Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events.

BACKGROUND: Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non-high-density lipoprotein cholesterol (non-HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non-HDL-C and LDL-C levels with adult ASCVD events and determined whether non-HDL-C has better utility than LDL-C in predicting adult ASCVD events. METHODS: This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non-HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. RESULTS: After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non-HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14-1.41] to 1.35 [95% CI, 1.13-1.60] per unit increase in the risk factor z score). Non-HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006-0.0102] and 0.0038 [95% CI, 0.0008-0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non-HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non-HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98-3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23-3.06]). CONCLUSIONS: Childhood non-HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non-HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non-HDL-C. These findings suggest that both non-HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non-HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.

Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events.

BACKGROUND: Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear. METHODS: In a prospective cohort study involving participants in the International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression. RESULTS: In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean [±SD] age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events. CONCLUSIONS: In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife. (Funded by the National Institutes of Health.).

Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD). METHODS: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8-17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression. RESULTS: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4-2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9-6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8-7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0-3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data. CONCLUSIONS: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events.

Importance: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. Objective: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. Design, Setting, and Participants: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. Exposures: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia. Main Outcomes and Measures: Incident fatal and nonfatal CVD events adjudicated by medical records. Results: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). Conclusions and Relevance: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.

Large-Scale Data Harmonization Across Prospective Studies.

The Preconception Period Analysis of Risks and Exposures Influencing Health and Development (PrePARED) Consortium creates a novel resource for addressing preconception health by merging data from numerous cohort studies. In this paper, we describe our data harmonization methods and results. Individual-level data from 12 prospective studies were pooled. The crosswalk-cataloging-harmonization procedure was used. The index pregnancy was defined as the first postbaseline pregnancy lasting more than 20 weeks. We assessed heterogeneity across studies by comparing preconception characteristics in different types of studies. The pooled data set included 114,762 women, and 25,531 (22%) reported at least 1 pregnancy of more than 20 weeks' gestation during the study period. Babies from the index pregnancies were delivered between 1976 and 2021 (median, 2008), at a mean maternal age of 29.7 (standard deviation, 4.6) years. Before the index pregnancy, 60% of women were nulligravid, 58% had a college degree or more, and 37% were overweight or obese. Other harmonized variables included race/ethnicity, household income, substance use, chronic conditions, and perinatal outcomes. Participants from pregnancy-planning studies had more education and were healthier. The prevalence of preexisting medical conditions did not vary substantially based on whether studies relied on self-reported data. Use of harmonized data presents opportunities to study uncommon preconception risk factors and pregnancy-related events. This harmonization effort laid the groundwork for future analyses and additional data harmonization.

HIV and hypertension epidemiology.

PURPOSE OF REVIEW: The aim of this study was to provide an overview of the burden, pathogenesis, and recent recommendations for treating hypertension among people living with HIV (PLWH). This review is relevant because of the increase in the prevalence of HIV as a chronic disease and the intersection of the increasing prevalence of hypertension. RECENT FINDINGS: The contribution of HIV to the pathogenesis of hypertension is complex and still incompletely understood. Evidence suggests that chronic inflammation from HIV, antiretroviral treatment (ART), and comorbidities such as renal disease and insulin resistance contribute to developing hypertension in PLWH. Treatment is not distinct from guidelines for HIV-noninfected people. Nonpharmacological guidelines such as decreasing blood pressure by promoting a healthy lifestyle emphasizing exercise, weight loss, and smoking cessation are still recommended in the literature. The pharmacological management of hypertension in PLWH is similar, but special attention must be given to specific drugs with potential interaction with ART regimens. Further research is needed to investigate the pathways and effects of hypertension on HIV. SUMMARY: There are different pathways to the pathogenesis of hypertension in PLWH. Clinicians should take it into consideration to provide more precise management of hypertension in PLWH. Further research into the subject is still required.

Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study.

BACKGROUND: Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. OBJECTIVES: We aimed to identify associations between dietary dairy intake (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in 2 independent study populations of United States adults. METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in 2 subgroups of the Atherosclerosis Risk in Communities study (ARIC; n = 3776). Results from the 2 subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n = 785). RESULTS: In the ARIC study and BHS, the mean age was 54 and 48 years, 61% and 29% were Black, and the mean dairy intake was 1.7 and 1.3 servings/day, respectively. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n = 14; low-fat dairy, n = 10; high-fat dairy, n = 5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy, and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS. CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including 3 associations found in 2 independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.

Bidirectional temporal relationships between uric acid and insulin and their joint impact on incident diabetes.

BACKGROUND AND AIMS: This study aims to examine the temporal relationship between uric acid (UA) and insulin and their joint impact on T2DM in middle-aged adults. METHODS AND RESULTS: The cohort consisted of 1351 non-diabetic adults who had serum UA and insulin measured twice at baseline and follow-up over 7.7 years on average, and incidence of T2DM in the outcome survey12.2 years later. After adjusting for covariates, the path coefficient from baseline UA to follow-up insulin was 0.082 (p < 0.001); the path from baseline insulin to follow-up UA was 0.060 (p = 0.030). In the mediation model with baseline UA as the predictor, total effect of baseline UA on incident T2DM was 0.089 (p = 0.016). The mediation effect through follow-up insulin on the UA-T2DM association was 28.1%. The direct effect of baseline UA on T2DM (0.064) became nonsignificant (p = 0.078). In the mediation model with baseline insulin as the predictor, total effect of baseline insulin on T2DM was 0.218 (p < 0.001). The mediation effect through follow-up UA on the insulin-T2DM association was 5.5%. The direct effect of baseline insulin on T2DM (0.206) remained significant (p < 0.001). The baseline hyperinsulinemia-follow-up hyperuricemia group showed the highest incidence rate of T2DM (27.9%). CONCLUSIONS: The bidirectional temporal relationship suggests that UA and insulin influence each other in non-diabetic individuals, and the directionality plays pathogenic roles in the development of T2DM.

Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial.

BACKGROUND: Thioredoxin Interacting Protein (TXNIP) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions. METHODS: We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses. RESULTS: We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P < 0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction = 0.007) and HOMA-IR (P-interaction = 0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (ß: -0.14; 95% CI: -0.24, -0.03; P = 0.011) and HOMA-IR (ß: -0.15; 95% CI: -0.26, -0.03; P = 0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P > 0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention. CONCLUSIONS: Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.

Obesity during childhood is associated with higher cancer mortality rate during adulthood: the i3C Consortium.

BACKGROUND: In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. METHODS: We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3-19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. RESULTS: 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03-1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01-1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03-1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12-1.63). CONCLUSIONS: Higher childhood BMI was independently associated with increased overall cancer mortality.

Prevalence Implications of the 2017 American Academy of Pediatrics Hypertension Guideline and Associations with Adult Hypertension.

OBJECTIVE: To evaluate the impact of the 2017 American Academy of Pediatrics hypertension Clinical Practice Guideline (CPG), compared with the previous guideline ("Fourth Report"), on the frequency of hypertensive blood pressure (BP) measurements in childhood and associations with hypertension in adulthood using data from the International Childhood Cardiovascular Cohort Consortium. STUDY DESIGN: Childhood BPs were categorized in normal, prehypertensive/elevated, and hypertensive (stage 1 and 2) ranges using the Fourth Report and the CPG. Participants were contacted in adulthood to assess self-reported hypertension. The associations between childhood hypertensive range BPs and self-reported adult hypertension were evaluated. RESULTS: Data were available for 34 014 youth (10.4 ± 3.1 years, 50.6% female) with 92 751 BP assessments. Compared with the Fourth Report, the CPG increased hypertensive readings from 7.6% to 13.5% and from 1.3% to 2.5% for stage 1 and 2 hypertensive range, respectively (P < .0001). Of 12 761 adults (48.8 ± 7.9 years, 43% male), 3839 (30.1%) had self-reported hypertension. The sensitivity for predicting adult hypertension among those with hypertensive range BPs at any point in childhood, as defined by the Fourth Report and the CPG, respectively, was 13.4% and 22.4% (specificity 92.3% and 85.9%, P < .001), with no significant impact on positive and negative predictive values. Associations with self-reported adult hypertension were similar and weak (c-statistic range 0.61-0.68) for hypertensive range BPs as defined by the Fourth Report and CPG. CONCLUSIONS: The CPG significantly increased the prevalence of childhood BPs in hypertensive ranges and improved the sensitivity, without an overall strengthened association, of predicting self-reported adult hypertension.

Hypertension and cognitive function: a review of life-course factors and disparities.

PURPOSE OF REVIEW: Dementia is a life-course condition with modifiable risk factors many from cardiovascular (CV) origin, and disproportionally affects some race/ethnic groups and underserved communities in the USA. Hypertension (HTN) is the most common preventable and treatable condition that increases the risk for dementia and exacerbates dementia pathology. Epidemiological studies beginning in midlife provide strong evidence for this association. This study provides an overview of the differences in the associations across the lifespan, and the role of social determinants of health (SDoH). RECENT FINDINGS: Clinical trials support HTN management in midlife as an avenue to lower the risk for late-life cognitive decline. However, the association between HTN and cognition differs over the life course. SDoH including higher education modify the association between HTN and cognition which may differ by race and ethnicity. The role of blood pressure (BP) variability, interactions among CV risk factors, and cognitive assessment modalities may provide information to better understand the relationship between HTN and cognition. SUMMARY: Adopting a life-course approach that considers SDoH, may help develop tailored interventions to manage HTN and prevent dementia syndromes. Where clinical trials to assess BP management from childhood to late-life are not feasible, observational studies remain the best available evidence.

Life-Course Cumulative Burden of Body Mass Index and Blood Pressure on Progression of Left Ventricular Mass and Geometry in Midlife: The Bogalusa Heart Study.

RATIONALE: Data are limited regarding the influence of life-course cumulative burden of increased body mass index (BMI) and elevated blood pressure (BP) on the progression of left ventricular (LV) geometric remodeling in midlife. OBJECTIVE: To investigate the dynamic changes in LV mass and LV geometry over 6.4 years during midlife and to examine whether the adverse progression of LV geometric remodeling is influenced by the cumulative burden of BMI and BP from childhood to adulthood. METHODS AND RESULTS: The study consisted of 877 adults (604 whites and 273 blacks; 355 males; mean age=41.4 years at follow-up) who had 5 to 15 examinations of BMI and BP from childhood and 2 examinations of LV dimensions at baseline and follow-up 6.4 years apart during adulthood. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and systolic BP (SBP). After adjusting for age, race, sex, smoking, alcohol drinking, and baseline LV mass index, the annual increase rate of LV mass index was associated with all BMI measures (ß=0.16-0.36, P<0.05 for all), adult SBP (ß=0.07, P=0.04), and total AUC of SBP (ß=0.09, P=0.01) but not with childhood and incremental AUC values of SBP. All BMI and SBP measures (except childhood SBP) were significantly associated with increased risk of incident LV hypertrophy, with odds ratios of BMI (odds ratio=1.85-2.74, P<0.05 for all) being significantly greater than those of SBP (odds ratio=1.09-1.34, P<0.05 for all except childhood SBP). In addition, all BMI measures were significantly and positively associated with incident eccentric and concentric LV hypertrophy. CONCLUSIONS: Life-course cumulative burden of BMI and BP is associated with the development of LV hypertrophy in midlife, with BMI showing stronger associations than BP. Visual Overview: An online visual overview is available for this article.

Lifestyle behaviors and cardiovascular risk profiles among parous women by gestational diabetes status, 2007-2018.

BACKGROUND AND AIMS: Women with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20-44 by history of GDM. METHODS AND RESULTS: Using data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history. CONCLUSION: Among parous U.S. women ages 20-44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.

Metabolomics study of blood pressure salt-sensitivity and hypertension.

BACKGROUND AND AIMS: Identify novel metabolite associations with blood pressure (BP) salt-sensitivity and hypertension. METHODS AND RESULTS: The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Replication study includes 698 Chinese participants who underwent a 3-day baseline examination followed by a 7-day low-sodium feeding and 7-day high-sodium feeding. Latent mixture models identified three trajectories of blood pressure (BP) responses to the sodium interventions. We selected 50 most highly salt-sensitive and 50 most salt-resistant participants for untargeted metabolomics profiling. Multivariable adjusted mixed logistic regression models tested the associations of baseline metabolites with BP salt-sensitivity. Multivariable adjusted mixed linear regression models tested the associations of BP salt-sensitivity with metabolite changes during the sodium interventions. Identified metabolites were tested for associations with hypertension among 1249 Bogalusa Heart Study (BHS) participants using multiple logistic regression. Fifteen salt-sensitivity metabolites were associated with hypertension in the BHS. Baseline values of serine, 2-methylbutyrylcarnitine and isoleucine directly associated with high salt-sensitivity. Among them, serine indirectly associated with hypertension while 2-methylbutyrylcarnitine and isoleucine directly associated with hypertension. Baseline salt-sensitivity status predicted changes in 14 metabolites when switching to low-sodium or high-sodium interventions. Among them, glutamate, 1-carboxyethylvaline, 2-methylbutyrylcarnitine, 3-methoxytyramine sulfate, glucose, alpha-ketoglutarate, hexanoylcarnitine, gamma-glutamylisoleucine, gamma-glutamylleucine, and gamma-glutamylphenylalanine directly associated with hypertension. Conversely, serine, histidine, threonate and 5-methyluridine indirectly associated with hypertension. Together, these metabolites explained an additional 7% of hypertension susceptibility when added to a model including traditional risk factors. CONCLUSIONS: Our findings contribute to the molecular characterization of BP response to sodium and provide novel biological insights into salt-sensitive hypertension.

Do diets with higher carbon footprints increase the risk of mortality? A population-based simulation study using self-selected diets from the USA.

OBJECTIVE: Are diets with a greater environmental impact less healthy? This is a key question for nutrition policy, but previous research does not provide a clear answer. To address this, our objective here was to test whether American diets with the highest carbon footprints predicted greater population-level mortality from diet-related chronic disease than those with the lowest. DESIGN: Baseline dietary recall data were combined with a database of greenhouse gases emitted in the production of foods to estimate a carbon footprint for each diet. Diets were ranked on their carbon footprints and those in the highest and lowest quintiles were studied here. Preventable Risk Integrated Model (PRIME), an epidemiological modelling software, was used to assess CVD and cancer mortality for a simulated dietary change from the highest to the lowest impact diets. The diet-mortality relationships used by PRIME came from published meta-analyses of randomised controlled trials and prospective cohort studies. SETTING: USA. PARTICIPANTS: Baseline diets came from adults (n 12 865) in the nationally representative 2005-2010 National Health and Nutrition Examination Survey. RESULTS: A simulated change at the population level from the highest to the lowest carbon footprint diets resulted in 23 739 (95 % CI 20 349, 27 065) fewer annual deaths from CVD and cancer. This represents a 1·83 % (95 % CI 1·57 %, 2·08 %) decrease in total deaths. About 95 % of deaths averted were from CVD. CONCLUSIONS: Diets with the highest carbon footprints were associated with a greater risk of mortality than the lowest, suggesting that dietary guidance could incorporate sustainability information to reinforce health messaging.

Effect of Telmisartan on Walking Performance in Patients With Lower Extremity Peripheral Artery Disease: The TELEX Randomized Clinical Trial.

Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities. Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022. Interventions: The trial randomized patients using a 2 × 2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n = 30), telmisartan plus attention control (n = 29), placebo plus exercise (n = 28), or placebo plus attention control (n = 27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants. Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline. Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P = .08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD. Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT02593110.

Influential Periods in Longitudinal Clinical Cardiovascular Health Scores.

The prevalence of ideal cardiovascular health (CVH) among adults in the United States is low and decreases with age. Our objective was to identify specific age windows when the loss of CVH accelerates, to ascertain preventive opportunities for intervention. Data were pooled from 5 longitudinal cohorts (Project Heartbeat!, Cardiovascular Risk in Young Finns Study, The Bogalusa Heart Study, Coronary Artery Risk Development in Young Adults, Special Turku Coronary Risk Factor Intervention Project) from the United States and Finland from 1973 to 2012. Individuals with clinical CVH factors (i.e., body mass index, blood pressure, cholesterol, blood glucose) measured from ages 8 to 55 years were included. These factors were categorized and summed into a clinical CVH score ranging from 0 (worst) to 8 (best). Adjusted, segmented, linear mixed models were used to estimate the change in CVH over time. Among the 18,343 participants, 9,461 (52%) were female and 12,346 (67%) were White. The baseline mean (standard deviation) clinical CVH score was 6.9 (1.2) at an average age of 17.6 (8.1) years. Two inflection points were estimated: at 16.9 years (95% confidence interval: 16.4, 17.4) and at 37.2 years (95% confidence interval: 32.4, 41.9). Late adolescence and early middle age appear to be influential periods during which the loss of CVH accelerates.

Temporal relationship between body mass index and uric acid and their joint impact on blood pressure in children and adults: the Bogalusa Heart Study.

OBJECTIVE: This study aimed to examine the temporal relationship between body mass index (BMI) and uric acid (UA), and their joint effect on blood pressure (BP) in children and adults. METHODS: The longitudinal cohorts for temporal relationship analyses consisted of 564 and 911 subjects examined twice 5-14 years apart from childhood to adulthood. The cross-sectional cohorts for mediation analyses consisted of 3102 children and 3402 nondiabetic adults. Cross-lagged panel analysis models were used to examine the temporal relationship between BMI and UA, and mediation analysis models the mediation effect of UA on the BMI-BP association. RESULTS: After adjusting for age, race, sex and follow-up years in children, and additionally smoking and alcohol drinking in adults, the path coefficients (standardized regression coefficients) from baseline BMI to follow-up UA (0.145 in children and 0.068 in adults) were significant, but the path coefficients from baseline UA to follow-up BMI (0.011 in children and 0.016 in adults) were not. In mediation analyses, indirect effects through UA on the BMI-systolic BP association were estimated at 0.028 (mediation effect = 8.8%) in children and 0.033 (mediation effect = 13.5%) in adults (P < 0.001 for both). Direct effects of BMI on systolic BP (0.289 in children and 0.212 in adults) were significant. The mediation effect parameters did not differ significantly between Blacks and Whites. CONCLUSIONS: Changes in BMI precede alterations in UA, and the BMI-BP association is in part mediated through BMI-related increase in UA both in children and in adults. These findings have implications for addressing mechanisms of obesity hypertension beginning in early life.