Association of Nonacute Opioid Use and Cardiovascular Diseases: A Scoping Review of the Literature

BACKGROUND In this scoping review, we identified and reviewed 23 original articles from the PubMed database that investigated the relationship between nonacute opioid use (NOU) and cardiovascular outcomes. METHODS AND RESULTS We defined NOU to include both long-term opioid therapy and opioid use disorder. We summarized the association between NOU and 5 classes of cardiovascular disease, including infective endocarditis, coronary heart disease (including myocardial infarction), congestive heart failure, cardiac arrythmia (including cardiac arrest), and stroke. The most commonly studied outcomes were coronary heart disease and infective endocarditis. There was generally consistent evidence of a positive association between community prevalence of injection drug use (with opioids being the most commonly injected type of drug) and community prevalence of infective endocarditis, and between (primarily medically indicated) NOU and myocardial infarction. There was less consensus about the relationship between NOU and congestive heart failure, cardiac arrhythmia, and stroke. CONCLUSIONS There is a dearth of high-quality evidence on the relationship between NOU and cardiovascular disease. Innovative approaches to the assessment of opioid exposure over extended periods of time will be required to address this need

Determinants of vascular age: An epidemiological perspective

BACKGROUND: Vascular age is an emerging health indicator and predictor of end-organ damage to the heart, brain, and kidney. Although there have been many review publications concerning risk factors for vascular aging, most include cross-sectional epidemiological studies, limiting inferences about temporality. There is a need for a review of longitudinal epidemiological studies with repeated measures of vascular structure and function to allow for a systematic examination of determinants of vascular age and the association of vascular aging with outcomes. CONTENT: Arterial stiffness is the most frequently used measure of vascular aging. We report here results of an extensive literature review of longitudinal cohort studies with repeated measures of arterial stiffness to characterize determinants of vascular age. Additionally, we summarize population-based studies that have focused on the association of arterial stiffness with end-organ damage and adverse cardiovascular outcomes. SUMMARY: Changes in arterial stiffness are evident in early childhood. In adults, arterial stiffness has been observed to progress at the average rate of 0.2 to 0.7 m/s for every 5 years of life. The state of the science is limited by the small number of studies with repeated measures of arterial stiffness and determinants of arterial stiffness progression, as well as limited studies in children and diverse race/ethnic groups. Several extant studies suggest that beyond age, cardiometabolic risk factors and adverse lifestyle behaviors contribute to arterial stiffening. Therefore, arterial stiffness is important in the assessment of healthy vascular aging and a possible target for the prevention of subclinical and clinical disease

Cardiometabolic Health and Carotid-Femoral Pulse Wave Velocity in Children: A Systematic Review and Meta-Regression

Objective: To identify, in children the normal rate of carotid-femoral pulse wave velocity (cfPWV) progression, and whether presence of cardiometabolic risk factors is associated with cfPWV. Study design: Electronic databases (PubMed, Google Scholar) were searched from inception to May 2018, for all studies which reported cfPWV in children (<19 years of age). Random effects meta-regression quantified the association between time (years) and cfPWV, and a systematic review was performed to determine whether cardiometabolic risk factors are associated with cfPWV. Results: Data from 28 articles were eligible for inclusion, including 9 reference value (n = 13 100), 5 cardiovascular risk (n = 5257), 10 metabolic risk (n = 2999), and 8 obesity-focused (n = 8760) studies. Meta-regression findings (9 studies) showed that the increase in cfPWV per year (age) was 0.12 m/second (95% CI, 0.07-0.16 m/second) per year, and when stratified by sex the CIs overlapped. Systematic review findings showed that cardiometabolic risk factors were positively associated with cfPWV, including positive associations with blood pressure, impaired glucose metabolism, and metabolic syndrome. However, obesity was not consistently associated with cfPWV. Conclusions: Arterial stiffness in children progresses with age and is associated with cardiometabolic risk factors. Although further longitudinal studies are warranted, the presented reference data will be valuable to epidemiologists tracking children, and to scientists and clinicians prescribing therapies to mitigate risk in a population that is increasingly more vulnerable to cardiovascular disease

Peripheral Artery Disease Prevalence and Incidence Estimated From Both Outpatient and Inpatient Settings Among Medicare Fee‐for‐Service Beneficiaries in the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND: Outpatient ascertainment of peripheral artery disease (PAD) is rarely considered in the measurement of PAD clinical burden; therefore, the clinical burden of PAD likely has been underestimated while contributing to a decreased awareness of PAD in comparison to other circulatory system disorders. METHODS AND RESULTS: The purpose of this study was to estimate the age-standardized annual period prevalence and incidence of PAD in the outpatient and inpatient settings using data from the Atherosclerosis Risk in Communities (ARIC) study linked with Centers for Medicare and Medicaid Services claims. The majority (>70%) of all PAD encounters occurred in the outpatient setting. The weighted mean age-standardized prevalence and incidence of outpatient PAD was 11.8% (95% CI 11.5-12.1) and 22.4 per 1000 person-years (95% CI 20.8-24.0), respectively. Black patients had higher weighted mean age-standardized prevalence (15.6%; 95% CI 14.6-16.4) compared with white patients (11.4%; 95% CI 11.1-11.7). Black women had the highest weighted mean age-standardized prevalence (16.9%; 95% CI 16.0-17.8). Black patients also had a higher incidence rate of PAD (31.3 per 1000 person-years; 95% CI 27.3-35.4) compared with white patients (25.4 per 1000 person-years; 95% CI 23.5-27.3). PAD prevalence and incidence did not differ by sex alone. CONCLUSIONS: This study provides comprehensive estimates of PAD in the inpatient and outpatient settings where the majority of PAD burden was found. PAD is an important circulatory system disorder similar in prevalence to stroke and coronary heart disease

The Transcription co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation into Enterocyte vs Secretory Lineages

BACKGROUND & AIMS: Notch signaling maintains intestinal stem cells (ISCs). When ISCs exit the niche, Notch signaling among early progenitor cells at position +4/5 regulates their specification toward secretory vs enterocyte lineages (binary fate). The transcription factor ATOH1 is repressed by Notch in ISCs; its de-repression, when Notch is inactivated, drives progenitor cells to differentiate along the secretory lineage. However, it is not clear what promotes transition of ISCs to progenitors and how this fate decision is established. METHODS: We sorted cells from Lgr5-Gfp knock-in intestines from mice and characterized gene expression patterns. We analyzed Notch regulation by examining expression profiles (by quantitative reverse transcription PCR and RNAscope) of small intestinal organoids incubated with the Notch inhibitor DAPT, intestine tissues from mice given injections of the γ-secretase inhibitor dibenzazepine, and mice with intestine-specific disruption of Rbpj. We analyzed intestine tissues from mice with disruption of the RUNX1 translocation partner 1 gene (Runx1t1, also called Mtg8) or CBFA2/RUNX1 partner transcriptional co-repressor 3 (Cbfa2t3, also called Mtg16), and derived their organoids, by histology, immunohistochemistry, and RNA sequencing. We performed chromatin immunoprecipitation and sequencing analyses of intestinal crypts to identify genes regulated by MTG16. RESULTS: The transcription co-repressors MTG8 and MTG16 were highly expressed by +4/5 early progenitors, compared with other cells along crypt-villus axis. Expression of MTG8 and MTG16 were repressed by Notch signaling via ATOH1 in organoids and intestine tissues from mice. MTG8- and MTG16-knockout intestines had increased crypt hyperproliferation and expansion of ISCs, but enterocyte differentiation was impaired, based on loss of enterocyte markers and functions. Chromatin immunoprecipitation and sequencing analyses showed that MTG16 bound to promoters of genes that are specifically expressed by stem cells (such as Lgr5 and Ascl2) and repressed their transcription. MTG16 also bound to previously reported enhancer regions of genes regulated by ATOH1, including genes that encode delta-like canonical Notch ligand and other secretory-specific transcription factors. CONCLUSIONS: In intestine tissues of mice and human intestinal organoids, MTG8 and MTG16 repress transcription in the earliest progenitor cells to promote exit of ISCs from their niche (niche exit) and control the binary fate decision (secretory vs enterocyte lineage) by repressing genes regulated by ATOH1

Mind the Gap: Hospitalizations from Multiple Sources in a Longitudinal Study

Background Medicare claims and prospective studies with self-reported utilization are important sources of hospitalization data for epidemiologic and outcomes research. Objectives To assess the concordance of Medicare claims merged with interview-based surveillance data to determine factors associated with source completeness. Methods The Atherosclerosis Risk in Communities (ARIC) study recruited 15,792 cohort participants aged 45 to 64 years in the period 1987 to 1989 from four communities. Hospitalization records obtained through cohort report and hospital record abstraction were matched to Medicare inpatient records (MedPAR) from 2006 to 2011. Factors associated with concordance were assessed graphically and using multinomial logit regression. Results Among fee-for-service enrollees, MedPAR and ARIC hospitalizations matched approximately 67% of the time. For Medicare Advantage enrollees, completeness increased after initiation of hospital financial incentives in 2008 to submit shadow bills for Medicare Advantage enrollees. Concordance varied by geographic site, age, veteran status, proximity to death, study attrition, and whether hospitalizations were within ARIC catchment areas. Conclusions ARIC and MedPAR records had good concordance among fee-for-service enrollees, but many hospitalizations were available from only one source. MedPAR hospital records may be missing for veterans or observation stays. Maintaining study participation increases stay completeness, but new sources such as electronic health records may be more efficient than surveillance for mobile elderly populations

Operationalizing Frailty in the Atherosclerosis Risk in Communities Study Cohort

Background: Factors that may contribute to the development of frailty in late life have not been widely investigated. The Atherosclerosis Risk in Communities (ARIC) Study cohort presents an opportunity to examine relationships of midlife risk factors with frailty in late life. However, we first present findings on the validation of an established frailty phenotype in this predominantly biracial population of older adults. Methods: Among 6,080 participants, we defined frailty based upon the Cardiovascular Health Study (CHS) criteria incorporating measures of weight loss, exhaustion, slow walking speed, low physical activity, and low grip strength. Criterion and predictive validity of the frailty phenotype were estimated from associations between frailty status and participants' physical and mental health status, physiologic markers, and incident clinical outcomes. Results: A total of 393 (6.5%) participants were classified as frail and 50.4% pre-frail, similar to CHS (6.9% frail, 46.6% pre-frail). In age-adjusted analyses, frailty was concurrently associated with depressive symptoms, low self-rated health, low medication adherence, and clinical biomarker levels (ie, cholesterol, hemoglobin A1c, white blood cell count, C-reactive protein, and hemoglobin). During 1-year follow-up, frailty was associated with falls, low physical ability, fatigue, and mortality. Conclusions: These findings support the validity of the CHS frailty phenotype in the ARIC Study cohort. Future studies in ARIC may elucidate early-life exposures that contribute to late-life frailty

Ubiquinol Improves Symptoms in Children with Autism

Background. Autism is a spectrum of neurodevelopmental disorders with manifestation within 3 years after birth. Manifestations of autism include behavior problems (hyperactivity, toys destruction, self-harm, and agression) and sleep and eating disorders. Etiology of autism is poorly understood. Oxidative stress and antioxidants can participate in pathobiochemical mechanisms of autism. Methods. Twenty-four children, aged 3–6 years, with autism according to the DSM IV criteria and using CARS were included in the study. Concentrations of CoQ10-TOTAL, γ- and α-tocopherol, β-carotene, and lipid peroxidation were determined in plasma before and after three months of supportive therapy with ubiquinol at a daily dose 2×50 mg. Data on behavior of the children were collected from parents at the same time. Results. Ubiquinol supportive therapy improved symptoms in children with autism, as communication with parents (in 12%), verbal communication (in 21%), playing games of children (in 42%), sleeping (in 34%), and food rejection (in 17%), with CoQ10-TOTAL plasma level above 2.5 μmol/L. Conclusions. Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time. We assume that plasma concentration of CoQ10-TOTAL and lipid peroxidation could be used as relevant biomarkers of ubiquinol supportive therapy

Incidence of Heart Failure Observed in Emergency Departments, Ambulatory Clinics, and Hospitals

Reports on the burden of heart failure (HF) have largely omitted HF diagnosed in outpatient settings. We quantified annual incidence rates ([IR] per 1,000 person years) of HF identified in ambulatory clinics, emergency departments (EDs), and during hospital stays in a national probability sample of Medicare beneficiaries from 2008 to 2014, by age and race/ethnicity. A 20% random sample of Medicare beneficiaries ages ≥65 years with continuous Medicare Parts A, B, and D coverage was used to estimate annual IRs of HF identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Of the 681,487 beneficiaries with incident HF from 2008 to 2014, 283,451 (41%) presented in ambulatory clinics, 76,919 (11%) in EDs, and 321,117 (47%) in hospitals. Overall, incidence of HF in ambulatory clinics decreased from 2008 (IR 22.2, 95% confidence interval [CI] 22.0, 22.4) to 2014 (IR 15.0, 95% CI 14.8, 15.1). Similarly, incidence of HF-related ED visits without an admission to the hospital decreased somewhat from 2008 (IR 5.5, 95% CI 5.4, 5.6) to 2012 (IR 4.2, 95% CI 4.1, 4.3) and stabilized from 2013 to 2014. Similar to previous reports, HF hospitalizations, both International Classification of Diseases, Ninth Revision, Clinical Modification code 428.x in the primary and any position, decreased over the study period. More than half of all new cases of HF in Medicare beneficiaries presented in an ambulatory clinic or ED. The overall incidence of HF decreased from 2008 to 2014, regardless of health-care setting. In conclusion, consideration of outpatient HF is warranted to better understand the burden of HF and its temporal trends

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk