Lipidomics profiling of biological aging in American Indians: the Strong Heart Family Study.

Telomeres shorten with age and shorter leukocyte telomere length (LTL) has been associated with various age-related diseases. Thus, LTL has been considered a biomarker of biological aging. Dyslipidemia is an established risk factor for most age-related metabolic disorders. However, little is known about the relationship between LTL and dyslipidemia. Lipidomics is a new biochemical technique that can simultaneously identify and quantify hundreds to thousands of small molecular lipid species. In a large population comprising 1843 well-characterized American Indians in the Strong Heart Family Study, we examined the lipidomic profile of biological aging assessed by LTL. Briefly, LTL was quantified by qPCR. Fasting plasma lipids were quantified by untargeted liquid chromatography-mass spectrometry. Lipids associated with LTL were identified by elastic net modeling. Of 1542 molecular lipids identified (518 known, 1024 unknown), 174 lipids (36 knowns) were significantly associated with LTL, independent of chronological age, sex, BMI, hypertension, diabetes status, smoking status, bulk HDL-C, and LDL-C. These findings suggest that altered lipid metabolism is associated with biological aging and provide novel insights that may enhance our understanding of the relationship between dyslipidemia, biological aging, and age-related diseases in American Indians.

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions. Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model. Design, Setting, and Participants: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021. Exposure: Blood DNA methylation. Main Outcome and Measure: Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts. Results: The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts. Conclusions and Relevance: In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.

Association Between Cardiovascular Risk Factors and the Diameter of the Thoracic Aorta in an Asymptomatic Population in the Central Appalachian Region.

BACKGROUND: Effects of cardiovascular (CV) risk factors on the diameter of the thoracic aorta have not been fully studied. This study examined the associations between CV risk factors and diameter of thoracic aorta. MATERIALS AND METHODS: Study population comprised of 1273 asymptomatic adults aged ≥18 years from Central Appalachia region of the United States who participated in a coronary artery screening between January 2014 and December 2016. Descriptive statistics and multiple linear regression analyses were performed to examine associations between multiple CV risk factors and diameters of the thoracic aorta. RESULTS: Mean (±SD) age of participants was 57.9±9.7 years; that of body mass index (BMI) was 29.4±5.9. The mean aortic sinus, ascending aorta, and descending aorta diameter were 34.1±4.4 mm, 33.8±4.4 mm, and 26.0±3.6 mm, respectively. Increasing age, being male, and having a higher BMI were associated with wider aortic sinus, ascending aorta, and descending aorta diameters. Hypertension (p < 0.05) and obesity (p < 0.0001) were significantly associated with wider diameter for all measured aortic diameters. Participants with diabetes had wider descending aorta compared to those without (26.6±3.9 mm vs. 25.9±3.5 mm, P = 0.012). Participants who had ever smoked a cigarette had significantly wider descending aorta diameter compared to never smokers (26.3±3.6 mm vs. 25.9±3.5 mm, p = 0.031). CONCLUSIONS: The study results suggest that decreasing BMI and management of CV risk factors such as hypertension and modifying behavioral risk factors such as smoking are likely to be emphasized in order to decrease the rate of aortic dilatation and subsequent aortic dissection, if aortic dilatation is detected during a CT scan.

Association between cardiovascular risk factors and the diameter of the main pulmonary artery in asymptomatic population in the Appalachian region.

BACKGROUND: Pulmonary artery (PA) diameter may be altered in association with cardiovascular (CV) risk factors as noted in aorta in systemic hypertension. The flow of blood from the right ventricle to the PA and all the way to the capillary level depends on the pulmonary vascular resistance and to a lesser extent compliance and impedance of the PA, which are the fundamental conduit for maintenance of the right heart hemodynamics. Our objective is to determine the association between CV risk factors and the main pulmonary artery (MPA) diameter. METHODS: The study population are asymptomatic individuals with no known diagnosis of CV diseases in central Appalachia (n=1,282). Adults aged 18 years or older were eligible for the screening if they were referred by a physician. For self-referral, only males aged ≥45 years and females aged ≥55 years were eligible. Unadjusted and adjusted linear regression analyses were performed. RESULTS: The mean MPA diameter was significantly higher among males compared to females (27.19±4.20 vs. 24.99±3.91 mm, P<0.0001). Participants with diabetes also had wider MPA diameter (26.79±4.56 mm) compared to those without diabetes (25.93±4.11 mm) (P=0.015). Further, hypertensive (26.42±4.15 vs. 25.71±4.21 mm, P=0.002) and obese (27.25±4.11 vs. 25.28±4.07 mm, P<0.0001) participants had significantly wider MPA diameter compared to non-hypertensive and non-obese participants, respectively. Multivariable model showed that age, sex and body mass index (BMI) were significantly associated with MPA diameter. A 1-year increase in age increased MPA diameter by 0.046 mm (P<0.0001). The diameter of MPA was wider among males by 2.16 mm compared to females (P<0.0001). Finally, with one unit increase in BMI, the MPA diameter increased by 0.16 mm (P<0.0001). CONCLUSIONS: MPA diameter was significantly associated with age, sex, and BMI. Further prospective studies are needed to correlate computed tomography (CT) measurement of MPA diameter with pulmonary pressure as assessed by echocardiogram to diagnose pulmonary hypertension (PH).

Explaining Pharmacy Students' Dispensing Intentions in Substance Abuse-Related Gray Areas Using the Theory of Planned Behavior.

Objective. To examine the extent to which theory of planned behavior (TPB) constructs and demographic characteristics explain pharmacy students' dispensing intentions in ethically or legally gray areas involving potential substance misuse or abuse. Methods. Two cohorts of third-year Doctor of Pharmacy (PharmD) students (n=159) were provided with five written cases describing common "gray area" dispensing scenarios in community practice involving medications and devices with potential for misuse or abuse (eg, long-term buprenorphine maintenance prescription without evidence of tapering, early refill of a narcotic for an out-of-town patient, non-prescription sale of pseudoephedrine). Students completed a 12-item survey instrument for each case. Items assessed whether the student would dispense the medication or device in the given scenario, how many times in 10 similar scenarios the student would dispense the medication or device, attitudes regarding dispensing, and subjective norm and perceived behavioral control beliefs. Results. Wide variation in the percentages of students who would dispense the medications or devices was noted across the five scenarios (14% in the buprenorphine scenario to 61% in the pseudoephedrine scenario). Attitude scores significantly predicted dispensing decisions in all scenarios (p<.001), whereas subjective norm and perceived behavioral control beliefs were significant predictors of dispensing only in select case scenarios. Gender and community pharmacy work experience did not consistently predict dispensing intentions. Conclusion. Student attitudes consistently predicted intent to dispense across five gray practice scenarios. These findings can be used to inform development of educational interventions that influence students' attitudes and self-awareness in community practice decision-making scenarios involving potential substance misuse or abuse.

Student Pharmacists' Personal Finance Perceptions, Projected Indebtedness Upon Graduation, and Career Decision-making.

Objective. To evaluate the extent to which Doctor of Pharmacy students' personal finance perceptions, projected student loan indebtedness, and demographic characteristics predict postgraduation career intentions. Methods. Students at three pharmacy colleges completed a 31-item survey instrument that assessed personal finance perceptions, self-efficacy beliefs, anticipated student loan debt upon graduation, postgraduate intentions, anticipated practice setting upon graduation, and demographic characteristics. Logistic regression models were used to examine the extent to which personal finance perceptions, student loan indebtedness, and demographic characteristics predicted postgraduate intentions and anticipated practice setting. Results. There were 763 usable responses obtained (response rate=90.3%). Students reported an anticipated personal student loan debt at graduation of $162,747 (SD=$87,093) and an estimated 7.4 (SD=5.8) years to pay off non-mortgage debt postgraduation. Fifty-three percent of students reported planning to practice in a community pharmacy setting postgraduation, and 54% indicated they intended to enter practice directly. Student loan indebtedness was not a significant predictor of whether students planned to pursue postgraduate training. There was a significant association between debt influence and pressure perceptions and students' plans to pursue postgraduate training (aOR=0.78; 95% CI=0.65-0.94). The odds of indicating hospital (vs chain community) pharmacy as the anticipated setting decreased 36% with every one point increase in debt influence and pressure perceptions (aOR=0.64; 95% CI=0.50-0.81). Conclusion. Pharmacy students' perceived debt pressure and influence predicted their intention to enter practice directly (vs pursuing postgraduate training) and to select a career in chain community pharmacy (vs hospital pharmacy). Student loan indebtedness was not a significant predictor of postgraduate training intentions. These findings suggest that interventions that equip students to manage the pressure associated with large student loan debts should be explored.

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.

The Progress of Tobacco Control Research in Sub-Saharan Africa in the Past 50 Years: A Systematic Review of the Design and Methods of the Studies.

Over one billion of the world's population are smokers, with increasing tobacco use in low- and middle-income countries. However, information about the methodology of studies on tobacco control is limited. We conducted a literature search to examine and evaluate the methodological designs of published tobacco research in Sub-Saharan Africa (SSA) over the past 50 years. The first phase was completed in 2015 using PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. An additional search was completed in February 2017 using PubMed. Only tobacco/smoking research in SSA countries with human subjects and published in English was selected. Out of 1796 articles, 447 met the inclusion criteria and were from 26 countries, 11 of which had one study each. Over half of the publications were from South Africa and Nigeria. The earliest publication was in 1968 and the highest number of publications was in 2014 (n = 46). The majority of publications used quantitative methods (91.28%) and were cross-sectional (80.98%). The commonest data collection methods were self-administered questionnaires (38.53%), interviews (32.57%), and observation (20.41%). Around half of the studies were among adults and in urban settings. We conclud that SSA remains a "research desert" and needs more investment in tobacco control research and training.

Diabetes, subclinical atherosclerosis and multiple cardiovascular risk factors in hard-to-reach asymptomatic patients.

AIM: To examine the association of cardiovascular disease risk factors with and their cumulative effect on coronary artery calcium in hard-to-reach asymptomatic patients with diabetes. METHODS: A total of 2563 community-dwelling asymptomatic subjects from Central Appalachia participated in coronary artery calcium screening at a heart centre. Binary variable was used to indicate that coronary artery calcium was either present or absent. Independent variables consisted of demographic and modifiable risk factors and medical conditions. Descriptive statistics and multinomial logistic regression analyses were conducted. RESULTS: In total, 55.8% and 13.7% of study participants had subclinical atherosclerosis (coronary artery calcium ⩾1) and diabetes, respectively. The presence of coronary artery calcium was higher in subjects with diabetes (68.5%) than those without (53.8%). Compared to subjects without diabetes with coronary artery calcium = 0, obesity, hypertension, hypercholesterolaemia and smoking increased the odds of the presence of coronary artery calcium (coronary artery calcium score ⩾1) regardless of diabetes status; however, with larger odds ratios in subjects with diabetes. Compared to subjects without diabetes with coronary artery calcium score = 0, having 3, 4 and ⩾5 risk factors increased the odds of presence of coronary artery calcium in subjects with diabetes by 14.06 (confidence interval = 3.26-62.69), 32.30 (confidence interval = 7.41-140.82) and 47.12 (confidence interval = 10.35-214.66) times, respectively. CONCLUSION: There is a need for awareness about subclinical atherosclerosis in patients with diabetes and more research about coronary artery calcium in subpopulations of patients.

The associated risk factors for coronary artery calcium in asymptomatic individuals with and without diabetes in rural Central Appalachia.

AIM: To examine the risk factor of coronary artery calcium (CAC) in individuals with diabetes and those without diabetes in Central Appalachia. METHODS: Study population included 2479 asymptomatic participants who underwent CAC screening between August 2012 and November 2016. CAC score was classified into four categories [0 (no plaque), 1-99 (mild plaque), 100-399 (moderate plaque), and ≥400 (severe plaque)]. Multinomial logistic regression analyses were conducted to test the association between CAC and cardiovascular disease (CVD) risk factors among participants with diabetes, age and gender matched controls, and randomly selected controls. RESULTS: 13.6% of total participants had diabetes. Around 69%, 59.8%, and 57.7% of the participants with diabetes, matched controls, and randomly selected controls had CAC score ≥1, respectively. Participants with diabetes had higher prevalence of all CVD risk factors than controls. Among participants with diabetes, hypertension and physical inactivity increased the odds of CAC = 100-399, while among those without diabetes, hypertension and hypercholesteremia increased the odds of having CAC = 1-99 and CAC ≥ 400. CONCLUSION: Half of study participants had subclinical atherosclerosis (i.e., CAC), and individuals with diabetes had higher CAC scores. This study suggests that individuals with diabetes in Central Appalachia might benefit from screening for CAC.

Geographic and Individual Correlates of Subclinical Atherosclerosis in an Asymptomatic Rural Appalachian Population.

BACKGROUND: This study aimed to examine the association between subclinical atherosclerosis (ascertained as coronary artery calcium [CAC]) in asymptomatic individuals in the Central Appalachian region of the United States and individual- and geographic-level factors. MATERIALS AND METHODS: Data were obtained from participants in CAC screening between 2012 and 2016. CAC score was assessed as CAC = 0 (no plaque), 1 ≤ CAC ≤ 99 (mild plaque), 100 ≤ CAC ≤ 399 (moderate plaque) and CAC ≥ 400 (severe plaque). Additionally, data on demographics (age, sex and race), medical conditions, lifestyle factors and family history of coronary artery disease were obtained. Further, zip codes of place of residence for participants were used to generate geographic-level data. Descriptive statistics were used to estimate the prevalence of CAC, and multinomial logistic regression models were used to delineate significant factors. RESULTS: Of 1,512 participants, 57.6% had CAC > 0. The prevalence of mild, moderate and severe plaques was 31.6%, 16.3% and 9.7%, respectively. Demographics (age and sex), medical conditions, lifestyle factors and family history of coronary artery disease were associated with increased risk for subclinical atherosclerosis. Further, the proportion of minority residents significantly increased the risk for severe plaque (relative risk ratio = 1.06, P = 0.04) and the proportion of residents on government assistance significantly decreased the risk for mild plaque (relative risk ratio = 0.93, P = 0.03). CONCLUSIONS: The results imply that the proportion of minority residents in a geographic area is associated with increased relative risk for subclinical atherosclerosis, while the proportion of residents on government assistance decreased such risk. However, future geographic or neighborhood-level studies with a larger sample size are needed to delineate further the consistency of these results in the Central Appalachian population.