Association of Anthropometric Indices With Midlife Cardiovascular Risk in Young Individuals Without Obesity and Traditional Risk Factors.

BACKGROUND: The aim of this study was to assess how early-adulthood body mass index (BMI) and waist circumference (WC) relate to long-term cardiovascular structure, function, and prognosis in individuals without obesity and with low cardiovascular risk factor (CVRF) burden. METHODS AND RESULTS: A total of 2024 participants aged 18 to 30 from the CARDIA (Coronary Artery Risk Development in Young Adults) study, without obesity and with low CVRFs defined as the absence of cardiovascular disease (CVD), diabetes, hypertension, current smoking, and dyslipidemia were included. A CVRF-optimal subgroup was also defined, with blood pressure<120/80 mm Hg, fasting glucose <100 mg/dL, total cholesterol <200, low-density lipoprotein cholesterol <130, and women with high-density lipoprotein cholesterol ≥50 mg/dL. Coronary artery calcification, carotid intima-media thickness, left ventricular mass, left ventricular ejection fraction, longitudinal peak systolic strain, and diastolic function were assessed in midlife. Cox regression was used to calculate hazard ratios of BMI and WC for all-cause death and CVD events. Logistic regression was used to estimate odds ratios for subclinical CVD. Over 33.9 years (median follow-up), 5.2% (n=105) died, and 2.6% (n=52) had CVD events. Each 1-SD BMI increase was associated with 27% (95% CI, 1.10-1.47), 24% (1.08-1.43), 42% (1.20-1.68), 28% (1.05-1.57), 51% (1.20-1.90), and 49% (1.10-2.02) higher odds of coronary artery calcification presence, increased carotid intima-media thickness, left ventricular hypertrophy, reduced left ventricular ejection fraction, low longitudinal peak systolic strain, and diastolic dysfunction, respectively, in the CVRF-low group. Generally, similar associations were found for WC and in the CVRF-optimal subgroup. No significant associations between BMI and WC with CVD and death were found. CONCLUSIONS: Elevations in BMI and WC among young low-risk individuals, even within the nonobesity range, are associated with midlife cardiovascular health.

Association Between HDL2-C and HDL3-C with Cardiovascular Disease: A Nested Case-Control Study in an Iranian Population.

Background: The contribution of high-density lipoprotein cholesterol (HDL-C) subclasses to incident cardiovascular disease (CVD) and coronary heart disease (CHD) remains a subject of debate. Objectives: The objective of this study was to investigate these associations in a population with a high prevalence of dyslipidemia and CVD. Methods: In a nested case-control study, HDL-C and its subclasses (HDL2-C and HDL3-C) in 370 age and gender-matched case and control subjects were determined. This study employed multivariable-adjusted conditional logistic regression to calculate the odds ratios (ORs) for the associations between HDL-C, HDL2-C, HDL3-C, and HDL2-C/HDL3-C (both as continuous and categorical variables) with incident CVD and CHD. The present study models were adjusted for a comprehensive set of confounders, including body mass index, current smoking, hypertension, type 2 diabetes mellitus, use of lipid-lowering drugs, family history of premature CVD, non-HDL-C, and triglycerides. Results: In multivariate analysis, when considering lipoprotein parameters as continuous variables, a 1-unit increase in HDL-C and HDL3-C was associated with a reduced risk of incident CVD and CHD. For CVD, the ORs (95% confidence intervals [CI]) were 0.95 (0.92 - 0.98) and 0.95 (0.93 - 0.98) for HDL-C and HDL3-C, respectively. The corresponding values for CHD were 0.94 (0.91 - 0.97) and 0.94 (0.91 - 0.97). In the categorical approach to lipoprotein parameters, higher quartiles of HDL-C and HDL3-C, compared to the first quartile, were significantly associated with a lower risk of incident CVD and CHD. The ORs (95% CI) for the fourth quartiles were 0.43 (0.25 - 0.74, P for trend = 0.003) and 0.46 (0.27 - 0.78, P for trend = 0.005) for HDL-C and HDL3-C regarding CVD and 0.32 (0.17 - 0.59) and 0.32 (0.18 - 0.59) (all P for trend = 0.001) regarding CHD, respectively. Paradoxically, across quartiles of HDL2-C/HDL3-C, this lipid ratio was associated with a higher risk of CHD (92% higher risk in the fourth quartile). Conclusions: The results showed that HDL3-C, but not HDL2-C, was primarily responsible for the protective effect of HDL-C against CVD, particularly CHD, in Iranian adults.

Impact of optimal cholesterol levels on subclinical atherosclerosis in the absence of risk factors in young adults.

BACKGROUND AND AIMS: We aimed to assess the association of blood lipids with the prevalence, incidence, and progression of subclinical atherosclerosis among young individuals without dyslipidemia and other traditional cardiovascular risk factors (CVRFs). METHODS: A total of 1270 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study aged 32-46 years free of cardiovascular disease, diabetes, hypertension, current smoking, and dyslipidemia (total cholesterol [TC] ≥ 240 mg/dL, triglycerides [TG] ≥ 150 mg/dL, low-density lipoprotein cholesterol [LDL-C] ≥ 160 mg/dL, high-density lipoprotein cholesterol [HDL-C] < 40 mg/dL, or taking lipid-lowering medications) were included. A subgroup with optimal lipids within the low-CVRF group was defined with TC < 200 mg/dL, LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL, and women with HDL-C ≥ 50 mg/dL. RESULTS: 1-SD higher TC (25.9 mg/dL), LDL-C (24.7 mg/dL), and non-HDL-C (26.6 mg/dL) were associated with a greater risk of presence (hazard ratios: 1.30-1.36), incidence (1.30-1.32), and progression (1.31-1.35) of coronary artery calcium (CAC) and a 42-44% greater odds of composite mean carotid intima-media thickness (CIMT) ≥ 75th percentile [780 µm] (p < 0.05). Repeating the analyses in a subset of participants with a CAC score of zero did not alter the association of TC, LDL-C, and non-HDL-C with CIMT. In the subgroup with optimal lipids, these lipid indices remained associated with an increased risk of presence and incidence of CAC and greater CIMT measures. CONCLUSIONS: Among adults aged 32-46 years, in the absence of traditional CVRFs, elevated cholesterol levels, even within what is considered optimal, are associated with atherosclerosis and arteriopathy.

The difference between 2-hour post-challenge and fasting plasma glucose associates with the risk of cardiovascular disease in a normoglycemic population: the Tehran lipid and glucose study.

BACKGROUND: Elevated fasting plasma glucose (FPG) and 2-hour post-challenge glucose (2hPG) levels are known to be independent risk factors for cardiovascular disease (CVD). However, there is limited data on the association of the difference between these measures and the risk of CVD. This study aims to investigate this association in normoglycemic Iranian adults, particularly in those with low-normal FPG levels. METHODS: This prospective cohort study included 4,594 30-65-year-old participants from the Tehran Lipid and Glucose Study. Using multivariable Cox proportional hazards regression models adjusting for age, sex, body mass index, hypertension, hypercholesterolemia, smoking, education level and FPG, hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for the association between 2hPG-FPG, both as continuous and categorical variables, and the CVD risk. Analyses of receiver operating characteristic curves were undertaken to determine the optimal 2hPG-FPG cut-off value. RESULTS: During a median of 17.9 years of follow-up, 459 CVD events occurred. A one-unit increase in 2hPG-FPG was significantly associated with an elevated risk of cardiovascular disease in both normoglycemic (HR 1.10, 95% CI (1.01-1.19)) and low-normal FPG individuals (HR 1.16, 95% CI (1.04-1.30)); this association resisted adjustment for Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) among normoglycemic individuals. However, those with 2hPG levels greater than FPG levels had a non-significant increased risk of incident CVD compared to those with 2hPG levels of less than or equal to FPG, with corresponding HR values of 1.18 (95% CI: 0.95-1.46) in normoglycemic and 1.32 (95% CI: 0.98-1.79) in low-normal FPG, respectively. For incident CVD, the optimal cut-off value for the 2hPG-FPG was found to be 1.06 mmol/L, which was applicable for both normoglycemic and low FPG populations; using this criterion, the corresponding risks for incident CVD were 1.36 (95% CI: 1.12-1.64) and 1.57 (95% CI: 1.22-2.03), respectively. CONCLUSIONS: The difference between 2hPG and FPG levels within the normoglycemic range is related to an increased risk of CVD, an issue that was independent of HOMA-IR. A cut-off point for 2hPG-FPG > 1.06 mmol/L may stratify persons at higher risk. These findings were particularly notable in those with low-normal FPG.

Rapid decline of kidney function increases fracture risk in the general population: Insights from TLGS.

BACKGROUND: Although the association between Chronic Kidney Disease (CKD) and all-cause fractures was addressed in previous studies, the association between estimated glomerular filtration rate (eGFR) decline and fractures was poorly addressed. For the first time we examined the association between rapid kidney function decline (RKFD) and fracture incidence among Iranian general population. METHODS: In a Tehranian community-based cohort, RKFD was defined as a 30 % decline in eGFR over 2-3 years. Cox proportional hazards models, adjusted for age, sex, current eGFR, diabetes mellitus, hypertension, dyslipidemia, current smoking, obesity status, waist circumference, prevalent cardiovascular diseases, aspirin, steroid use, education level, and marital status, were used to examine the association of RKFD with different fracture outcomes. RESULTS: Among 5305 (3031 women) individuals aged ≥30 years, during the median follow-up of 9.62 years, 226 fracture events were observed. The multivariable hazard ratio of RKFD for any-fracture events, lower-extremity, and major osteoporotic fractures were 2.18 (95 % CI, 1.24-3.85), 2.32 (1.15-4.71), and 2.91 (1.29-6.58), respectively. These associations remained significant after accounting for the competing risk of death. The impact of RKFD on the development of incident all-cause fractures was not modified by gender [men: 2.64 (1.11-6.25) vs. women: 2.11 (1.00-4.47)] and according to current CKD status [without CKD: 2.34 (1.00-5.52) vs. with CKD: 2.59 (1.04-6.44)] (all P for interaction >0.5). CONCLUSIONS: RKFD can increase the incidence of fractures among general population, the issue that was equally important among non-CKD individuals, emphasizing the need for early identification and management in those with rapidly declining eGFR.

Gender differences in midlife to later-life cumulative burden and variability of obesity measures and risk of all-cause and cause-specific mortality.

BACKGROUND/OBJECTIVES: Previous studies have reported the gender-specific association between general and central obesity measures, using snapshot assessments, and mortality events. This study seeks to further explore this link by examining how the longitudinal cumulative burden and variability of obesity measures from midlife to later-life impact mortality events in the Atherosclerosis Risk in Communities (ARIC) study population, specifically in relation to gender differences. SUBJECTS/METHODS: Using data from the ARIC study, a total of 7615 (4360 women) participants free of cardiovascular disease, cancer, and early mortality events were included in the data analysis. Longitudinal cumulative burden (estimated by the area under the curve (AUC) using a quadratic mixed-effects method) and variability (calculated according to average successive variability (ASV)) were considered as exposures, separately and all together. Cox proportional hazard regression models were used to estimate multivariable-adjusted standardized hazard ratios. RESULTS: The mean age was 62.4 and the median follow-up was 16.9 years. In men, AUCs of waist-related obesity measures, and also ASVs of all obesity measures were associated with increased all-cause mortality risk. In women, waist circumference and waist-to-height ratio AUCs were associated with increased all-cause mortality risk. Regarding cardiovascular mortality, all adiposity measures ASVs in both genders and waist-related obesity measures AUCs in men were associated with increased risk. Significant gender differences were found for the associations between cumulative and variability of waist-to-hip ratio for all-cause mortality and all adiposity measures ASVs for cardiovascular mortality risk with higher impact among men. CONCLUSIONS: Cumulative burden and variability in general and central obesity measures were associated with higher all-cause and cardiovascular mortalities among men. In women, general obesity measures variability, as well as cumulative and variability of central adiposity measure, increased all-cause mortality risk.

Association between dietary antioxidants intake and the risk of type 2 diabetes mellitus in a prospective cohort study: Tehran Lipid and Glucose Study.

The present prospective cohort study aimed to determine whether dietary antioxidants were associated with incident type 2 diabetes mellitus (T2DM). Another objective was to find out whether such associations could be modified by the BMI status. A total of 2188 Tehranian adults aged 21-84 years, free of T2DM with the validated FFQ, was entered in the study. Multivariable Cox proportional hazards models adjusting for confounders were used to assess the association between dietary antioxidants and incident T2DM in total population, as well as in subjects with various BMI statuses. During 8·9 (8·1-9·6) years of follow-up, dietary vitamin E significantly decreased the incident T2DM, after adjustment for confounders. However, other dietary antioxidants were not shown to be significantly associated with incident T2DM. The interaction between dietary vitamin E, Mg and BMI status was found to influence the risk of T2DM (Pfor interaction < 0·05). After stratification of subjects based on BMI status, it was found that vitamin E and Mg decreased the risk of T2DM only among normal-weight individual. Also, an inverse association was found among dietary vitamin C, dietary Zn and the risk of T2DM in individuals with normal weight but not in overweight and obese individuals; however, the interaction test tended to be significant for these dietary variables. Dietary antioxidants including vitamin E, vitamin C, Zn and Mg when accompanied by healthy weight, may bring benefits to the prevention of T2DM.

Cumulative Blood Pressure in Early Adulthood and Coronary Artery Calcium and Carotid Intima-Media Thickness in Middle Age Among Adults With Maintained Blood Pressure of <130/80 mm Hg: A Post Hoc Analysis.

BACKGROUND: To examine the association of blood pressure (BP) levels with coronary artery calcium and carotid intima-media thickness (CIMT) in people with maintained BP below the hypertension range based on current definitions. METHODS AND RESULTS: In this post hoc analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) prospective observational cohort study conducted in 4 US cities, we examined 1233 study participants (mean [SD] age at year 20 examination was 45.3 [3.5] years; 65.4% women). Participants with BP assessments across 20 years and untreated BP of <130/80 mm Hg were included. Multivariable logistic or linear regression models, adjusted for age, sex, race, education, diabetes, body mass index, serum creatinine, smoking, alcohol intake, physical activity, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides, were used to examine the associations between cumulative BP measures with coronary artery calcium and CIMT. Higher long-term cumulative systolic BP and pulse pressure across early adulthood were associated with higher CIMT (both P<0.001) but not coronary artery calcium in the multivariable-adjusted model. The associations remained significant even after adjustment for a single BP measurement at year 0 or year 20. The odds ratio (OR) of a maximal CIMT >1.01 mm was ≈50% higher per 1-SD increase in systolic BP (OR, 1.50 [95% CI, 1.19-1.88]) and pulse pressure (OR, 1.46 [95% CI, 1.19-1.79]). Similar findings for CIMT were observed among individuals with a coronary artery calcium score of 0 as well as those with maintained BP of <120/80 mm Hg throughout young adulthood. CONCLUSIONS: Long-term cumulative systolic BP and pulse pressure across early adulthood within the nonhypertensive range were associated with adverse midlife alterations in CIMT.

Resting heart rate and the risk of incident type 2 diabetes mellitus among non-diabetic and prediabetic Iranian adults: Tehran lipid and glucose study.

BACKGROUND: Resting heart rate (RHR) has been found to be a potential risk factor for developing type 2 diabetes mellitus (T2DM), with a highly significant heterogeneity among previous studies. Therefore, we examined the association of RHR and risk of incident T2DM among non-diabetic and prediabetic adults. METHODS: The study population included 2431 men and 2910 women aged ≥ 20 years without T2DM at baseline (2001-2005). Participants were followed for incident T2DM by about 3-year intervals up to April 2018. The multivariable Cox proportional models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The models were adjusted for age, body mass index, waist circumference, educational level, physical activity, smoking, hypertension, family history of diabetes, triglycerides/ high-density lipoprotein cholesterol ratio, and fasting plasma glucose. RESULTS: During a median follow-up of 12.2 years, 313 men and 375 women developed T2DM. Interestingly, a significant sex-difference was found (all P-values for sex interaction < 0.025). Among men, compared to the first quintile (< 68 bpm: beats per minute), those who had RHR of over 84 bpm were at higher T2DM risk with a HR (95%CI) of 1.69 (1.16-2.47). Furthermore, considering RHR as a continuous variable, an increase of 10 bpm caused 17% significantly higher risk among men with a HR of 1.17 (1.05-1.30). However, among women, there was no significant association between incident T2DM and RHR. Moreover, among prediabetic participants at baseline, the association of RHR and risk of T2DM progression was generally similar to the general population, which means higher RHR increased the risk of T2DM development only among men with a HR of 1.26 (1.09-1.46) for 10 bpm increase. CONCLUSIONS: Among men, being either non-diabetic or prediabetic at baseline, higher RHR can be associated with incident T2DM; however, women didn't show a significant association. Further studies are needed to determine the added value of RHR as a potential modifiable risk factor in screening and risk prediction of incident T2DM.

Diagnostic dilemma in a patient with history of medullary thyroid carcinoma and abnormal serum liver enzymes; a case report with six years follow up.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C-cells. Calcitonin (Ctn) and carcinoembryonic antigen (CEA) are useful biomarkers for monitoring MTC cases. CASE PRESENTATION: Here, we describe a 48-year-old woman, who presented in 2014 with bilateral thyroid nodules. Report of fine needle aspiration was suspicious for MTC; initial laboratory evaluation showed serum Ctn level of 1567 pg/mL. After excluding type 2 multiple endocrine neoplasia syndrome clinically, total thyroidectomy and neck lymph node dissection were performed. The final histopathological diagnosis was right lobe MTC with neither vascular invasion nor lymph node involvement. On regular follow-up visits, Ctn and CEA levels have been undetectable, and repeated cervical ultrasonographic exams were unremarkable from 2014 to 2021. As liver enzymes became elevated in 2016, the patient was further evaluated by a gastroenterologist. Abdominopelvic ultrasonography revealed a coarse echo pattern of the liver parenchyma with normal bile ducts. A liver fibroscan showed a low fibrosis score (7kPa). The patient was recommended to use ursodeoxycholic acid. According to the progressive rise of liver enzymes with a cholestatic pattern in October 2020, a liver biopsy was performed that showed tiny nests of neuroendocrine-like cells with a background of primary biliary cholangitis (PBC). Immunohistochemical stainings were positive for chromogranin A (CgA), and synaptophysin and negative for Ctn, CEA, and thyroglobulin. Further imaging investigations did not reveal any site of a neuroendocrine tumor in the body. Considering normal physical exam, imaging findings, as well as normal serum levels of Ctn, CEA, CgA, and procalcitonin, the patient was managed as a PBC. CONCLUSION: In follow-up of a patient with MTC, we reported progressively increased liver enzymes with a cholestatic pattern. Liver biopsy revealed nests of neuroendocrine-like cells with a background of PBC, the findings that might suggest acquiring neuroendocrine phenotype by proliferating cholangiocytes.

Gender differences in change of metabolic syndrome status and its components on all-cause and cause-specific mortalities: Over a decade follow-up study.

BACKGROUND: Accumulating evidence suggests a close association between metabolic syndrome (MetS) and excess risk of mortality. However, whether the dynamic change of MetS and its components could affect cause-specific mortalities and how this relation could be influenced by gender is yet to be clarified. METHODS AND RESULTS: In this longitudinal cohort, we entered 4904 Iranian adults>30 years (2820 women) from March-1999 and followed up until December-2018. MetS was determined using the joint interim societies (JIS) criteria. Due to change in MetS status over three years, we divided individuals into MetS-free, MetS-recovery, MetS-developed, and MetS-persistent groups. The same categories were defined for each MetS component. Multivariate Cox regression models were employed to compute the adjusted hazard ratios (HRs) and female-to-male relative HRs (F/M-RHRs) for risk of all-cause, cardiovascular (CV), non-CV, and cancer mortalities. To resolve reverse causation, mortalities during the first three years of follow-up were excluded. Subgroup analysis was conducted for non-diabetic and non-hypertensive participants. During 12.5 years of follow-up, 357 all-cause, 112 CV-, and 79 cancer-mortalities occurred. Compared to MetS-free, MetS-persistent raised all-cause- and CV-mortalities in both genders. Same association was found for non-diabetic (HR = 1.66 (1.03-3.00)) or non-hypertensive (HR = 1.89 (1.09-3.64)) women. Moreover, MetS-persistent women with neither hypertension nor diabetes had increased all-cause mortality risk by 88% (F/M-RHR = 3.99 (1.53-5.58)). Women with stable MetS had excess risk of cancer-mortality by 40% (F/M-RHR = 1.63 (1.02-5.06)). Generally, among both genders, recovery from MetS declined risk of mortality events. Regarding MetS components, persistent elevated fasting plasma glucose (FPG) was related to all-cause mortality in both genders, but with stronger association in women (F/M-RHR = 1.41 (1.11-2.49), and CV-mortality only in women (F/M-RHR = 3.04 (1.02-5.96). Both development and stable status of high blood pressure (BP) increased the risk of CV-mortality merely in women (F/M-RHR = 3.10 (0.60-6.87) and F/M-RHR = 3.24 (1.26-6.11), respectively). Development or recovery from each Triglyceride, HDL-C, and waist circumference variables did not solely affect risk of mortality events in both genders. CONCLUSION: Stable status of MetS could increase risk of mortalities with an overall stronger association in women. Although elevated BP and FPG are the main drivers for mortality risk, MetS among women could carry the corresponding effect even in absence of hypertension and diabetes.

Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Diagnostic performance of different anthropometric indices among Iranian adolescents for intima media thickness in early adulthood: A prospective study and literature review.

Background: There is debate regarding which anthropometric indices is the most appropriate predictor of cardiovascular disease (CVD) among adolescents. The purpose of this study was to investigate the association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) in adolescents with high carotid intima-media thickness (cIMT) in early adulthood, as the surrogate marker of CVD in a cohort study. Methods: A total of 875 Iranian adolescents (female = 421) aged 10-17 years old were entered the study. The cIMT was measured in early adulthood (20-38 years old) after 18.2 (median) years of follow-up and defined as > 90th percentile for sex and age groups. The gender specific association between a 1-SD increase in each anthropometric measures with high cIMT was examined using multivariate logistic regression analysis adjusted for age, smoking, family history of CVD, systolic blood pressure, total cholesterol, and fasting blood sugar. In the multivariable analysis, the interaction between sex and age groups with anthropometric measures were significant (all p-values < 0.05). Results: Among males, all anthropometric measures including BMI, WC, WHR, and WHtR were associated with high cIMT; the corresponding odds ratios were 1.43 (1.05-1.94), 1.63 (1.22-2.19), 1.33 (1.03-1.71), and 1.41 (1.07-1.87), respectively. However, after considering the related adulthood anthropometric measurements, the association remained significant for WC 1.48 (1.04-2.10) and WHR [1.28 (0.99-1.66), P = 0.06]. Moreover, among early adolescent boys aged 10-14 years, all of the anthropometric measures were significantly associated with high cIMT in the multivariate analysis that included the related adulthood anthropometric measures. The area under the curve (AUC) for the anthropometric measurements among males ranged from 0.576 for WHtR up to 0.632 for WC, without any superiority between them. Among females, only in linear regression analysis, a significant association were found between the higher value of WC and WHtR with cIMT measurement in adulthood; however, the risk reached to null after considering adult anthropometric measures. Conclusion: General and central obesity measures were significantly associated with high cIMT only among Iranian male adolescents, the relationship that were more prominent among pre-pubertal males.

Lifetime risk of cardiovascular disease stratified by traditional risk factors: Findings from the cohort of Tehran lipid and glucose study.

BACKGROUND: We aimed to estimate the lifetime risk (LTR) of cardiovascular disease (CVD) in the Iranian population, stratified by sex and traditional risk factors including high body mass index (BMI), hypertension, diabetes, smoking, and hypercholesterolemia. METHODS: We included 10222 (4430 men) participants aged ≥20 years without CVD at baseline. LTRs at index ages 20 and 40 years and number of years lived without CVD was estimated. We further assessed the effect of traditional risk factors on the LTR of CVD and the number of years lived without CVD, stratified by sex and index ages. RESULTS: During a median follow-up of 18 years, 1326 participants (774 men) developed CVD and 430 (238 men) died from non-cardiovascular causes. At age 20, the remaining LTR for CVD was 66.7% (95% CI 62.9-70.4) in men and 52.0% (47.6-56.8) in women, with similar LTRs at age 40 for both men and women. The LTRs at both index ages for those with ≥3 risk factors were about 30% and 55% higher in men and women, respectively, than those without any of the five risk factors. At the age of 20, men with ≥3 risk factors lived 24.1 fewer years without CVD compared with men with no risk factors; the corresponding value was 8 years in their female counterparts. CONCLUSIONS: Our findings suggest that both sexes may benefit from effective prevention strategies early in the life course, despite the observed differences between men and women in LTR for CVD and number of years lived without CVD.

Changes in Fasting plasma glucose status and risk of mortality events in individuals without diabetes over two decades of Follow-up: a pooled cohort analysis.

BACKGROUND: We aimed to assess the gender-specific impact of 3-year changes in fasting plasma glucose (FPG) status on the risk of all-cause, cardiovascular (CV), and cancer mortality in individuals without type 2 diabetes (T2DM) during an 18-year follow-up. METHODS: The study population included 14,378 participants aged 30-60 years (8272 women) from three population-based cohort studies, including Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Tehran Lipid and Glucose Study. Subjects were classified into six categories based on the approximately three-year changes in FPG status: (1) normal FPG (NFG) to NFG (reference category); (2) NFG to impaired fasting glucose (IFG) (i.e., 126 > FPG ≥ 100 mg/dl); (3) NFG to T2DM; (4) IFG to NFG; (5) IFG to IFG; (6) IFG to T2DM. Multivariable stratified Cox regression, adjusting for age, body mass index (BMI), BMI-Change, smoking status, hypertension, and hypercholesterolemia was used to estimate hazard ratios (HRs (95% CI)) for all-cause and cause-specific mortality events. Women-to-men ratios of HRs (RHRs) for each category were also estimated. RESULTS: During follow-up, 2,362 all-cause mortality events were recorded. Among women, all categories of FPG change, excluding IFG-NFG (HR, 95%CI 1.24 (0.98-1.57), p = 0.07), were associated with a higher risk of all-cause mortality compared to the NFG-NFG category. Moreover, women in IFG-T2DM group were at increased risk for CV mortality (2.21 (1.42-3.44)). We also found that women in NFG-IFG (1.52 (1.20-1.91)), NFG-T2DM (2.90 (1.52-5.51)), and IFG-IFG (1.30 (1.02-1.66)) categories had a higher risk for cancer mortality. However, among men, a higher risk of all-cause mortality was found for only two groups of NFG-T2DM (1.78 (1.15-2.74)) and IFG-T2DM (1.34 (1.04-1.72)). Women with IFG-IFG had a 24% higher risk for all-cause mortality events than their men counterparts (RHR; 1.24 (1.01-1.54)). After further adjustment for physical activity, results were in line with the main findings, excluding T2DM up to six years after the measurement period and early mortality events. CONCLUSION: In women, the IFG status, whether as incident, persistent, or converted to T2DM, had a higher risk for mortality events; however, among men, only conversion to T2DM conferred an excess risk of all-cause mortality.

The clinical value of metabolic syndrome and its components with respect to sudden cardiac death using different definitions: Two decades of follow-up from the Tehran Lipid and Glucose Study.

BACKGROUND: To evaluate the impact of different definitions of metabolic syndrome (MetS) and their components on the risk of sudden cardiac death (SCD) among the Iranian population according to the World Health Organization (WHO), International Diabetes Federation (IDF), Adult Treatment Panel III (ATP III), and Joint Interim Statement (JIS) criteria. METHODS: The study population included a total of 5,079 participants (2,785 women) aged ≥ 40 years, free of cardiovascular disease (CVD) at baseline. Participants were followed for incident SCD annually up to 20 March 2018. Multivariable Cox proportional hazards regression models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MetS and its components for incident SCD. RESULTS: The prevalence of MetS ranged from 27.16% to 50.81%, depending on the criteria used. Over a median of 17.9 years of follow-up, 182 SCD events occurred. The WHO, IDF, and JIS definitions were strong predictors of SCD with multivariable-adjusted HRs (95% CI) of 1.68 (1.20-2.35), 1.51 (1.12-2.03), and 1.47 (1.08-1.98), respectively; these associations significantly attenuated after further adjustment for MetS components. MetS by the ATP III definition was not associated with the risk of SCD after controlling for antihypertensive, glucose-lowering, and lipid-lowering medication use. Among the components of MetS, high blood pressure (WHO definition), high waist circumference (using the national cutoff of ≥ 95 cm), and high glucose component by the JIS/IDF definitions remained independent predictors of SCD with HRs of 1.79 (1.29-2.48), 1.46 (1.07-2.00), and 1.52 (1.12-2.05), respectively. CONCLUSIONS: The constellation of MetS, except for when defined with ATP III definition, is a marker for identifying individuals at higher risk for SCD; however, not independent of its components. Among MetS components, abdominal obesity using the population-specific cutoff point, high glucose component (JIS/IDF definitions), and high blood pressure (WHO definition) were independent predictors of SCD.

Association between Wrist Circumference and Risk of Any Fracture in Adults: Findings from 15 Years of Follow-Up in the Tehran Lipid and Glucose Study.

We evaluated whether wrist circumference (WrC), as a novel anthropometric measure, is associated with incidences of any fractures. The study population included 8288 adults (45.3% men) aged ≥30 years, who were followed for incidences of any fractures from 31 January 1999 to 16 March 2016. We used Cox proportional hazard models adjusted for well-known risk factors to evaluate the association of WrC, both as continuous and categorical variables (bottom tertile as reference), with incidences of any fractures and major osteoporotic fractures (MOF). Over 15 years of follow-ups, 348 fractures occurred (men = 162). For a 1 cm increase in WrC, hazard ratios (HRs) were 1.18 (95% CI: 1.03-1.35) for incident any fractures and 1.22 (1.01-1.49) for incident MOF. In addition to WrC, age, female sex, lower BMI, higher WC, current smoking, and usage of steroidal medications were significantly associated with the incidences of any fractures. Moreover, participants in the middle and top tertiles of WrC had a higher risk of incidence for any fractures [HR = 1.62 (1.19-2.20) and 1.70 (1.14-2.55), respectively, p-value for trend = 0.012]. We presented WrC as a strong and independent risk factor for incidences of any fractures that might be considered in the risk prediction of bone fracture in Iranian adults.

Determinants of the progression to type 2 diabetes and regression to normoglycemia in people with pre-diabetes: A population-based cohort study over ten years.

AIMS: To determine the rates and predictors of the regression to normoglycemia and progression to diabetes among subjects with pre-diabetes. METHODS: A 10-year longitudinal population-based study was conducted among 1329 participants with pre-diabetes in the Tehran Lipid and Glucose Study. Pre-diabetes was divided into isolated IFG (iIFG), isolated IGT (iIGT), and combined IFG/IGT. Univariate and stepwise multivariable Cox regression was used to evaluate predictors of glycemic conversions. RESULTS: The cumulative incidences of normoglycemia and diabetes were 43.7% (95%CI 40.9-46.4) and 40.1% (37.3-42.7), respectively. Isolated IGT returned to normoglycemia more than iIFG (HR:1.26, 1.05-1.51), but there was no difference in how quickly they progressed to diabetes. Regression to normoglycemia was associated with younger age, female sex, lower BMI, no familial history of diabetes, higher HDL-C, and ex-smoking. Older age, higher BMI, diastolic blood pressure, total cholesterol, lower HDL-C, and familial history for diabetes were associated with progression to diabetes. The influence of BMI on glycemic status conversions diminished with age. At approximately above 60 years old, the hazards of BMI for any conversions faded out. CONCLUSIONS: The modifiable predictors of regression to normoglycemia and progression to diabetes are roughly the same. The importance of BMI attenuates in elderly subjects.

Three-year weight change and risk of all-cause, cardiovascular, and cancer mortality among Iranian adults: over a decade of follow-up in the Tehran Lipid and Glucose Study.

BACKGROUND: We investigated the impact of weight change on mortality in a population-based cohort setting. METHODS: We conducted two weight measurements for 5436 participants aged ≥ 30 years with an approximate 3-year interval. Based on their weight change, we categorized participants to: > 5% weight loss, 3-5% weight loss, stable weight (± < 3%), 3-5% weight gain, > 5% weight gain. We followed participants for mortality annually up to March 20th 2018. We applied the multivariable Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of weight change categories for all-cause, cardiovascular (CV), and cancer mortality, considering stable weight as reference. The Cox models was adjusted for age, sex, educational level, body mass index, smoking status, hypertension, hypercholesterolemia, diabetes, and cardiovascular disease (CVD) at baseline. RESULTS: During a median follow-up of 14.4 years, 629 deaths (247 CV and 126 cancer deaths) have occurred. Over 5% weight loss and gain were associated with increased risk of all-cause mortality in multivariable analysis with HRs of 1.47 [95% CI: 1.17-1.85] and 1.27 [1.02-1.57], respectively; however, a 3-5% loss or gain did not alter the risk of all-cause mortality significantly. These significant risks for wight change > 5% were not modified by the presence of diabetes, obesity, and smoking status; however, the unfavorable impact of weight change on mortality events was more prominent in those older than > 65 years (P-value for interaction: 0.042). After excluding those with history of CVD, diabetes, and cancer during the weight measurements period, these associations significantly attenuated (HR: 1.29 [0.89-1.87] for > 5% weight loss and 1.12 [0.84-1.50] for > 5% weight gain). Additionally, a > 5% weight loss was also associated with about 60% higher risk for CV mortality (HR: 1.62 [1.15-2.28]), and a 3-5% weight loss was associated with about 95% higher risk of cancer mortality (HR: 1.95 [1.13-3.38]). CONCLUSIONS: Our findings showed a U-shaped association across weight change categories for all-cause mortality risk with over 5% weight gain and loss causing higher risk. Moreover, weight loss can have adverse impact on CV and cancer mortality events.

Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review.

BACKGROUND: Among candidate genes related to type 2 diabetes (T2DM), one of the strongest genes is Transcription factor 7 like 2 (TCF7L2), regarding the Genome-Wide Association Studies. We aimed to conduct a systematic review of the literature on the modification effect of TCF7L2 on the relation between glycemic parameters and lifestyle factors. METHODS: A systematic literature search was done for relevant publications using electronic databases, including PubMed, EMBASE, Scopus, and Web of Science, from January 1, 2000, to November 2, 2021. RESULTS: Thirty-eight studies (16 observational studies, six meal test trials, and 16 randomized controlled trials (RCTs)) were included. Most observational studies had been conducted on participants with non-diabetes showing that TCF7L2 modified the association between diet (fatty acids and fiber) and insulin resistance. In addition, findings from meal test trials showed that, compared to non-risk-allele carriers, consumption of meals with different percentages of total dietary fat in healthy risk-allele carriers increased glucose concentrations and impaired insulin sensitivity. However, ten RCTs, with intervention periods of less than ten weeks and more than one year, showed that TCF7L2 did not modify glycemic parameters in response to a dietary intervention involving different macronutrients. However, two weight loss dietary RCTs with more than 1-year duration showed that serum glucose and insulin levels decreased and insulin resistance improved in non-risk allele subjects with overweight/obesity. Regarding artichoke extract supplementation (ALE), two RCTs observed that ALE supplementation significantly decreased insulin concentration and improved insulin resistance in the TT genotype of the rs7903146 variant of TCF7L2. In addition, four studies suggested that physical activity levels and smoking status modified the association between TCF7L2 and glycemic parameters. However, three studies observed no effect of TCF7L2 on glycemic parameters in participants with different levels of physical activity and smoking status. CONCLUSION: The modification effects of TCF7L2 on the relation between the lifestyle factors (diet, physical activity, and smoking status) and glycemic parameters were contradictory. PROSPERO REGISTRATION NUMBER: CRD42020196327.