4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 1/19 JAMA Netw Open. 2022 Apr; 5(4): e227559. Published online 2022 Apr 26. doi: 10.1001/jamanetworkopen.2022.7559: 10.1001/jamanetworkopen.2022.7559 PMCID: PMC9044117 PMID: 35471573 Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Saharan Africa Engelbert A. Nonterah, MD, PhD, Daniel Boateng, PhD, Nigel J. Crowther, PhD, Kerstin Klipstein-Grobusch, PhD, Abraham R. Oduro, MD, PhD, Godfred Agongo, PhD, Shukri F. Mohamed, PhD, Palwendé R. Boua, PhD, Solomon S. R. Choma, MSc, Shane A. Norris, PhD, Stephen M. Tollman, MD, PhD, Michiel L. Bots, MD, PhD, Michèle Ramsay, PhD, and Diederick Grobbee, MD, PhD Navrongo Health Research Centre, Ghana Health Service, Navrongo, Ghana Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands Department of Chemical Pathology, National Laboratory Health Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Department of Biochemistry and Forensic Sciences, School of Chemical and Biochemical Sciences, C.K. Tedam University of Technology and Applied Sciences, Navrongo, Ghana African Population Health Research Centre, Nairobi, Kenya Institut de Recherché en Sciences de la Santé, Clinical Research Unit of Nanoro, Nanoro, Burkina Faso DIMAMO Health Demographic Surveillance Site, Department of Pathology and Medical Sciences, School of Health Care Sciences, Faculty of Health Sciences, University of Limpopo, Polokwane, South Africa MRC/Wits Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa MRC/Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Sydney Brenner Institute of Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author. Article Information Accepted for Publication: February 17, 2022. Published: April 26, 2022. doi:10.1001/jamanetworkopen.2022.7559 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Nonterah EA et al. JAMA Network Open. Corresponding Author: Engelbert A. Nonterah, MD, PhD, Navrongo Health Research Centre, Ghana Health Service, Navrongo, Ghana (drenanonterah@gmail.com). 1 , 2 2 3 2 , 4 1 1 , 5 6 7 8 9 10 2 11 2 1 2 3 4 5 6 7 8 9 10 11 JAMA Network Open https://pubmed.ncbi.nlm.nih.gov/35471573 https://pubmed.ncbi.nlm.nih.gov/?term=Nonterah%20EA%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Boateng%20D%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Crowther%20NJ%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Klipstein-Grobusch%20K%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Oduro%20AR%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Agongo%20G%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Mohamed%20SF%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Boua%20PR%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Choma%20SS%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Norris%20SA%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Tollman%20SM%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Bots%20ML%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Ramsay%20M%5BAuthor%5D https://pubmed.ncbi.nlm.nih.gov/?term=Grobbee%20D%5BAuthor%5D https://jamanetwork.com/pages/cc-by-license-permissions mailto:dev@null 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 2/19 Author Contributions: Drs Nonterah and Boateng had full access to all of the data in the study and take responsi- bility for the integrity of the data and the accuracy of the data analysis. Concept and design: Nonterah, Crowther, Klipstein-Grobusch, Oduro, Tollman, Bots, Ramsay, Grobbee. Acquisition, analysis, or interpretation of data: Nonterah, Boateng, Crowther, Klipstein-Grobusch, Oduro, Agongo, Mohamed, Boua, Choma, Norris, Bots, Ramsay. Drafting of the manuscript: Nonterah, Boateng, Crowther, Oduro, Mohamed. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Nonterah, Boateng. Obtained funding: Norris, Ramsay, Grobbee. Administrative, technical, or material support: Oduro, Agongo, Mohamed, Boua. Supervision: Crowther, Klipstein-Grobusch, Oduro, Tollman, Bots. Conflict of Interest Disclosures: None reported. Funding/Support: Dr Nonterah was supported by the Global Health Support Program of the University Medical Center Utrecht, Utrecht University, the Netherlands, and the Navrongo Health Research Centre, Ghana. The African-Wits-INDEPTH (International Network for the Demographic Evaluation of Populations and Their Health in Low- and Middle-Income Countries) genomic study (AWI-Gen) Collaborative Centre is funded by the National Human Genome Research Institute, Office of the Director; Eunice Kennedy Shriver National Institute of Child Health & Human Development; the National Institute of Environmental Health Sciences, the Office of AIDS Research; and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (award No. U54HG006938) and its supplements, as part of the H3Africa Consortium. Additional funding was leveraged from the Department of Science and Technology, South Africa (award No. DST/CON 0056/2014). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, manage- ment, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We would like to express our appreciation to the participants for their generosity and sacrifice in spending many hours responding to questionnaires, being measured, and having samples taken. We also acknowledge the remarkable contributions of our field workers, phlebotomists, laboratory scientists, administra- tors, data personnel, and other staff who contributed to the data and sample collections, processing, storage, and shipping. Additional Information: The AWI-Gen data used in the current study can be accessed from the European Genome-Phenome Archive (https://ega-archive.org/datasets) with phenotype dataset accession ID of EGA00001002482. Received 2021 Oct 15; Accepted 2022 Feb 17. Copyright 2022 Nonterah EA et al. JAMA Network Open. https://ega-archive.org/datasets https://www.ncbi.nlm.nih.gov/pmc/about/copyright/ 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 3/19 This is an open access article distributed under the terms of the CC-BY License. Key Points Question Are novel cardiovascular disease (CVD) risk factors, such as carotid atherosclerosis (carotid in- tima-media thickness) and microalbuminuria, associated with with 10-year atherosclerotic CVD (ASCVD) risk in sub-Saharan African adults free of established CVD? Findings In this cross-sectional study of 9010 adult participants, microalbuminuria measured using spot urine albuminuria was associated with both carotid atherosclerosis and a high 10-year risk of ASCVD. Meaning These �indings suggest that spot urine albuminuria can be used in rural and urban sub- Saharan African settings to screen for individuals with a higher risk of ASCVD; however, clinical events data may be needed to con�irm these �indings. This cross-sectional study evaluates the association of carotid atherosclerosis and microalbu- minuria with 10-year atherosclerotic cardiovascular disease (ASCVD) risk in middle-aged sub- Saharan African individuals. Abstract Importance Carotid atherosclerosis and microalbuminuria are associated with atherosclerotic cardiovascu- lar disease (ASCVD) but are understudied in sub-Saharan Africa. Objective To evaluate the association of carotid atherosclerosis and microalbuminuria with 10-year ASCVD risk in middle-aged sub-Saharan African individuals. Design, Setting, and Participants This cross-sectional study conducted analyses of baseline data from the African-Wits-INDEPTH (International Network for the Demographic Evaluation of Populations and Their Health in Low- and Middle-Income Countries) genomic study (AWI-Gen). Women and men aged 40 to 60 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 4/19 years without baseline CVD and drawn from Burkina Faso, Ghana, Kenya, and South Africa were included. Main Outcomes and Measures Hypotheses for the analyses were formulated after data collection. The main exposures were carotid atherosclerosis, assessed using carotid intima-media thickness (CIMT) using B-mode ul- trasonography, and microalbuminuria, measured using spot urine albumin (SUA) and urine al- bumin-creatinine ratio (uACR). The main outcome was high ASCVD risk, de�ined as a 2018 Pooled Cohort Equations score of 7.5% or greater. Associations were estimated using adjusted multivariable logistic regression analyses. Findings A total of 9010 participants with a mean (SD) age of 50 (6) years and 4533 (50.3%) women were included. High CIMT, SUA, and uACR were each associated with older age (eg, mean [SD] age of participants with high vs reference range CIMT: 55 [5] years vs 50 [6] years; P < .001) and high prevalence of both diabetes and hypertension (eg, hypertension among those with high vs reference range SUA: 213 of 1117 [19.1%] vs 356 of 2549 [14.0%]; P < .001). Smokers were likely to have higher vs reference range SUA (210 [18.8%] vs 407 [16.0%]) and uACR (138 of 707 [19.5%] vs 456 of 2797 [16.3%]). Carotid atherosclerosis was common in Burkina Faso (82 of 262 [31.3%]) and Ghana (91 [34.7%]), while microalbuminuria, measured by SUA, was common in Kenya (272 [24.4%]) and South Africa (519 [46.5%]). SUA was associated with higher odds of carotid atherosclerosis (odds ratio [OR], 1.77; 95% CI, 1.04-3.01) compared with uACR (OR, 0.51; 95% CI, 0.27-0.95). Common CIMT, SUA, and uACR were associated with 10-year ASCVD risk, with CIMT having a stronger association with 10-year ASCVD risk in both women (OR, 1.95; 95% CI, 1.78-2.14) and men (OR, 1.73; 95% CI, 1.55-1.93) than SUA (women: OR, 1.29; 95% CI, 1.12-1.43; men: OR, 1.46; 95% CI, 1.26-1.55) and uACR (women: OR, 1.32; 95% CI, 1.10-1.54; men: OR, 1.35; 95% CI, 1.15-1.46). Conclusions and Relevance The presence of microalbuminuria measured by SUA may indicate risk of subclinical carotid atherosclerosis and high 10-year ASCVD risk in middle-aged residents of sub-Saharan Africa. These data should be con�irmed in longitudinal studies of cardiovascular events. Introduction Cardiovascular disease (CVD) is a leading cause of death and disability worldwide, with low- and middle-income countries, such as those in sub-Saharan Africa, experiencing 80% of CVD- related global deaths. Most of these deaths in sub-Saharan Africa occur in younger age groups compared with the rest of the world, posing health concerns and loss of productive workforce. Established classical cardiovascular risk factors, such as age, sex, smoking, body mass index, blood pressure, hyperglycemia, and dyslipidemia, are major contributors to CVD in many pop- ulations. These factors alone do not explain the total risk for CVD, and several novel factors— 1 2 3 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 5/19 such as markers of in�lammation, atherosclerosis, and microalbuminuria—contribute to CVD risk. Common carotid intima-media thickness (CIMT) assessed by B-mode ultrasonography is a marker of carotid atherosclerosis that occurs early in life as a low-grade sustained in�lamma- tion and progresses with age and the presence of CVD risk factors. Microalbuminuria mea- sured by spot urine albumin (SUA) and albumin-creatinine ratio (uACR) is associated with car- diovascular events, such as congestive heart failure, stroke, and myocardial infarction. The risk is higher in people with hypertension or type 2 diabetes (T2D); therefore in high-income countries, most studies have focused on these populations. Few studies have examined the associations of microalbuminuria and carotid atherosclerosis with CVD in African populations. This is partly due to the dif�iculty in assessing CVD risk in Africa as a result of scarce clinical events data. To our knowledge, the PURE (Prospective Urban Rural Epidemiology) and INTERHEART studies are the only studies to have investigated the as- sociation of classical risk factors with CVD end points using African populations. These studies were limited by their small sample sizes and, in the case of the PURE study, by selection bias, and neither study examined these novel risk factors. Thus, population-level data on estab- lished CVD and associated risk factors is still largely absent in sub-Saharan Africa. This has led to the use of risk equations to assess CVD risk in sub-Saharan African populations. The 2018 revised Pooled Cohort Equation (PCE) is commonly used because of its high accuracy for 10- year atherosclerotic CVD (ASCVD) risk prediction and good performance in African American populations. To explore cost-effective methods for assessing CVD risk, it is important to examine the associ- ation of both classical and novel CVD risk factors, including carotid atherosclerosis and microalbuminuria. Furthermore, comparing the association of CIMT and microalbuminuria with CVD will offer new insights on factors for population-level CVD screening programs. This study thus measured the association of microalbuminuria with CIMT and the association of both these variables with 10-year ASCVD risk in a large population of middle-aged adults from Burkina Faso, Ghana, Kenya, and South Africa. Methods The Human Hereditary and Health Africa (H3A) Africa-Wits-INDEPTH (International Network for the Demographic Evaluation of Populations and Their Health in Low- and Middle-Income Countries) Partnership for Genomic Studies (AWI-Gen) study received ethics approval from the Human Research Ethics Committee of the University of the Witwatersrand, Johannesburg, South Africa. Ethical approvals were also obtained from relevant ethics bodies in the participat- ing sites. Community engagement, broad consent, and individual informed consent were ob- tained prior to carrying out study procedures. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for obser- vational studies. Study Design and Population We conducted a population-based cross-sectional study using the AWI-Gen cohort between 2013 and 2016. Data were collected from adults residing in health and sociodemographic surveillance sites located in Nanoro (Burkina Faso), Navrongo (Ghana), Nairobi (Kenya), and 4,5 6,7 8,9 10,11 12 3 13 14,15 http://www.equator-network.org/reporting-guidelines/strobe/ 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 6/19 DIMAMO and Agincourt (South Africa). Additional data were collected from an urban cohort in Soweto, South Africa. Participants were nonpregnant women and men aged 40 to 60 years with no self-reported pre- vious diagnosis of CVD (based on response to the question “Has a doctor or other health pro- fessional ever told you that you had coronary heart disease, angina [also called angina pec- toris], heart attack [also called myocardial infarction], or stroke?”). Participants with measured CIMT greater than 1.5 mm were excluded, as this was consistent with plaque and not atherosclerosis. Data Collection A structured questionnaire for obtaining information on sociodemographic variables, clinical history, and behavioral risk factors was administered by trained researchers. Sociodemographic variables included self-reported sex, age at time of data collection, highest level of education attained, and household socioeconomic status using intrasite-generated wealth quintiles. Physical measurements included weight and height for computing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), waist and hip circumference, and blood pressure. Fasting levels of glucose, lipids, and insulin were mea- sured from blood samples, while albumin and creatinine were measured from urine samples. Data collection tools were standardized across sites with centralized training of researchers. Details of data collection instruments and study procedure have been published elsewhere. Estimated 10-Year ASCVD Risk Estimated 10-year ASCVD risk was computed using the revised 2018 PCE. This risk equation estimates the 10-year absolute risk of ASCVD, de�ined as death due to coronary heart disease or nonfatal myocardial infarction or fatal or nonfatal stroke over a 10-year period in people free of established CVD. The PCE permits the derivation of sex- and race-speci�ic estimates of 10-year risk for ASCVD for adults aged 40 to 79 years (which falls within AWI-Gen study’s age category of 40 to 60 years). Variables in the PCE include age, sex, African race, tobacco smok- ing, total and high-density lipoprotein cholesterol levels, treated or untreated systolic blood pressure, and diabetes status. A PCE score of 7.5% or greater classi�ies an individual partici- pant at a high ASCVD risk, while less than 7.5% is considered low risk. Age, sex, and race were self-reported at the time of data collection. We de�ined smoking as self-reported cigarette and pipe smoking, chewing tobacco use, and snuff use in the 12 months prior to data collec- tion. Blood pressure was measured with the participant seated and with the arm resting on a chair at the level of the heart. An appropriately sized cuff was then applied, and 3 readings were taken with the �irst discarded, while an average of the last 2 was used as the blood pres- sure reading. Hypertension was de�ined as previous diagnosis by a health care professional, taking medication for the condition, or systolic blood pressure of 140 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater. Fasting blood samples were taken for the measurement of fasting glucose and lipid fractions in a central laboratory using standard- ized procedures. The coef�icient of variation of the glucose and lipid measurements ranged be- tween 0.2% and 1.5%. Diabetes status was de�ined as fasting glucose levels of 126.13 mg/dL or greater (to convert to millimoles per liter, multiply by 0.0555) and/or known diagnosis of dia- betes and taking medication at the time of data collection. 16 17 16 12 18 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 7/19 Carotid Atherosclerosis Assessed by CIMT A LOGIQ e B-mode ultrasound system (GE Healthcare) with a 12L-RS straight transducer was used to measure right and left intima-media thickness of the common carotid arteries (CCAs). The IMT was measured within a 10-mm segment of the CCA starting from 1 cm away from the bulb. Measurements were taken of minimum, maximum, and average distance in millimeters to 2 decimal places. The average of the right and left far wall measurement were averaged to get the outcome of common CIMT. Carotid atherosclerosis was de�ined as common CIMT of 0.90 mm or greater. Microalbuminuria SUA Midstream urine samples (10-15 mL voided into a sterile collection pot) were collected in accordance with the procedures followed by the World Health Organization. Samples were centrifuged at 1500 to 2000 × g for 5 minutes and the supernatant aliquoted into cryovials for storage at −80 °C until analysis. Albumin concentrations in urine samples were determined us- ing a turbidimetric assay on a Cobas 501 autoanalyser (Roche Diagnostics). The measuring range was 3 to 400 mg/L for albumin (to convert to grams per deciliter, multiply by 0.001), and the coef�icient of variation was less than 2.7%. The use of spot urine as opposed to 24-hour urine collection or albumin-creatinine ratio (ACR) was previously validated in the general population. Microalbuminuria was de�ined as spot urine albumin concentration of 20 mg/L or greater (or 20-400 mg/L within the con�ines of the measuring range of the study population). uACR Urinary albumin concentration was measured with immunoturbidimetry as described previously, and urine creatinine was measured by an IDMS-traceable Jaffe method on the Cobas 501 instrument (Roche Diagnostics). The measuring range for the urine creatinine assay was 3.75 to 550 mmol/L with a coef�icient of variation of 2.8%. uACR of more than 3 mg/mmol was de�ined as microalbuminuria. Statistical Analysis Characteristics of the AWI-Gen participants are described using counts and proportions for categorical data and means and SDs for normally distributed continuous data. Baseline charac- teristics were strati�ied by carotid atherosclerosis and microalbuminuria. Differences between these groups were determined using Pearson χ test for categorical data and t test for continu- ous data. A mixed-effect multivariable logistic regression analysis using country as a random effect was used to determine the association between microalbuminuria and CIMT in the combined sam- ple and for women and men. Adjustments were made for classic CVD risk factors (ie, age, sex [except in the sex-strati�ied analyses], smoking, BMI, systolic blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, and diabetes), and HIV status. The associations of carotid atherosclerosis and microalbuminuria with 10-year ASCVD risk were determined using multivariable logistic regression analyses. Owing to differences in their units of measurements, we �irst generated sex and country speci�ic z scores for common CIMT, 19,20,21,22 16 23,24 25 25,26 2 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 8/19 SUA, and uACR, thus allowing direct comparison of the odds ratios (ORs). We calculated z scores using the following equation: (x − μ) / σ, where x is the raw, individual value; μ is the population mean; and σ is the population SD. We generated a binary form of PCE based on the American Heart Association de�inition of high 10-year ASCVD risk as PCE score of 7.5% or greater. We applied adjusted logistic regression analyses to determine the associations of CIMT, SUA, and uACR with high 10-year ASCVD risk. Adjustments were made in a sequential manner using BMI, HIV status, and sociodemographic factors (age, sex [except sex-speci�ic analyses], educational level, and household socioeconomic status), which have been demonstrated to be associated with CVD. Akaike and bayesian information criteria (AIC/BIC) were used to compare the models, and the model with the lowest value was considered a better model. This was fur- ther con�irmed using the Hosmer-Lemeshow (H-L) goodness of �it test, which determines whether the observed ORs match the expected ORs in the population and population sub- groups (ie, countries and sex speci�ic subgroups), and a P > .05 was considered a good �it. For the country level comparisons of the strength of association of CIMT, SUA, and uACR z scores with high 10-year ASCVD risk scores, we conducted an inverse variance logistic regres- sion meta-analysis. The best �itted model (fully adjusted model, ie, model 3) was used for these country and sex comparative pooled analyses. The adjusted ORs are presented as forest plots with the within-group variance measured using I , where a high I and P < .05 indicate high within-group variance. Heterogeneity was measured to assess differences between study groups, with a P > .05 indicating low heterogeneity between groups. Associations are reported as ORs with 95% CIs. Statistical signi�icance was set at a 2-tailed P < .05. All analyses were con- ducted using Stata version 14.2 (StataCorp). Results Study Population Basic Characteristics The study consisted of 9010 participants with mean (SD) age of 50 (6) years and 4533 (50.3%) women. Presented in Table 1 is a comparison of the characteristics of the study participants categorized by carotid atherosclerosis and microalbuminuria status. A higher proportion of men vs women had carotid atherosclerosis (145 of 262 [55.4%] vs 117 [44.6%]; P = .02) and microalbuminuria, assessed by SUA, (581 of 1117 [52.0%] vs 536 [48.0%]; P = .01). Participants with tertiary level education, compared with those with no formal education, had lower levels of carotid atherosclerosis (8 [3.1%] vs 146 [55.9%]; P < .001) and microalbumin- uria assessed by SUA (33 [3.0%] vs 358 [32.1%]; P = .03). High CIMT, SUA, and uACR were each associated with older age (eg, mean [SD] age of participants with high CIMT vs reference range CIMT: 55 [5] years vs 50 [6] years; P < .001). Smokers were likely to have higher vs reference range SUA (210 [18.8%] vs 407 [16.0%]) and uACR (138 of 707 [19.5%] vs 456 of 2797 [16.3%]). Participants from Ghana and Burkina Faso had higher levels of carotid atherosclero- sis (Ghana: 91 [34.7%]; Burkina Faso: 82 [31.3%]) compared with participants from Kenya and South Africa (Kenya: 22 [8.4%]; South Africa: 67 [25.6%]) and the opposite was observed for microalbuminuria (Kenya: 272 [24.4%]; South Africa: 519 [46.5%]; Ghana: 151 [13.5%]; Burkina Faso: 175 [15.7%]). Participants with carotid atherosclerosis, microalbuminuria and high ASCVD risk had higher proportions of hypertension and diabetes (eg, hypertension among those with high vs reference range SUA: 213 [19.1%] vs 356 [14.0%]; P < .001). 2 2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/table/zoi220237t1/ 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 9/19 Association of Microalbuminuria With CIMT The associations of microalbuminuria with CIMT in the combined sample and in women and men are presented in Figure 1. In the combined population, high SUA was signi�icantly associ- ated with higher risk of carotid atherosclerosis (adjusted OR, 1.77; 95% CI, 1.04-3.01), but this association was not signi�icant when disaggregated by sex. uACR was not associated with a higher risk for elevated CIMT in women and men or in the combined population. There was signi�icant within-country variance in measured SUA and uACR, but there was no heterogeneity between women and men (eFigure in the Supplement). Association of Carotid Atherosclerosis and Microalbuminuria With High 10-Year ASCVD Risk Presented in Table 2 are the associations of carotid atherosclerosis or microalbuminuria with high 10-year ASCVD risk, strati�ied by sex. In the combined population, common CIMT and both measures for microalbuminuria were associated with 10-year ASCVD risk in all the models, in- cluding the disaggregated models for women and men. Thus, in model 3 of the combined popu- lation, participants with higher common CIMT had higher odds of 10-year ASCVD risk (OR, 1.85; 95% CI, 1.75-1.99) compared with SUA (OR, 1.37; 95% CI, 1.24-1.45) and uACR (OR, 1.34; 95% CI, 1.18-1.43). This observed pattern was similar in women and men (Table 2). In the fully adjusted model 3 for combined population, men and women were well �itted due to lower AIC/BIC values and H-L tests with P values greater than .05. The fully adjusted model was thus used in meta-analyses to compare associations of carotid atherosclerosis and microalbuminuria with 10-year ASCVD risk for the various countries strati- �ied by sex (Figure 2 and Figure 3). For instance, among women in Burkina Faso, carotid ather- osclerosis was associated with a 2-fold increased risk of microalbuminuria (OR, 2.23; 95% CI, 1.68-2.96). This observed association was similar but higher than observed in Ghana (OR, 1.98; 95% CI, 1.63-2.42), South Africa (OR, 1.91; 95% CI, 1.65-2.21), and Kenya (OR, 1.79; 95% CI, 1.48-2.17). Among men, similar observations were made with Kenya (OR, 2.09; 95% CI, 1.54- 2.28), with a stronger association than that observed in Ghana (OR, 1.70; 95% CI, 1.27-2.27), South Africa (OR, 1.69; 95% CI, 1.47-1.94), and Burkina Faso (OR, 1.49; 95% CI, 1.03-2.16). These analyses show that across all countries, microalbuminuria and carotid atherosclerosis were signi�icantly associated with 10-year ASCVD risk in women and men. However, the magni- tude of these associations differed between the countries and sex. In most instances, the strength of association of CIMT with ASCVD risk was higher compared with SUA and uACR. Discussion The present study found that microalbuminuria was associated with CIMT independent of the traditional ASCVD risk factors. We also found that carotid atherosclerosis and microalbumin- uria were associated with high 10-year ASCVD risk in middle-aged adults from sub-Saharan Africa. The results from this study offer new insights on factors that can be used to identify in- dividuals at a high risk of ASCVD. The �indings showed differences in the prevalence of carotid atherosclerosis and microalbu- minuria between countries. Participants from Kenya and South Africa reported high levels of microalbuminuria compared with those from Burkina Faso and Ghana, while the opposite was https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/figure/zoi220237f1/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/table/zoi220237t2/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/table/zoi220237t2/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/figure/zoi220237f2/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/figure/zoi220237f3/ 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 10/19 observed for common CIMT. The higher prevalence of microalbuminuria in Kenya and South Africa may be because of the higher prevalence of cardiometabolic diseases and HIV infection. The higher prevalence of alcohol use in Burkina Faso and Ghana may result in chronic liver disease and hence low circulatory serum albumin and creatinine levels. Studies involving HIV- exposed and HIV-naive individuals in rural South Africa and Hawaii reported HIV as an impor- tant predictor of microalbuminuria. This may be because HIV nephropathy and associated immune complex kidney disease leads to increased leakiness of nephrons to creatinine and albumin. The present study found that higher educational attainment was associated with lower levels of carotid atherosclerosis and microalbuminuria. Similar associations have been reported in pre- vious studies and may re�lect the association between poor education and higher levels of car- diovascular risk factors. We observed that SUA had a stronger association with CIMT than did uACR, as has been re- ported previously. The underlying mechanisms for the observed association remain un- clear. However, vascular endothelial damage may cause atherosclerosis and albuminuria. Endothelial dysfunction increases vascular leakiness in target vessels. If these endothelial changes occur in the glomerular capillaries, the associated increased permeability in the glomerular barrier will cause increased excretion of albumin into the urine. Carotid atherosclerosis and microalbuminuria were associated with high 10-year ASCVD risk in women and men. Large epidemiological studies such as the Kuopio Ischaemic Heart Disease Risk Factor Study, Atherosclerosis Risk in Communities study, and the Cardiovascular Health Study have made similar observations with myocardial infarction and stroke. The Rotterdam and USE Intima-Media Thickness studies recently reported a signi�icant association of CIMT with ASCVD risk. While CIMT and microalbuminuria were associated with ASCVD, microalbuminuria is more apparent in individuals with hypertension and T2D, as evident in our data. Con�irming this, a review of studies in Europe, North America, and Australia observed mi- croalbuminuria occurs in the elderly (5%), those with hypertension (11%-17%), and those with T2D (20%-30%). Among individuals with diabetes and those with advanced age, bio- chemical alterations to the extracellular matrix may lead to glomerulosclerosis and premature atherosclerosis, while insulin resistance leads to endothelial structural and functional damage. Our study has a number of strengths. Owing to different units of measurements, the use of z scores was an appropriate statistical method to enable comparisons of the magnitude of the association of carotid atherosclerosis and microalbuminuria with 10-year ASCVD risk. The up- dated 2018 PCE equation has an improved accuracy among all races and sex subgroups. We however acknowledge that the PCE was developed using data from African American partici- pants and there may be underlying differences with populations in Africa owing to environ- mental, biological, behavioral, and clinical factors. The use of a centralized laboratory and cen- tralized training of researchers minimized data variability. The country-level meta-analysis is a unique strength of this study, as it enabled us to compare differences in these associations across countries in different stages of epidemiological, demographic, and nutrition transition. Limitations 27 28 29,30 31,32 33,34 35,36,37 9,38 39 21,40,41,42 43,44 45 46 12 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 11/19 This study has limitations. The cross-sectional design prevents us from establishing causality. Social desirability and recall bias may also arise from the self-reported responses to certain questions such as previous history of CVD, smoking, and alcohol use. In addition, owing to limi- tations in access to health care in populations within this study it is feasible that some partici- pants did have a history of CVD of which they were unaware. This is important to note, as the PCE was developed for use in individuals without established CVD. Additionally, the absence of clinical events data affects the observed associations, and hence, the results must be inter- preted with caution. Conclusions In this study, the presence of SUA may indicate subclinical carotid atherosclerosis and high 10- year ASCVD risk in middle-aged individuals from sub-Saharan Africa. These data suggest that SUA may be used to assess ASCVD risk in both sexes, and with limited regional variation in our results, SUA could be used in many countries across Africa. 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Distribution of Sociodemographic and Cardiometabolic Variables by Carotid Atherosclerosis and Microalbuminuria Variable Carotid atherosclerosis SUA uACR Participants with reference range CIMT (n = 8611), No. (%) Participants with high CIMT (n =  262), No. (%) P value Participants with reference range SUA (n = 2549), No. (%) Participants with high SUA (n =  1117), No. (%) P value Participants with reference range uACR (n = 2797), No. (%) Part with uACR 707 (%) Age, mean (SD), y 50 (6) 55 (5) <.001 50 (6) 51 (6) .007 50 (6) 51 (6 Sex Women 4350 (50.5) 117 (44.6) .02 1370 (53.8) 536 (48.0) .01 1442 (51.6) 361 Men 4261 (49.5) 145 (55.4) 1179 (46.3) 581 (52.0) 1355 (48.4) 346 BMI, mean (SD) 24.1 (6.1) 24.3 (6.2) .62 24.8 (6.0) 24.8 (6.1) .95 24.8 (6.4) 25.1 Household SES Quartile 1, poorest 1185 (13.8) 32 (12.2) .47 368 (14.5) 130 (11.6) .18 394 (14.1) 84 (1 Quartile 2, poorer 1695 (19.7) 53 (20.2) 531 (20.9) 255 (22.8) 590 (21.1) 154 Quartile 3, poor 1597 (18.4) 40 (15.3) 455 (17.9) 200 (17.9) 482 (17.3) 135 Quartile 4, less poor 1889 (22.0) 57 (21.8) 541 (21.2) 235 (21.0) 598 (21.4) 150 Quartile 5, least poor 2259 (26.3) 80 (30.5) 652 (25.6) 297 (26.6) 731 (26.2) 184 Highest level of education No formal education 3335 (38.8) 146 (55.9) <.001 909 (35.7) 358 (32.1) .03 995 (35.6) 216 Primary 2493 (29.0) 61 (23.4) 793 (31.2) 387 (34.7) 875 (31.3) 245 Secondary 2449 (28.5) 46 (17.6) 740 (29.1) 339 (30.4) 811 (29.0) 224 Tertiary 319 (3.7) 8 (3.1) 104 (4.1) 33 (3.0) 113 (4.0) 22 (3 Country a b c 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 17/19 Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index (calculated as weight in kilo- grams divided by height in meters squared); CIMT, common carotid intima-media thickness; HDL-C, high-density lipoprotein cholesterol; PCE, Pooled Cohort Equation; SBP, systolic blood pressure; SES, socioeconomic status in wealth quintile Q1-Q5; SUA, Spot urine albuminuria; uACR, urine albumin-creatinine-ratio. SI conversion factors: To convert cholesterol and HDL-C to millimoles per liter, multiply by 0.0259. High CIMT de�ined as common CIMT of 0.9 mm or greater. High SUA de�ined as SUA concentration of 20 mg/L or greater. High uACR de�ined as uACR greater than 3 mg/mmol. Diabetes was de�ined as previous diagnosis by a health care professional (which excluded gestational diabetes), taking medication for the condition, or a fasting blood glucose level of 126.13 mg/dL or greater (to convert to millimoles per liter, multiply by 0.0555). Figure 1. Association of Microalbuminuria With Carotid Intima-Media Thickness (CIMT) in the Combined Sample and in Women and Men IV indicates inverse variance; NA, not applicable. a b c d 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 18/19 Table 2. Association of CIMT and Microalbuminuria With High CVD 10-Year Risk in Combined Study Populations and in Women and Men Models Common CIMT z score SUA z score uACR z score OR (95% CI) P value AIC/BIC OR (95% CI) P value AIC/BIC OR (95% CI) P value AIC/BIC All Model 1 1.55 (1.46- 1.65) <.001 5973.58 1.29 (1.20- 1.39) <.001 3163.38 1.27 (1.16- 1.39) <.001 2983.43 Model 2 1.93 (1.80- 2.07) <.001 5264.00 1.32 (1.22- 1.42) <.001 2908.98 1.28 (1.16- 1.40) <.001 2752.09 Model 3 1.85 (1.73- 1.99) <.001 5196.41 1.37 (1.24- 1.45) <.001 2809.06 1.34 (1.18- 1.43) <.001 2653.46 H-L χ , 7.63 .47 NA χ , 6.46 .58 NA χ , 6.83 .56 NA Women Model 1 1.62 (1.50- 1.75) <.001 3596.79 1.24 (1.11- 1.38) <.001 1929.75 1.22 (1.06- 1.42) .01 1797.27 Model 2 2.01 (1.83- 2.20) <.001 3214.92 1.21 (1.08- 1.36) .01 1811.38 1.23 (1.05- 1.44) .01 1689.03 Model 3 1.95 (1.78- 2.14) <.001 3157.65 1.29 (1.12- 1.43) <.001 1750.11 1.32 (1.10- 1.54) .02 1624.27 H-L χ , 5.72 .68 NA χ , 11.84 .16 NA χ , 10.70 .22 NA Men Model 1 1.52 (1.38- 1.68) <.001 2245.76 1.43 (1.30- 1.57) <.001 1153.68 1.34 (1.19- 1.52) <.001 1124.66 Model 2 1.83 (1.64- 2.03) <.001 2058.06 1.40 (1.27- 1.55) <.001 1107.17 1.30 (1.52- 1.47) <.001 1076.01 Model 3 1.73 (1.55- 1.93) <.001 2052.30 1.46 (1.26- 1.55) <.001 1079.40 1.35 (1.15- 1.46) <.001 1049.15 H-L χ , 13.35 .10 NA χ , 8.55 .38 NA χ , 8.66 .37 NA Abbreviations: AIC, Akaike information criterion; BIC, Bayesian information criterion; CIMT, carotid intima-media thickness; H-L, Hosmer-Lemeshow; NA, not applicable; OR, odds ratio; SUA, spot urine albuminuria; uACR, urine albu- min-creatinine-ratio. Model 1 was the unadjusted model; model 2, adjusted for sex, education, and country; model 3, adjustments as for model 2 plus household socioeconomic status, body mass index, and HIV status. Model 1 was the unadjusted model; model 2, adjusted for education and country; model 3, adjustments as for model 2 plus household socioeconomic status, body mass index, and HIV status. a 2 2 2 b 2 2 2 b 2 2 2 a b 4/3/24, 12:26 PM Carotid Atherosclerosis, Microalbuminuria, and Estimated 10-Year Atherosclerotic Cardiovascular Disease Risk in Sub-Sahar… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044117/?report=printable 19/19 Figure 2. Association of Carotid Atherosclerosis and Microalbuminuria With 10-Year Atherosclerotic Cardiovascular Disease (ASCVD) Risk in the Various Countries for Women CIMT indicates carotid intima-media thickness; IV, inverse variance; NA, not applicable; SUA, spot urine albumin; uACR, urine albumin-creatinine ratio. Figure 3. Association of Carotid Atherosclerosis and Microalbuminuria With 10-Year Atherosclerotic Cardiovascular Disease (ASCVD) Risk in the Various Countries for Men CIMT indicates carotid intima-media thickness; IV, inverse variance; NA, not applicable; SUA, spot urine albumin; uACR, urine albumin-creatinine ratio.