using MRI fusion biopsy.

Objectives: The aim of this study is to evaluate the impact of radiologist and urologist variability on detection of prostate cancer (PCa) and clinically significant prostate cancer (csPCa) with magnetic resonance imaging (MRI)-transrectal ultrasound (TRUS) fusion prostate biopsies. Patients and methods: The Prospective Loyola University MRI (PLUM) Prostate Biopsy Cohort (January 2015 to December 2020) was used to identify men receiving their first MRI and MRI/TRUS fusion biopsy for suspected PCa. Clinical, MRI and biopsy data were stratified by radiologist and urologist to evaluate variation in Prostate Imaging-Reporting and Data System (PI-RADS) grading, lesion number and cancer detection. Multivariable logistic regression (MVR) models and area under the curve (AUC) comparisons assessed the relative impact of individual radiologists and urologists. Results: A total of 865 patients (469 biopsy-naïve) were included across 5 urologists and 10 radiologists. Radiologists varied with grading 15.4% to 44.8% of patients with MRI lesions as PI-RADS 3. PCa detection varied significantly by radiologist, from 34.5% to 66.7% (p = 0.003) for PCa and 17.2% to 50% (p = 0.001) for csPCa. Urologists' PCa diagnosis rates varied between 29.2% and 55.8% (p = 0.013) and between 24.6% and 39.8% (p = 0.36) for csPCa. After adjustment for case-mix on MVR, a fourfold to fivefold difference in PCa detection was observed between the highest-performing and lowest-performing radiologist (OR 0.22, 95%CI 0.10-0.47, p < 0.001). MVR demonstrated improved AUC for any PCa and csPCa detection when controlling for radiologist variation (p = 0.017 and p = 0.038), but controlling for urologist was not significant (p = 0.22 and p = 0.086). Any PCa detection (OR 1.64, 95%CI 1.06-2.55, p = 0.03) and csPCa detection (OR 1.57, 95%CI 1.00-2.48, p = 0.05) improved over time (2018-2020 vs. 2015-2017). Conclusions: Variability among radiologists in PI-RADS grading is a key area for quality improvement significantly impacting the detection of PCa and csPCa. Variability for performance of MRI-TRUS fusion prostate biopsies exists by urologist but with less impact on overall detection of csPCa.

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Utility of magnetic resonance imaging in establishing a venous pressure gradient in a patient with possible nutcracker syndrome.

Nutcracker syndrome is characterized by abnormal acute angulation of the superior mesenteric artery origin from the aorta, with resulting compression and hypertension of the crossing left renal vein. The radiologic studies used in diagnosis are typically limited to standard cross-sectional anatomic imaging with computed tomography or magnetic resonance imaging, with occasional use of Doppler ultrasound imaging for hemodynamic quantification. The standard for acquiring anatomic and physiologic information continues to be invasive venography. We describe the successful novel application of phase-encoded magnetic resonance imaging as a noninvasive method for acquiring anatomic and hemodynamic data in a case of possible nutcracker syndrome in a young patient.